ivan

Once the homeostasis of potassium, sodium and chloride in human cells is out of balance, it will lead to a series of diseases such as hypertension, depression and epilepsy. At the cell membrane, there is a class of proteins known as cation-chloride cotransporters that effectively regulate ion homeostasis in the cell. The group of Guo Jiangtao of Zhejiang University School of Medicine solved the 2.9-Å high-resolution cryo-EM structure of a member of this class of proteins, the human potassium-chloride cotransporter KCC1, revealing the binding site of potassium and chloride ions and proposing a model for the potassium-chloride cotransport mechanism. The work was published October 25 in Science.

Because KCC2, a member of the potassium-chloride cotransporter, continuously transports intracellular potassium and chloride ions to the extracellular space, the intracellular chloride concentration of inhibitory neurons can be maintained low. If KCC2 is mutated, inhibitory neurotransmission is disrupted, which triggers various neurological disorders. But why has the veil of the KCC family never been unveiled? The reason, Guo introduced, is that samples of potassium-chlorine cotransporters are not easy to obtain, and high-resolution structural elucidation of membrane proteins with smaller molecular weights is challenging.

After extensive optimization of protein expression and purification conditions, the group finally obtained sufficient amounts of KCC1 protein samples that could be used for cryo-EM data collection. At this point, the 300 kv high-performance cryo-EM Titan Krios at the Zhejiang University Cryo-EM Center came in handy. In order to reduce electron radiation damage to proteins, protein samples need to be collected in a frozen environment. Prior to data collection, the researchers used liquid ethane to quickly freeze the protein solution sample on a "copper grid". The EM data collection process is a bit like making a movie: 40 consecutive photographs are taken in 8 seconds to form a "micromovie".

The group finally obtained two sets of three-dimensional structures of KCC1 at 2.9 Å resolution, which is helpful for the design of drugs against KCC and providing help in treating diseases such as epilepsy.

1. Advanced data analysis

2.1 Analysis of population genetic diversity

The main indicators are: calculation of population genetic diversity index

Common analysis software: Arlequin, VCFtools, etc.

2.2 Group Evolution Research

• Principal component analysis (PCA)
• Phylogenetic analysis
• Genetic structure (STRUCTURE)

Whole-genome group evolution analysis is to re-sequence the whole genome of different subgroups or different geographically distributed varieties of the same species. By comparing with the reference genome sequence, a large number of high-precision SNP, InDel and other mutation information are obtained to carry out the population genetics, such as structure, group principal components, linkage disequilibrium and selective elimination, to reveal a series of problems, such as the evolutionary mechanism of species, environmental adaptability, and population evolution history at the molecular level.

• Genetic Map Construction

2.3 Population genetic structure analysis

2.4 QTL positioning

QTL positioning generally requires detailed phenotypic data records and construction of groups, of course, natural groups are also possible (but the genetic background has a greater impact, and ideal results can be expected)

2.5 Whole genome association analysis (GWAS)

With the development of second-generation sequencing technology and the continuous reduction of sequencing costs, it has become easier and easier to use whole-genome variation data for genotyping, resulting in the increasing sample size and number of markers used for association analysis. The original MLM model time taken for the solution can be expressed by mpn3 (m is the number of markers, p is the number of iterations of the solution process, and n is the number of samples). It can be seen that as the sample size increases, the calculation time will be 3 times for each step of the iteration. Fang grows, which makes the calculation time very long.

In GWAS analysis, population structure and genetic background are the main factors causing high false positives. Under the condition of false positive control, how to use genetic markers to a greater extent to improve the calculation efficiency of individual data and improve the detection efficiency is the main problem in the development of analytical software algorithms. Plink is the GWAS software that was released earlier. Its calculation flux and speed are very high. It can realize various non-parametric tests based on allele frequency, general linear model (GLM) and logistic regression. The software is widely used in case-control studies of human complex diseases, which greatly promotes the progress of GWAS.

Genomic data can be used to locate genes and functional mutations that affect phenotypic traits.

However, the current utilization cost is relatively high, so in the early design of the experiment, try to collect more phenotypic information to make full use of the data.

Common analysis software and algorithms: PLINK, Tassel5.0, GAPIT, GenABEL (R library), EMMAX, SNPassoc (R package), GRAMMAR-Gamma, FaST-LMM, FaST-LMM-Select and BOLT-LMM.

2.6 Selective scavenging analysis (selection pressure analysis)

Selective scavenging analysis mainly observes that the somatic mutations may be a complex process and genomic features related to the specific traits of the species under the action of natural selection and artificial selection through genomic DNA sequencing of the species.

Natural selection analysis, we choose signal detection analysis

Judgment of positive selection: Analyze the positive selection trends of SNP and SNV regions, and explain the functionality of SNV and SNP at the level of evolution and population genetics; for control and case group samples, we use different statistical algorithms to calculate SNP, CNV in each sample, and then find the SV with positive selection features.

Autosomal signal detection and analysis

In the current mainstream analysis, only autosomal selection signal analysis is generally considered, and functional regions and mutations related to important economic traits, domestication, and adaptation are explored.

Analysis of sex chromosome selection signals

The study found that 19% to 26% of the reduction in genome polymorphism was caused by autosomal selection, and 12% to 40% was attributed to the selection of sex chromosomes (Mcvicker et al. 2009). Therefore, it is necessary to reveal the genetic mechanism and the correlation with important traits by detecting and analyzing the selection signals of X chromosomes of different species. Studies on adaptation, economic traits, and gender antagonism have been conducted on horses, pigs, sheep, and humans (Heyer & Segurel 2010; Ma Yunlong et al. 2012; Zhu et al. 2015; Liu Xuexue et al. 2015; Lucotte et al. 2016; Liu et al. 2018).

The analysis of sex chromosomes on the basis of a more complete assembly of reference genome sex chromosomes can make full use of and mine the information contained in the genome data, which is also a good research content. It can be used as a research paper for research and analysis.

2.7 Prediction of mutation function

According to the selective clearance analysis, GWAS analysis, QTL-seq and other analytical methods to obtain candidate genes related to biological special traits or phenotypes, the following software can be used to predict gene function changes caused by mutations, and provide data support for subsequent functional verification (Zhang Liang & Su Zhixi 2016).

PolyPhen2: determine the size of the mutation function

SIFT:

LRT:

Condel

Logit

Mutation Taster-2

Mutation Assessor

To be continued in Part VI…

Mesenchymal stem cells (MSCs) are derived from mesoderm at the early stage of embryo development, and are a heterogeneous cell population. MSCs in the body contain stem cells and differentiating progeny from the early stages of embryonic development and thereafter. Almost all human tissues contain MSCs, which are abundant in various tissues and organs, such as bone marrow, fat, dental pulp, umbilical cord, and placenta. MSCs from different sources have different protein expression profiles, and their characteristics are slightly different, but they have functions such as self-renewal ability, multi-directional differentiation potential, and immune regulation.

MSCs differentiation has the potential to differentiate into a variety of cell types. By regulating the differential expression of genes under the stimulation of specific signals and local microenvironments, they can not only differentiate into cell types derived from mesoderm, including cardiomyocytes, vascular endothelial cells, and lipid, osteogenic and chondrogenic cells can also be transdifferentiated into cells derived from endoderm such as gastrointestinal epithelial cells, lung cells, intestinal epithelial cells, muscle cells, etc., and can also be transdifferentiated into epidermal cells such as epidermal cells and nerve cells. Multiple signaling pathways participate in the cell differentiation process of MSCs, of which the two major signaling pathways, Wnt and TGF-β families, play a key role in cell differentiation. Activation of Wnt signaling pathway receptors on the surface of bone marrow stem cells leads to downstream signal transduction to regulate cellular processes such as proliferation and differentiation of bone marrow stem cells. MSCs have the ability of multi-directional differentiation of mesenchymal stem cells tri-lineage and can be widely used in the fields of drug screening, tissue engineering and cell therapy.

Figure 1. The multi-directional differentiation potential of MSCs

The early stages of MSCs research focused on their self-renewal, differentiation potential and tissue regeneration capacity as adult stem cells, and proposed the mechanism of host cell replacement. The mechanism of MSCs cell replacement includes two aspects, cell trans-differentiation and cell fusion. Cell trans-differentiation refers to the migration of MSCs to tissue injury sites and differentiation across the germ layer under the mediation of chemokines. Tissue-specific cells and connected cells replace damaged cells to play a role in tissue regeneration and repair. Cell fusion refers to the fusion of MSCs with host cells, which leads to reprogramming of the host cell's nucleus, and the fused cells express MSCs-specific genes, thereby avoiding apoptosis in damaged host cells. The results of animal experiments and clinical trials show that, regardless of autologous or allogeneic MSCs transplantation, only a small number of cells can colonize and survive for longtime during tissue damage repair. But it is not the main mechanism that MSCs play a role as cell therapy. MSCs involved in tissue damage repair also involves a series of complex biological processes such as tissue endogenous stem / progenitor cell activation, immune regulation and inflammatory response.

The study found that different inflammatory microenvironments can polarize MSCs into two types similar to M1 / ​​M2 macrophages, namely pro-inflammatory MSC1 and anti-inflammatory MSC2. When the tissue is damaged, the inflammatory factors secreted by the injury site make macrophages differentiate into M1 macrophages that promote inflammation. MSCs acquire the anti-inflammatory phenotype MSC2, which secretes a large amount of nitric oxide (NO) and indolamine 2,3-dioxygenase (IDO) to inhibit the function of lymphocytes and weaken the immune response to reduce tissue damage caused by excessive stress. In chronic inflammatory environment, macrophages differentiate into M2 macrophages that inhibit inflammation, at this time inflammatory factors such as IFN-γ and TNF-α are at low concentrations. It cannot activate the immunosuppressive function of MSCs, so that it can obtain the proinflammatory phenotype MSC1. MSC1 recruit lymphocytes to chemo to the inflammation area and activates them by secreting chemokines, and because of insufficient secretion of NO and IDO, these recruitments cannot be inhibited. The immune response of lymphocytes intensifies the intensity of the inflammatory response and causes tissue damage. This indicates that MSCs play a regulating and balancing role on the strength of mesenchymal stem cell immunomodulation. There is an important relationship between the activation of Toll-like receptors (TLRs) and the polarization of MSCs. TLRs is a special pattern recognition receptor. Its chemical structure is a type I transmembrane protein, which can recognize different disease-related molecular patterns (PAMPs) such as lipopolysaccharide (LPS), virus replication intermediate dsRNA, and heat shock protein. Signaling pathways, which stimulate immune cell responses, have an important effect on maintaining the homeostasis of the immune response during tissue injury sites. There are currently 11 members of the TLRs family that have been found to differ in expression in different cells. For example, TLR1 is expressed in monocytes, lymphocytes and NK cells. It is expressed in dendritic cells (DCs) and has important regulatory effects in both innate and adaptive immune responses. TLRs are also expressed on the surface of MSCs, among which TLR3 and TLR4 are highly expressed, which have an important effect on the polarization of MSCs. dsRNA can bind to TLR3 on the surface of MSCs, polarize MSCs to MSC2, and secrete anti-inflammatory factors NO, IDO, prostaglandin E2 (PGE2), transforming growth factor β (TGF-β), hepatocyte growth factor (HGF), etc. Inhibit the proliferation of T cells, promote the generation and activation of T regulatory cells (Tregs), and thus suppress the activation of immune functions. LPS can activate TLR4 on the surface of MSCs, polarize MSCs to MSC1 type, significantly reduce the production of anti-inflammatory factors, and secrete macrophage inflammatory protein 1α (MIP-1α), MIP-1β, CXC chemokine ligand 9 (CXCL9), regulating the activation of normal T cell expression and secretion factors (RANTES, CCL5) and other chemokines, recruit lymphocytes to chemoattract the site of inflammation and enhance the T cell-mediated immune response, and promote the occurrence of inflammatory response . Co-culture experiments of MSCs and tumor cells in vitro can also confirm that MSCs can have a two-way effect of suppressing and enhancing immunity after polarization: When co-cultured with MSC1 and tumor cells, it can inhibit tumor growth and reduce tumor cell migration ability and invasiveness; when MSC2 is co-cultured with tumor cells, it can promote tumor cell proliferation and increase value, which is conducive to growth.

The "nest" of stem cells is a special microenvironment on which stem cells depend. The "nest" can regulate the behavior of stem cells and keep stem cells growth, regeneration and differentiation of stem cells in balanced state. MSCs homing is defined as the process in which MSCs are captured in the vasculature of the target tissue and migrate through the vascular endothelial cells to the target tissue. The homing of MSCs is a continuous process, which manifests itself as the MSCs roll against the walls of the capillaries, then adhere to the surface of the endothelial cells and pass through the endothelial cells, and finally penetrate from the blood vessels to the target tissue. The mechanism of MSCs migrating across endothelial cells and homing to target tissues may involve the interaction of chemokines, growth factors, adhesion molecules and other receptors and their ligands expressed on the surface of MSCs. At present, more researches include stromal cell derived factor 1 (SDF-1), CXC chemokine receptor (CXCR), CC chemokine receptor (CCR), HGF and its receptor c-met (HGF / c- met), monocyte chemotactic protein (MCP), MIP and adhesion molecules, etc.

CXC chemokine: SDF-1 is also known as CXCL-12, and its receptor is CXCR4. It was first discovered in cytokines secreted by mouse bone marrow stromal cells and expressed on blood cells, hematopoietic stem cells, embryonic stem cells and other surfaces. The main function of the SDF-1 / CXCR4 axis is to regulate the chemotaxis and homing of precursor cells, which plays a key role in the recruitment and migration of MSCs. Compared with other chemokines, SDF-1 showed stronger chemotaxis ability to MSCs.

CC chemokine: A variety of CC chemokines, such as CCL2, CCL3, CCL4, CCL5, CCL7, etc. have chemotactic effects on cells. The expression of CCL2 and CCL3 is up-regulated in tissue injury and inflammation sites, while MSCs have the ability to be induced to express CC chemokine receptors. The study found that CCL3 is highly expressed in the myocardial infarction area of the experimental animal model of myocardial infarction. After treatment with MSCs, the heart with high CCL3 expression in the infarct area can recruit more MSCs, and myocardial function recovery is more significant than that of the control group. Overexpression of CCL3 receptor CCR1 can enhance the ability of MSCs to homing and implant into damaged myocardial tissue.

HGF / c- met: HGF is cytokine isolated from the serum of a partially hepatectomized rat model, which can promote DNA synthesis in liver cells. Its receptor is a tyrosine kinase called c-Met. After binding to c-met, HGF phosphorylates and initiates a specific signaling process. The HGF / c-met signaling pathway is widely involved in and regulates many physiological processes such as cell growth and migration, anti-apoptosis, promotion of proliferation and angiogenesis. Among them, HGF can promote the proliferation, migration and differentiation of MSCs, and mediate the targeted distribution of MSCs.

To be continued in Part II…

According to a recent study, researchers found that PROTAC can degrade multiple mutant BTK proteins and overcome non-Hodgkin's lymphoma resistant to the clinical first-line drug ibrutinib.

Anti-cancer drug resistance is undoubtedly the most painful thing for the patients involved. Ibrutini, which ranks in the top 20 in global sales, is a star molecule in the treatment of lymphoma and chronic lymphocytic leukemia in recent years. Even such targeted drugs with significant efficacy can hardly avoid the occurrence of drug resistance. On March 19th, the research team of Tsinghua University School of Pharmacy Rao Yi and the research group of Liu Wanli of the Chinese Academy of Sciences, and the research team of Peking University Cancer Hospital Zhu Jun published the latest research results online, titled “Degradation of Bruton's tyrosine kinase mutants by PROTACs for potential treatment of Ibrutinib—resistant Non-Hodgkin lymphomas. In this paper, by constructing a new highly soluble BTK protein efficient degradation agent, it successfully degraded a variety of clinically relevant mutant BTK proteins, and overcome the resistance. More importantly, the effectiveness of the new strategy to overcome tumor resistance has been verified by in vivo experiments.

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine protein kinase and plays an important role in the upstream part of B lymphocyte signaling pathway (BCR). As a member of the Tec kinase family, BTK plays a key role in the differentiation and development of B lymphocytes. Except for T lymphocytes and natural killer cells, BTK is only expressed in hematopoietic cells. In organisms, BTK protein plays a very important physiological function. In 1952, American pediatrician Ogdon Bruton discovered that if a certain antibody is lacking in children, it will cause X-associated blood globulin deficiency (XLA), resulting in recurrent bacterial infections and sepsis. In 1993, the gene responsible for X-associated gamma globulin deficiency was finally confirmed. In humans, if the BTK gene is absent in the genome, the number of B cells will be significantly reduced, and the serum gamma protein level will be reduced.

In activated B-cell-like (ABC-like) diffuse large B-cell lymphoma (DLBCL), BTK plays an important role in the immune escape of such cells. The BTK protein is the first TEC family kinase found to have dual functional conditions in terms of apoptosis. It can promote free radical-induced apoptosis in B lymphocytes, but can inhibit Fas-activated apoptosis. In the BCR pathway, BTK protein is activated by tyrosine protein kinase LYN and spleen tyrosine kinase SYK. When BTK protein is activated, it can activate the downstream protein PLC-γ2, and then promote endogenous calcium ions, Diglyceride (DAG) and inositol triphosphate (IP3), and ultimately activates the activation of nuclear factor (NF-κB), thereby inhibiting the apoptosis of B lymphocytes and promoting the occurrence of cancer.

Non-Hodgkin's lymphoma (NHL) is a type of B-cell malignancy, with more than 60,000 new cases come out each year in the United States. Disseminated large B-cell lymphoma (DLBCL) is the most common type of NHL, with an annual incidence of 0.08% in the United States and the United Kingdom. Mantle cell lymphoma (MCL), as a type of NHL, has a 5-year survival rate of less than 50%. BTK covalent inhibitor ibrutinib has been the first-line treatment for a variety of non-Hodgkin's lymphomas, including mantle cell lymphoma, chronic lymphocytic leukemia, and Fahrenheit's macroglobulinemia. In 2018, the global sales of ibrutinib was US $ 4.45 billion, an increase of 39.4% from 2017. Nevertheless, according to the latest clinical data reports, serious drug resistance has appeared against ibrutinib. The mutation of cysteine ​​at position 481 of the BTK protein to serine (C481S) reduced the activity of ibrutinib by nearly 500-fold. Clinical data has shown that this mutation is the root cause of patients’ resistant to ibrutinib. It also proves that other mutations at position 481 of the BTK protein can also cause ibrutinib to fail.

Rao Yi's group recruited E3 ubiquitinated ligase to target BTK protein by constructing a new skeleton PROTAC small molecule. The newly constructed BTK protein degrading agent can efficiently degrade BTK proteins of various mutation types (C481S / T / A / G / W) at a drug concentration of less than 50 nM in transfected HeLa cells. More importantly, the new strategy can cause the decrease of BTK protein levels in mutant DLBCL tumors, thereby effectively inhibiting the growth of tumors in the body, and overcoming the tumor BTK kinase caused by the mutation of C481 site to the clinical first-line drug ibrutinib Drug resistance. In addition, this study also explored the downstream signal of BTK protein, such as PLC-γ2, p38 and ERK1 / 2, which clarified the change of the downstream signal of the cell caused by the new PROTAC molecule acting on the BTK protein. It reveals why the new strategy exerts the anti-tumor effect from the mechanism level.

In addition to the treatment of DLBCL, the new PROTAC small molecule can also effectively inhibit MCL (mino and Z138), and its effect is better than the current clinical first-line drug ibrutinib. Another highlight of this study is the combination of PROTAC strategy with traditional small molecule inhibitors, such as copanlisib, dasatinib, etc., which greatly improves the anti-tumor effect of PROTAC strategy.

This work provides important information for the development of drug-resistant non-Hodgkin lymphoma based on PROTAC. At present, the team of researchers is further developing such new compounds, hoping to continue to improve their metabolic stability and antitumor effect.

[1] Cell: Analyzes the three-dimensional structure of the chemokine receptor CCR7 and identifies compounds that are expected to treat certain common cancers.

Doi:10.1016/j.cell.2019.07.028

In a new study, researchers from the Paul Scherrer Institute in Switzerland, together with the pharmaceutical giant Roche have taken an important step in developing medicinal agents that block certain cancer metastases. Aided by Swiss Light Source, they made clear the structure of a receptor that plays a key role in cancer cell migration. This discovery allows identification of medicinal agents to block the spread of certain cancer cells, which go through the lymphatic system of our body.

When a cancer cell spreads in the body, a secondary tumor called a metastasis can be formed. These secondary tumors cause approximately 90% of cancer patients to die. An important way to spread cancer cells is through the lymphatic system, which runs through the body like a vascular system and connects the lymph nodes to each other. Chemokine receptor 7 (CCR7) plays an important role as a specific membrane protein when leukocytes migrate through the lymphatic system to coordinate defense against pathogens. It is located in the cell membrane and receives external signals and transmits these signals to the interior of the cell. In collaboration with Roche, researchers at the Paul Scherrer Institute were able to identify the structure of CCR7 for the first time, laying the groundwork for developing drugs that would prevent some common cancer metastasis.

[2] Nat Commun: Foods rich in flavonoids can protect the body against cancer and heart disease

Doi:10.1038/s41467-019-11622-x

Recently, a research report was published in Nature Communications. Scientists from the University of Idisco found that eating flavonoid-rich foods (such as apples and tea) can help the body effectively fight cancer and heart disease, especially for smokers and heavy drinkers.

In this study, the researchers evaluated the dietary status of 53,048 Danes over a 23-year period and found that people who habitually consume moderate or large amounts of flavonoid-rich foods may not be very likely to die from cancer or heart disease. According to Researcher Dr. Nicola Bondonno, people who consume foods rich in flavonoids have a lower risk of death. This effect is especially true for those who are at higher risk of chronic diseases due to smoking and drinking more than two standard alcoholic beverages a day.

[3] MedChemComm: Special compounds in plant white chrysanthemum are expected to effectively kill leukemia cells

Doi:10.1039/C9MD00297A

In a recent study published in the international journal MedChemComm, scientists from the University of Birmingham said through research a special compound in the commonly seen plant everfew may have potential anti-cancer properties. In the article, researchers extracted the compound from the white chrysanthemum and modified it to kill chronic lymphocytic leukemia (CLL) cells in the laboratory.

In addition, the researchers studied the compound called Parthenolide (PAR), which scientists have discovered many years ago. Although it is commercially available, this compound is very expensive and poorly medicinal, and research on this compound is only at the basic research stage. Researchers have devised a new method that not only directly extracts parthenolide, but also modifies it to produce a variety of compounds that kill cancer cells in vitro. The subsequent properties of these compounds make them potential drugs for later clinical trials.

[4]Science Supplement: The highly selective compound BMS-986165 is expected to treat a series of autoimmune diseases and chronic inflammatory diseases.

Doi:10.1126/scitranslmed.aaw1736

Although recent advances in the treatment of autoimmune diseases and chronic inflammatory diseases have provided important benefits for some patients, unmet medical needs still remain high, especially for these debilitating patients who need better efficacy and stronger remission. In addition, many therapies representing current treatment criteria have safety issues that either limit its long-term use (eg, glucocorticoids) or are associated with a significant decline in host defense, which can result in severe infections or increased risk of malignancy.

Tyrosine Kinase 2 (TYK2) is a non-receptor tyrosine kinase that regulates signal transduction downstream of interleukin-23 (IL-23), IL-12 and type I interferon (IFN) receptors. These cytokines/receptors activate the function of helper T-cell 17 (TH17), TH1 cells, B cells, and bone marrow cells, which are involved in autoimmune diseases and chronic inflammatory diseases including systemic lupus erythematosus (SLE), lupus nephritis, Sjogren's syndrome, Crohn's disease, psoriasis and systemic sclerosis.

[5] Nat Metabol: Human clinical trials have found that the compound urinaryin A in pomegranate does have an anti-aging effect!

Doi:10.1038/s42255-019-0073-4

Recently, in a research report published in Nature Metabolism, scientists from institutions such as the Federal Institute of Technology in Lausanne, Switzerland, found that Urolithin A, a substance in pomegranate and other fruits, can improve the function of the cell mitochondria and help to slow down specific aging processes.

What to eat is a basic question that we may face each day, which is even more important as we age. Researchers have been working hard to explore the best diet choice that would minimize the risk of health problems like high blood pressure, obesity, type 2 diabetes and heart (cardiovascular) diseases.

We now have evidence that these above-mentioned chronic health problems also affect brain function via increasing neurodegeneration in the brain, and ultimately leading to high risks of Alzheimer's and other brain diseases, including vascular dementia and Parkinson's disease. This gives us a hint: if we can adopt a healthy diet that is conducive for preventing type 2 diabetes, obesity and heart disease, the risk of getting brain diseases can be naturally decreased at the same time.

Oxidative stress might be the chief culprit of Alzheimer's disease.

As we age, our metabolism becomes less and less efficient, and it is increasingly difficult to get rid of compounds produced by the so-called "oxidative stress." Normal human chemical reactions can sometimes cause chemical damage or produce by-products called free radicals, which in turn can cause damage to other chemicals in the body.

To neutralize these free radicals, our bodies rely on antioxidants or specific protein protection mechanisms. But as we age, the efficiency of these systems is getting lower and lower. Oxidative stress comes when our body can no longer neutralize the damage of free radicals. The toxic compounds produced by oxidative stress continue to accumulate, slowly damaging the brain and eventually causing symptoms of Alzheimer's disease.

To reduce such risks, the best way is to get lower oxidative stress and avoid the long-term inflammation it can cause. Although doing exercise is repeatedly and widely recommended by doctors and researchers, more intake of foods that contains a lot of antioxidants is also conducive. You can add a lot of food to your diet that has a positive impact on your brain health. These include fresh fruit, seafood, green leafy vegetables, beans (including beans, lentils and peas), nuts and healthy fats.

Fish

Fish is a good source of complete protein. More importantly, oily fish are rich in omega-3 fatty acids. Laboratory studies have shown that omega-3 fatty acids can prevent oxidative stress for patients with Alzheimer's disease as they are essential for memory, learning, and cognitive processes and can improve gut microbiota and function. At the same time, low intake of omega-3 fatty acids in the diet can lead to a faster decline in cognitive ability and lead to preclinical Alzheimer's disease (a memory loss can be seen as early as a few years ago).

However, Omega-3 fatty acids are generally deficient in Western diets, which is associated with decreased brain cell health and function. Fish can also provide vitamin D. This is important because the lack of vitamin D is also associated with Alzheimer's disease, Parkinson's disease, and vascular dementia. Vascular dementiaa is a common dementia caused by a series of small strokes as a result of a decrease in blood supply to the brain.

Berry

Berries are rich in antioxidants vitamin C (strawberry), anthocyanins (blueberries, raspberries and blackberries) and resveratrol (blueberries). In studies of mouse brain cells, anthocyanins are related to protein changes associated with less toxic Alzheimer's disease and can reduce oxidative stress and inflammation associated with brain cell (neuronal) damage. Human studies have shown that after intake of berries, brain function and blood flow are improved, and symptoms of brain inflammation are also alleviated.

Sweet potato and purple potato

Longevity is related to a few traditional diets, one of which is the diet of the Japanese Okinawa. Their staple food is purple sweet potatoes rich in anthocyanin antioxidants. Studies in mice have shown that anthocyanins in this potato can prevent the effects of obesity on blood sugar regulation and cognitive function, and can reduce brain inflammation caused by obesity.

Green vegetables and herbs

The traditional Mediterranean diet has also been studied for its relationship to longevity and reduced risk of Alzheimer's disease. Green vegetables and herbs play an important role in this diet. They are rich in antioxidants, including vitamins A and C, folic acid, polyphenols (such as apigenin) and carotenoid lutein (especially raw). Carotenoids are an orange or red pigment commonly found in carrots.

Antioxidants and anti-inflammatory chemicals in vegetables are thought to be responsible for slowing the pathogenesis of Alzheimer's disease, which is formed by specific proteins that are toxic to brain cells.

Parsley is rich in apigenin, a powerful antioxidant. It easily crosses the barrier between blood and brain (unlike many drugs), where it reduces inflammation and oxidative stress and helps restore brain tissue after injury.

Beetroot

Beetroot is rich in folic acid and polyphenolic antioxidants, as well as copper and manganese. In particular, beetroot is rich in beet blue pigment, which can reduce oxidative stress and has an anti-inflammatory effect. Due to its nitrate content, beetroot can also increase the body's nitric oxide levels. Nitric oxide can relax blood vessels and lower blood pressure, a benefit associated with drinking beetroot juice. A recent clinical study of the elderly showed that nitrate-rich beetroot juice also has significant benefits for heart and blood vessel health.

Reduce junk food intake

Just as important as adding good antioxidants to your diet is to minimize unhealthy foods intake. Some foods contain damaged fats and proteins, which are the main sources of oxidative stress and inflammation. A large intake of "junk food", including sweets, soft drinks, refined carbohydrates, processed meats and fried foods, is associated with obesity, type 2 diabetes and cardiovascular disease. These conditions are risk factors for cognitive decline and Alzheimer's disease, so they should be kept to a minimum to reduce health risks and prolong life.

While the general public can adopt a healthier diet to reduce the risk of Alzheimer's disease, those who already get this disease can resort to reasonable and scientific therapies and treatments. For now, amyloid hypothesis and tau hypothesis are intensively studied by researches, in an attempt to find a cure. To this end, Creative Peptides offers a large range of peptide for Alzheimer's research, such asβ-Amyloid (1-42), (1-40), (1-46) and Fragments, Amyloid (APP) Precursor 770 Fragments, β-Amyloid (HFIP-treated) and Salts (HCI,TFA), β-Amyloid Mutations, FRET-Substrates, Labeled Amyloid Peptides, Modified Amyloids, Modifiers of Aβ-Aggregation, β-and γ-Secretase Inhibitors, and Tau Fragments.

Glioblastoma is the most common and death-causing malignant tumor, on which scientists are working to find an effective viral therapy, and PVSRIPO virus, which performs quite well its first clinical trial, maybe a safer and more effective one. The tumor in the brain sounds horrible to everyone. According to the World Health Organization, there are more than 100 types of brain tumors. Among the tumors, the most common and death-causing malignant tumor is glioblastoma, of which the 5-year survival rate of patients suffering is only 5.1%.

So how can we deal with glioblastoma? Scientists are working on two kinds of ideas. One is the famous CAR-T therapy. In the 2016 New England Journal of Medicine, a case of successful CAR-T treatment of glioblastoma was reported, but CAR-T which costs hundreds of thousands of dollars is expensive and unaffordable for most people.

The other method is viral therapy for glioblastoma which has a unique advantage: the virus injected into humans can activate T cell-led immune response, which is the key to smashing glioblastoma.

Not all viruses can be used to break the tumor, since the brain is very important, and easy to be damaged by viruses while difficult to recover, so many factors must be considered carefully, including toxicity and side effects.

Then, scientists turned their attention to the poliovirus. Although poliovirus can kill neurons and cause polio, this mechanism can be modified to treat glioblastoma. In order to operate a virus to attack cancer cells, it is necessary to change a component called internal ribosome entry site (IRES), which determines the type of cell in which the virus is infected. The IRES of poliovirus can only target nerve cells, so with the help of genetic engineering technology, scientists put the IRES of human rhinovirus type 2 on the poliovirus, which create the key of this experiment - PVSRIPO recombinant virus.

The PVSRIPO virus not only dissolves cancer cells to release antigens and activate immune responses, but also actively infects immune cells such as dendritic cells and macrophages. Infection does not significantly kill immune cells, but activates them to release interferon, attracting more helpers to attack cancer cells, thus developing a dual immune activation capacity.

Based on the result of this experiment, Duke University's research team launched its first clinical trial in 2012 to validate the safety and efficacy of the PVSRIPO virus, and enrolled were 61 patients whose brain tumors were graded to be Level IV, where chemotherapy, surgery and other methods have completely failed.

According to the result, the performance of the PVSRIPO virus exceeded expectations. Among the patients treated, 21% survived for 3 years, and the 2 patients who received the first treatment even survived for 6 years, while the past 3-year survival rate of this kind of patients was only 4%, which means the survival rate has increased for four times.

In terms of safety, PVSRIPO also performed quite well. 69% of patients had only mild adverse reactions, mainly manifested as nervous system symptoms such as headache, convulsions, and hemiparesis. Even with increased dose, only 19% of patients had serious adverse reactions. It is a pity that one patient died of cerebral edema during treatment and may be associated with a viral infection.

"This is a solid step forward, and great progress in fighting with glioblastoma,” said a senior scientist in Creative Biolabs, a company specialized in engineering and construction of oncolytic virus, “but after all, treatment is not effective for many patients, so PVSRIPO therapy is not the final cure for glioblastoma."

Exploration won't stop there. Duke University, along with scientists around the world will do more to explore the therapeutic effects of oncolytic viruses combined with existing chemotherapy drugs, and look for ways to promote the current treatment to a safer and more effective one.

Chimeric antigen receptor T cell (CAR-T) therapy is one of the most promising tumor targeted immunotherapy techniques, which has been proved effective in the treatment of a variety of relapsed/refractory (R/R) B-cell malignancies, such as acute B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL) and B-cell lymphoma.

Needless to say, the most successful case of CAR-T cell therapy is a series of clinical trials targeting CD19 against B cell tumors. CD19 is a cell surface antigen specifically expressed in various differentiation stages of B lymphocytes. The majority of B-lineage malignancies including B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia and non-Hodgkin lymphoma cells express CD19. It is therefore considered an ideal target for CAR-T in the treatment of B-cell neoplasms. The results of clinical trials have shown that the cure rate of CD19 CAR-T for acute B-lymphocytic leukemia (B-ALL) has reached 90%.

However, 20% to 30% of patients with leukemia and lymphoma who achieve remission after treatment with CD19 CAR-T cell therapy will relapse one year later. A major obstacle to current CAR-T therapy is that these cunning tumor cells of up to a third of patients have learned how to no longer express targets previously recognized by immunotherapy, thereby relapsing again, which means that tumor cells escape CAR-T recognition attack by not expressing target/target deletion or target epitope masking.

Fortunately, with the consistent efforts of the researchers, novel possibilities have emerged when the first CAR-T treatment targeting the B-cell activating factor receptor (BAFF-R) on cancer cells successfully eradicated CD19 treatment-resistant human leukemia and lymphoma cells in animal models. A clinical trial will be launched next year for patients who relapse after CD19 immunotherapy and may be used as a first-line drug for CAR-T cell therapy.

How does a CAR-T cell therapy work? Firstly, T cells are extracted from patients’ blood. Next,

immune cells are genetically engineered in the laboratory to recognize and attack specific proteins (targets) associated with cancer, such as the B cell activating factor receptor BAFF-R. Then the engineered cells are reintroduced into the patient's body to start the journey of destroying tumor cells.

On one hand, in the BAFF-R CAR-T, animal models of human tumors, including Burkitt's lymphoma, Mantel cell and other non-Hodgkin's lymphoma subtypes, and acute lymphoblastic leukemia, were observed with significant tumor regression and prolonged survival after treatment. Particularly, an animal model with human Burkitt lymphoma are cured after a single treatment, with complete tumor regression and 100% long-term survival. On the other hand, animal models with CD19 positive and negative mixed human tumors, received CD19 CAR-T cell therapy or BAFF-R CAR-T cell therapy, respectively. Results showed that the former one, which is CD19 CAR-T cell therapy, has failed, while the other one achieved the eradication of both tumors. It demonstrates that BAFF-R CAR-T cells are consistently active against these tumors, while CD19 CAR-T cell therapy is greatly reduced in response to recurrent tumors after each case of immunotherapy compared to pre-treatment samples.

At present, CAR-T therapy in the treatment of hematological malignancies has achieved remarkable achievements, but in addition to the treatment of various complications, the recurrence of primary disease is still one of the major obstacles facing the therapy. The clinical efficacy of CD19 CAR-T therapy is expected to be enhanced by screening the ideal target antigen, exploring the best combination of target antigens, optimizing the patient's own conditions, and exploring the combination of treatment regimens.

Welcome to Tactical World Store. Today I want to introduce all our Best Tactical Backpacks of 2020. Firstly we need to know what is a Tactical Backpack?

Tactical backpacks are originally classic military equipment, but relying on their excellent abrasion resistance, durability and functionality, they are often used as daily commuter backpacks or extreme use, such as trekking, hiking or mountaineering. The best tactical backpack can maximize your storage space and keep you comfortable in the most demanding circumstances.

• Colors of Tactical Backpacks:

The outdoor bag is very conspicuous. In order to quickly lock the position outdoors, and improve safety and convenience. Tactical packs are basically military green, black, and gray. In addition to military necessity (concealment), the most important thing is to resist dirt! It is not dirty when thrown on the ground.

• Special Design of Tactical Backpacks:

MOLLE System and Modula are the most notable features of tactical backpacks.

The external MOLLE system can mount various EDC gadgets or small external bags. A tactical backpack can increase the capacity of at least 50% by the MOLLE system, which is equivalent to buying two bags at the price of one bag.

Modula is reflected in the tactical package with various levels of storage. With help of Modula design, you can customize your pack according to your special equipment. The tactical bag will be designed with multiple compartments from the inside to the outside, allowing you to scientifically partition the equipment and get it quickly and easily.

• Materials of Tactical backpacks:

Like most outdoor bags, tactical backpacks are basically made of Oxford cloth, nylon, and canvas; but outdoor backpacks are lightweight, and tactical backpacks are more wear-resistant.

Excellent abrasion resistance also means that the density of the fabric is greater, which also makes tactical backpacks tend to be heavier. After all, lightweight and abrasion resistance cannot be achieved at the same time. How strong is the abrasion resistance of the tactical backpack? Probably your back is tired, you can drag it all the way and it won't break ...

The following highlights 10 best tactical backpacks from Tactical World Store：

1. Blackhawk Tactical Backpack - Best Tactical Backpacks of 2020

Blackhawk Tactical Backpack: It can be used as 3-day assault pack, range bag, hunting backpack, survival backpack, army backpack, trekking backpack or day pack for daily use. 

Features of Blackhawk Tactical Backpack:

• The material is 900D Waterproof oxford cloth
• Backpack dimensions: 13''x20''x11''
• Weight: 2.75 pounds
• Capacity of Blackhawk: 45L
• Use for: Travel Handbag/Outdoor Mountaineering Backpack/Shoulder pack
• The molle tactical backpack has a molle system, Molle webbing throughout for attaching additional tactical pouches.
• Assault pack backpack with double-stitched, Heavy duty zippers and utility-style cord pull, Side and front load compression system, Ventilated mesh padded back area & shoulder strap, breathable and comfortable.
• Military backpack has hydration compatible that works great for a hydration bladder (backpack didn't include hydration bladder) as a hydration backpack or outdoor camping hiking backpack.

Some reviews of this Blackhawk Tactical Backpack:

Mick Yule: Would recommend! I never purchased tactical backpack before, but it has been amazing pack to me. This back pack comes very handy when traveling or camping. I really liked this tactical backpack, comfortable, roomy, durable.

Dora Billy: good quality and fast delivery. Wow! I have been buying tactical backpack so many years I love multi fuctional bags with many pockets and this fits the bill very well. Very roomy, with durable construction and materials, and a lot of MOLLE attachment points. Love it!

Ellis Ingersoll: Great Military Style Backpack. I am so glad I bought this military backpack. It is very comfortable to wear and very practical. During my travel I usually carry multiple items and it has many compartments for pretty much everything. I would highly recommend this to anyone who camps, travels, hikes, fishes, pretty much anything.

 2. Tour of Duty Outdoor 72 Backpack - Best Tactical Backpacks of 2020

Tour of Duty Outdoor Backpack: The high functionality and easy accessibility of the Tour of Duty Outdoor Backpack make it an ideal combat companion. Have to carry heavy loads for long distances? It's no problem for this pack. The ergonomic design works with your body to make it as comfortable as possible. The shoulder, sternum and waist straps contour to your form, locking you in while the breathable back foam pad provides blissful cushion. Spacious compartments utilize specialized designs for easy storage.

Features of Tour of Duty Outdoor 72 Backpack:

• Material: 600D military Oxford cloth
• Approximate weight: 61.73 oz
• Capacity: 60 L
• Main compartment (approx.): 19.7 in high x 13.0 in wide x 8.7 in deep
• Front pocket (approx.): 5.1 in high x 12.6 in wide x 3.9 in deep
• Side pocket (approx.): 7.9 in high x 4.7 in wide x 2.4 in deep
• It comes with an exterior zip pocket and a large mesh compartment on it.
• With 3 detachable pockets on the front and two sides.
• Large cargo with a large compartment in it.
• With a bite valve hole at the top of the package, and hidden by a cover.
• It comes with a hand strap and adjustable shoulder strap.
• Wide and thick belt, comfortable to carry heavy.
• With adjustable chest belt.

Some reviews of this Duty Outdoor 72 Backpack:

Josephine Hutt: Great asset for the price! So much space, 60L! And all the detachable pockets are great. I used this backpack everyday during 3 days of the trip and it held up very good. Great value for the money. This has been a great asset especially at the price!

June Keats: Great Camping Equipment. This back pack has a lot of features you'd expect in a low price, thanks to it being covered on all sides with Molle webbing, you can customize this bag as much as you want. The materials appear to be sturdy enough, though I haven't had it long enough to be sure how it will wear. My husband can use this backpack for our hiking and camping trip..and I think this bag will be a great addition to our camping equipment.

Tom Morley: Absolutely love this backpack. As an every day use bag you can remove both side compartments and the lower middle which are all seperate which means if you want to reduce the size you can! Second if this is a grab and go bag for emergencies you can deck it out with survival gear, food, medical supplies, hunting gear, spare set of clothes and knife! Also a great camping bag as well. Definitely recommend!

3. RUSH12 Tactical Military Backpack - Best Tactical Backpacks of 2020

RUSH12 Backpack:Our most popular tactical backpack, the RUSH12 is designed to provide superior storage capacity and organization without slowing you down.

Features of RUSH12 Tactical Military Backpack:

• Zipper closure
• Product dimensions: 4x14x18 inches
• Shipping weight: 2.75 pounds
• Tactical Backpack featuring 16 individual compartments, a roomy main storage area, and a hydration pocket. Equipped with an adjustable height sternum strap, two external compression straps, and contoured yoke shoulder strap system
• Made from durable 1050D nylon (Multicar: 1000D nylon), this military backpack is water-resistant and features self-repairing YKK zippers and 5.11’s signature centerline design.
• Molle is compatible with the wrap-around molle/5.11 slick stick web platform, internal multi-slot admin compartment, and a zippered fleece-lined eyewear pocket. strap system
• Our Military backpack has hook and loop nametape, flag patches and glove-friendly pull tabs; perfect for patrol, outdoor hiking, trekking and camping, survival expedition, or day pack.
• The Rush12 backpack can be used as a multipurpose pack, bug out bag, range bag, hunting backpack, survival backpack, hiking Rucksack, or everyday outdoor backpack. This assault pack is ready for any rescue or adventure for all of your gear and equipment.

Some reviews of this RUSH12 Tactical Military Backpack:

Griselda Galbraith: Definitely worth the money. This backpack is really sturdy, well made & quite comfortable. I like the fact that it has plenty of space for things like portable batteries and other small items while not sacrificing the ability to bring larger items as well. It has plenty of internal compartments and it's made very well.

Sebastian Penn: This backpack is perfect. It has more pockets than I know what to do with and for the price you can't beat it. Super lightweight, the straps are very comfortable. Built to last with heavy duty fabrics and hardware. Front organization pocket with additional key fob and mesh zipper pocket. Everything about this backpack feels sturdy. I love it and recommend it.

Julia Melville: Great Quality, great stitching, solid material. I can’t even tell you how many bags I have saved in my lists or how many I’ve ordered but this is probably one of my favorites by far. I have a 50l backpack that I’m using as a hiking bag and as for this Tactical backpack it’s now become my "Get Home Bag", perfect size for what I need it for.

4. Lightweight 24 Military Backpack - Best Tactical Backpacks of 2020

Lightweight 24 Military Backpack: Whether you're on a military operation or a weekend getaway, this Lightweight Packable Backpack has the storage space and durability to help you get the most out of your trip. This backpack features a Y-Harness tightening band and a fully adjustable shoulder straps. The MOLLE webbing and D-Ring on shoulder strap can be used for hanging small items. Built with durable nylon to protect the contents, this backpack is also compatible with a hydration pack, perfect for a long hike. Before you set off on your next journey, get this backpack to carry all of your essentials.

Features of Lightweight 24 Military Backpack:

• Total size: 17" x 9" x 10"
• Capacity (L.): 35L
• Main Material: 600D Oxford Cloth
• Total volume: 1348 cu. in.
• Sternum and waist straps for stability
• Ventilated mesh straps for non-stop comfort
• Compatible with a hydration pack
• Four individual compartments
• Main compartment: 17" x 15" x 5" with one zippered pocket and one mesh pocket
• Bottom front compartment: 10" x 8" x 2.5"
• Top front compartment: 4" x 7" x 2.5"

Some reviews of this Lightweight 24 Military Backpack:

Bard Halifax: Awesome EDC Bag! I purchased this tactical bag because I wanted something that was large enough to hold my EDC items, but was small enough to be considered for EDC. This bag is perfect . Full of features, reliable, and versatile with enough room to transport all the essentials and more.

Barbara Alfred: I have been using this lightweight backpack for a month now. So far it is holding up very well. This was a gift for my husband, he loves hiking and camping. The quality of fabric is really good, I think there’s nothing that could damage it.

Agatha Steele: Fantastic pack for the price. The straps are great for cinching it down and keeping it tight. They are comfortable and easily adjustable for all body types. The string pulls are great for field movements. The pocket set up is great for keeping items separate and easily accessible. You will NOT be disappointed.

5. Archon 3 Day Camo Ruck Pack - Best Tactical Backpacks of 2020

Archon 3 Day Camo Ruck Pack: Large Capacity Backpacking Backpack----There is no compartment in the main pocket, but a lot of space, match with drawstring design to contain your all stuff like clothes, shoes, camera, camping hammock, camping mat, sleeping bag. 2 side pockets with zippers to put water bottles, umbrella, front pocket to put your often use stuff like phone, tablet, notebook, top cap pocket to put wallet to prevent theft.

Features of Archon 3 Day Camo Ruck Pack:

• Waterproof 900D oxford fabric
• Product dimensions: 70x37x17 cm
• Shipping weight: 2 pounds
• Capacity: 75L
• Ergonomics & Scientific Strap Design----The 75L camping hiking backpack is designed with thick ventilated mesh padded shoulder straps that are breathable and add comfort. We add adjustable whistle chest strap and waist strap to spread shoulder bear stress and make travel easier. All strap was reinforced, so you don't worry tear or break.
• Molle System & D Ring Suspension----The molle travel backpack can use as a 3 days tactical backpack, molle external expansion system designed to be used in combination with other equipment, D shape buckle on the shoulder strap which can be used for hanging keys, cups, etc.
• Multi-function----The duffle backpack dimension is 13.4*6.7*28.75 inches (L x W x H ); multiple colors to choose, It is a very popular outdoor rucksack backpack for both men and women, whether you are into cycling, hiking, fishing, hunting, survival, sports, camping or are just traveling, it will fill your needs.

Some reviews of this Archon 3 Day Camo Ruck Pack:

Humphrey Rutherford: The perfect 3 day assault pack that you can easily pack for 5 days. These things can hold everything. Assault packs are built to be heavy duty and be abused, the ones I used in the military are very similar and in many ways this ones better. I take them into the field for days at a time and ive found I can count on this one its shown no stressing or fraying anywhere the zippers are heavy duty. Its still practically brand new.

Kevin Augustus: I love this bag! This backpack is so thick and weighty! About 2 pounds when I weighed it, and it's a 75L-capacity backpack. It has compartments and pockets everywhere! There is just so much places to hang and store things that I can't even begin to go over them. Worth the $$$! Amazing.

Wayne Emily: Bought this backapck for my husband as a gift and I was very impressed with the quality of the bag. I thought this was almost too good to be true. Lots of pockets, great quality, padding, and room for camel bag if needed. I liked the material and the sewing/stitching of the bag, very well made. Too good for the price you pay!

6. Archon Utility Tactical Sling Pack - Best Tactical Backpacks of 2020

Archon Utility Tactical Sling Pack: for a daily use bag and a carry on bag for travel, EDC, Outdoors, Trekking, Hiking, Climbing, Camping, Backpacking, Cycling.

Features of Archon Utility Tactical Sling Pack:

• 600D Wateresist nylon cloth
• Shipping weight: 1.5 pounds
• Capacity: Less than 10L
• Application: for a daily use bag and a carry on bag for travel, EDC, Outdoors, Trekking, Hiking, Climbing, Camping, Backpacking, Cycling
• MULTI-function: This tactical sling backpack is all-purpose and can be used for various uses. You can use it as a handbag, cross-body bag or chest bag, Six buckles are used for connecting the strap to simply switch to the other side for ambidextrous use.
• MOLLE System – The tactical sling bag is equipped with a MOLLE external expansion system. it can be combined with other bags and water bottles for capacity expansion or function expansion, This design enables the attachment of additional tactical pouches. 

Some reviews of this Archon Utility Tactical Sling Pack:

Truman Tuttle: This tactical sling pack was the perfect gift for my husband and he loves it. Zippered pockets have plenty of room for notebook, pens, range accessories, etc. I cannot recommend it with higher accolade.

Corey Benson: The size is perfect. It's made of high quality materials and great craftsmanship. I never needed to set the bag down to eat, use the phone, or while climbing or carrying other items.. great casual day bag. It’s compact but holds a ton of stuff and it is really great quality for an affordable price. Highly recommend it.

7. Blackhawk Pro Tactical Backpack - Best Tactical Backpacks of 2020

Features of Blackhawk Pro Tactical Backpack:

• 900D Waterproof oxford cloth
• Product dimensions: 11''x18''x12''
• Shipping weight: 2.6 pounds
• Capacity: 36L-55L
• Use for: Travel Handbag/Outdoor Mountaineering Backpack/Shoulder pack
• The molle tactical backpack has a molle system, Molle webbing throughout for attaching additional tactical pouches.
• Assault pack backpack with double-stitched, Heavy duty zippers and utility-style cord pull, Side and front load compression system, Ventilated mesh padded back area & shoulder strap, breathable and comfortable.
• Military backpack has hydration compatible that works great for a hydration bladder (backpack didn't include hydration bladder) as a hydration backpack or outdoor camping hiking backpack.

Some reviews of this Blackhawk Pro Tactical Backpack:

Hilary Sandy: Well Built, Versatile Backpack! I purchased this 34L Molle Bag and it is perfect. I use it for a daily bag to carry a EDC pack, laptop and rain gear for my work bag. Men will find this pack to be very adequate for most of their outdoor, range, bug-out, or work needs, yet women, teens and even older children will find this pack easy to carry over long hikes, to school, work, etc. I highly recommend the Blackhawk Elite Pro Outdoor Tactical Backpack.

Marshall Marshall: This military backpack is amazing. It can be used as a 3-day assault pack backpack, range bag, hunting backpack, survival backpack, army backpack, trekking backpack or day pack for daily use. I bought it for for a trip for hiking. I've carried a lot of packs, backpacks too, and I've never had a pack that carries so well and fits so nice. Pros: versatility, carry capacity, looks cool walking through an airport. It seems to be made of high quality material! Very happy with this backpack.

8. Compact Modular Style Backpack - Best Tactical Backpacks of 2020

Compact Modular Style Backpack: It is a highly functional pack for both urban and outdoor environments. Main compartment with contour shaped zipper for the benefit of top load and clamshell opening options. New sleek & discreet appearance blends in with the urban setting without notice. Large main compartment features easy access clamshell design with generous 50 liter capacity that provides ample storage options to safely & securely stow your mission essential gear.

Features of Compact Modular Style Backpack:

• Material: 900D Encryption Polyester
• 50L Capacity
• Large main compartment with gear tight down straps (22”H x 12”W x 7.5”D)
• Open-top quick access stash pocket
• Detachable rain cover with storage pocket
• Three reinforce grab handles
• Body contour shoulder strap
• Removable waist belt
• Hydration compatible (reservoir not included)

Some reviews of this Compact Modular Style Backpack:

Jack Cook: I've only had this backpack for a short time, however I already love it. The build quality on it seems really tough and well-built. Having had a number of heavy duty backpacks, i feel this one is going to last - and I really put my packs through torture. But the stitching, material thickness, the plastic/poly lining all seem awesomely built on this one...and quite lightweight for the load capacity...so, you're getting a decent pack for a pretty low price!

Jean Gregory: Amazing quality. I wanted a new backpack to use when transporting gear when camping and hunting. It has a great capacity, it is very durable and easy to use. Over all, amazing tactical backpack and would definitely recommend buying.

Emma Moulton: This backpack is absolutely amazing for the price and has so much storage. I got this bookpack for my son who loves hiking. I did not go wrong with this purchase! The quality of the bag is more than I expected! It's very spacious, and I'm sure he will use it for a very long time.

9. Atlas Rush 24 Assault Backpack - Best Tactical Backpacks of 2020

Atlas Rush 24 Assault Backpack: Made from rugged, water-resistant nylon, this pack keeps your gear secure and dry. The shoulder, sternum and waist straps adjust to provide a custom fit. The yoke system in the shoulder straps distributes weight evenly and thick padding increases comfort. Four pads on the back ventilate and support, while tacky rubber prevents the pack from jostling around when you're on the move. The spacious main storage compartments provide ample storage for big items, while smaller zippered pockets, key chain fobs and pockets with retention straps organize smaller gear. 

Features of Atlas Rush 24 Assault Backpack:

• Dimension: 19" x 13.7" x 7.9" 
• Capacity: 45L
• Small accessory pocket for flat item storage
• Velcro patch holder
• Front accessory pocket with organizer
• Side compression straps
• Side pouch fits most water bottles (bottles not included)
• Extra molles
• Hydration hose port
• Yoked style shoulder straps with adjustable sternum slider
• Padded mesh back

Some reviews of this Atlas Rush 24 Assault Backpack:

Byron Onions: great product. It has a very room main pocket, and also many small pockets for organizing things., and i love it is modular. This a great assault backpack for a full-day mission.

Carey Alerander: Very nice! I use it for traveling. It's very capacious and durable, also has many compartments. The quality is amazing. I am very happy with this purchase and highly recommends it to others.

Elroy Dillon: Definitely a great buy! I am very happy with the space and the velcro strips for patches. I love the tactical backpack for light weight abilities, great pockets and zippers, excellent storage, and shoulder and we straps! Also customer service was great!

10. RUSH24 Military Backpack - Best Tactical Backpacks of 2020

RUSH24 Military Backpack: One of the most popular tactical backpacks, the RUSH 24 Backpack is designed to hold enough gear for a full-day mission. Made from rugged, water-resistant nylon, this pack keeps your gear secure and dry. The shoulder, sternum and waist straps adjust to provide a custom fit. The yoke system in the shoulder straps distributes weight evenly and thick padding increases comfort. Four pads on the back ventilate and support, while tacky rubber prevents the pack from jostling around when you're on the move. The RUSH 24 Backpack works great for everything from everyday carry to deployment.

Features of RUSH24 Military Backpack:

• 20'' H x 12.5''  W x 8'' D
• Durable nylon construction
• Capacity: Less than 55L
• Strap ends have elastic keepers
• MOLLE-compatible webbing on the front and sides
• Main storage sections are flexible and have dividers
• This backpack has numerous options for organizing your gear, including MOLLE-compatible webbing on the sides and front, an admin organization pocket for maps and other documents, a hydration pocket, and a fleece-lined sunglasses pocket.
• The spacious main storage compartments provide ample storage for big items, while smaller zippered pockets, key chain fobs, and pockets with retention straps organize smaller gear. 

Some reviews of this Atlas Rush 24 Assault Backpack:

Judith Giles: Excellent Tactical Backpack. This tactical backpack is exactly what I was looking for! The backpack is extremely functional and well designed. It has a ton of nice pockets and pouches, everything is adjustable. Really high quality bag.

Sebastian Nixon: Recommended! My boyfriend is really like this tactical backpack. Very cool backpack, excellent quality, roomy, It can fit so much stuff and feels comfortable to haul around.

Bertram Housman: Very impressed! This tactical pack is huge inside. It's not heavy at all. I really like the detachable pockets. Material is super tough. It absolutely can be used as a military backpack. I can’t wait to go hiking with it.

These are the Best tactical backpacks of 2020 at Tactical World Store. Tactical World Store offers high quality (well-constructed, well designed) Military Tactical Backpacks for Law enforcement, the armed forces, outdoorsmen, rescue workers and more. With their military-inspired design, waterproof, flexibility, and ability to haul just about anything you might need. According to the buying guide to pick the perfect one for your need.

Abstract: Recently, a scientist team from the University of California has released their research, which shows that stem cell-based gene therapy can be efficient in treatment of X-linked chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a very rare, life-threatening primary immunodeficiency with the most common type of it being X-linked chronic granulomatous disease (X-CGD), which accounts for 60% - 65% of all types.

Patients with the disease often have a family history, and their parents are mostly married to close relatives. X-CGD mostly affects men, and women are usually carriers of the mutated gene. The main clinical symptom is juvenile onset (mostly within 2 years old, a few can be as late as 10 years old), often manifested by repeated attacks of fatal bacterial or fungal infections, which mainly occur in lymph nodes, subcutaneous tissues, lungs, liver, and gastrointestinal tract. Excessive inflammatory reactions gradually form granulomas, leading to enteritis, obstruction of the genital tract, and chronic wound healing.

X-CGD is caused by a mutation in CYBB gene, leading to difficulty in encoding the gp91phox protein, an important component of the NADPH oxidase complex. And this complex is necessary to respiratory bursts that can effectively kill ingested microorganisms. Due to this kind of mutations, specific white blood cells, including neutrophils, cannot effectively remove bacteria and fungi, so patients are unable to survive severe chronic bacterial and fungal infections.

So, can it be cured? Prophylactic antibiotics and antifungal drugs in current treatment schemes cannot prevent disease progression, and the only curative method at present is allogeneic hematopoietic stem cell transplantation. Although after transplantation from donors compatible with human leukocyte antigen (HLA), the long-term survival rate of patients can reach more than 90%, identifying healthy matched bone marrow donors is difficult, and recovery from transplantation can present complications such as graft-versus-host disease, risk of infection, and transplant rejection.

On January 27, 2020, Donald Kohn‘s team from the University of California, Los Angeles, , published a research paper titled Lentiviral gene therapy for X-linked chronic granulomatous disease in the Nature Medicine.

The study performed stem cell editing therapy on 9 patients with X-CGD. 6 of these patients have now recovered and have been able to stop other antibiotic treatments, which indicates that autologous gene therapy is a very promising treatment for chronic granulomatous disease.

The researchers removed hematopoietic stem cells from patients with X-CGD and modified the cells to correct genetic mutations. The patients' own genetically modified stem cells were then transplanted back into their own bodies. These stem cells are now capable of producing white blood cells, which in turn produce chemicals that enhance immunity.

"With this gene therapy, you can use the patient's own stem cells instead of donor cells for transplantation.” Commented by a specialist in Creative Biolabs, a company providing top-notch service for stem cell therapy development, “This means that these cells match the patient perfectly and should be a safer transplant without the risk of immune rejection.”

The 9 patients in the study ranged in age from 2 to 27 years. 4 of them were treated at Great Ormond Street Children's Hospital in London, and 5 were treated in the United States. In this study, 2 people died of severe infections within three months of receiving treatment because they had severe infections before they received gene therapy. 7 surviving patients were followed up for 12 to 36 months after receiving stem cell-based gene therapy. No new infections associated with chronic granulomatosis have occurred in all, and 6 of 7 have been able to stop prophylactic antibiotics that are commonly used.

Since the publication of the paper, 4 more patients have been treated. All patients are currently free of new infections and complications associated with chronic granulomas.

It is reported that Donald Kohn's team will work with US and European regulators to conduct larger clinical trials to further study the effectiveness of this innovative therapy. They also plan similar treatments for other types of chronic granulomatous disease caused by leukocyte protein deficiency.

SARS-CoV-2(2019-nCoV) is a single-stranded RNA coronavirus with a genome sequence of 29903bp. The genome has 10 genes and can efficiently encode 10 proteins. It can cause respiratory infections. Due to the rapid development of the epidemic, timely and effective diagnosis of patients with different degrees of clinical symptoms and suspected patients is needed. The detection of the SARS-CoV-2 RNA can provide direct evidence for diagnosis, and antigen / antibody detection can be used as supplementary evidence.

1. SARS-CoV-2 (2019-nCoV) nucleic acid detection

Currently, the sites targeted by new coronavirus nucleic acid detection mainly include three conserved gene sequences in the viral genome, namely the open reading frame 1ab (ORF1ab), the Nucleocapsid protein (N) gene, and the envelope protein (E) gene as a detection target. To confirm that a case is positive in the laboratory, two specific targets of ORF1ab and N genes of the new coronavirus in the same specimen should be confirmed to be positive by real-time fluorescence RT-PCR. If limited by a laboratory test kit, and only one target can be tested, at least the ORF1ab region of the SARS-CoV-2 (2019-nCoV) that is most conserved and specific should be tested.

1. SARS-CoV-2 (2019-nCoV) antigen detection

The novel coronavirus gene encodes multiple structural proteins, such as N protein, E protein, and S protein. These proteins include multiple epitopes. Based on the principle of specific binding of antigens to antibodies, the presence of antigens can be detected directly by antibodies, thereby directly proving the sample contains a new coronavirus. The applicable sample type of the antigen detection reagent is generally a sample of the infection site, such as a throat swab.

1. SARS-CoV-2 (2019-nCoV) antibody detection

The above-mentioned antigens of the novel coronavirus can be used as immunogens. After the virus infects the human body, it stimulates plasma cells to produce specific antibodies. By the principle of specific binding of antigens and antibodies, the presence of antibodies can be detected through the antigen, thereby indirectly proving that the human body is infected by novel coronavirus. The applicable sample types for antibody detection reagents are blood, including serum, plasma, and whole blood.

The antibodies detected are mainly divided into IgM and IgG. There is currently no systematic study on the production and duration of these two types of antibodies to novel coronaviruses. Generally, IgM antibodies are produced early, and they are produced quickly after infection, with a short maintenance time and rapid disappearance. Positive detection in blood can be used as an indicator of early infection. IgG antibodies are produced late, are maintained for a long time, and disappear slowly. Positive tests in the blood can be used as indicators of infection and previous infections.

1. Analysis of different detection methods

New virus RNA testing provides direct evidence for diagnosis. In view of the characteristics and current status of antigen / antibody detection reagents, their sensitivity and specificity are currently limited and cannot be used as the sole basis for the diagnosis and exclusion of SARS-CoV-2 (2019-nCoV). It is not suitable for screening in the general population and can only be used as a supplement to existing viral nucleic acid detection reagents.

Through the combined application of multiple detection methods of nucleic acids, antigens, and antibodies, the detection window period is shortened, and the positive detection rate is improved. It has a very important role in the auxiliary diagnosis of the SARS-CoV-2 (2019-nCoV).

The first: glycolipid

Glycolipids are lipid compounds containing ester compounds, a class of amphiphilic molecules that widely exist in organisms.

Classification: 

According to the lipid component, lipids can be divided into four types:

(1) glycosphingolipid containing sphingosine;

(2) glycosylacylglycerid containing grease;

(3) glycolipids derived from dolichol phosphate;

(4) steroid-derived glycolipids

Let's focus on glycosylacylglycerid and glycosphingolipid next. Glycosylacylglycerid’s sugar base structure is similar to phosphatide acyl glycerin, main chain is glycerin, containing the fatty acids, but not the chemical compounds such as phosphorous and choline. Glycerol lipids have many biological traits, such as antioxidant, antiviral, antibacterial, anti-tumor, anti-inflammation, anti-atherosclerosis and so on, and are found in nerve tissues, plants and microorganisms of animals

 Glycosphingolipids are derived from ceramides. The fatty acids are attached to the c-2 amino group of the long chain of sphingoamol. Glycosphingolipids containing one or more neutral glycosyls as polar heads are called neutral glycosphingolipids. As a component of cell membrane, glycolipids play an important role in cell adhesion, growth, differentiation, signaling and other processes. It’s also meaningful for glycomic profiling.

The second: N-glycan

As for N-glycan profiling, it’s necessary to introduce N-linked glycosylation consists of N- sugar synthesis, transfer and modification. It is a co-translation or post-translational modification of a new peptide chain by which the sugar chain passes a specific asparagine. So this glycosylation is called N- glycosylation. The process of N- glycosylation was performed in Endoplasmic reticulum (ER) and Golgi apparatus (GA).

Synthesis: The synthesis of N - sugar began in endoplasm omentum cytoplasmic side, formed after the dolichol phosphorylation activation state. Under the action of the glycosyl transferase ALG7 and ALG13/14, GlcNAc link to the dolichol. Then after the ALG1, ALG2 and ALG11 plus the five mannose  molecules, through Flipase transferred to the endoplasmic reticulum cavity side. Under the action of a series of glycosyltransferases (ALG3, ALG9, ALG12, ALG9, ALG6, ALG8, ALG10) in the endoplasmic reticulum, a oligosaccharide chain with 2 molecules of n-acetylglucosamine, 9 molecules of mannose and 3 molecules of glucose was formed, thus, antenna structure of a, b and c three claws was formed

Transfer: N - glycan decoration is a part of the nascent peptide chain through oligosaccharide base transferase (oligosaccharyltransferase, OST) complex. The glycosyl transferase is a more complex, in yeast by Wbp1p, Stt3p, Ost1p, Swp1p, Ost1p, Ost4p, Ost5p and Ost3p/Ost6p, responsible for the synthesis of oligosaccharides in the chain transfer to the nascent peptide chain specific asparagine (N - X - S/T and X! = P). OST is relatively conservative in eukaryotes and has homologous proteins in mammalian cells and arabidopsis thaliana

Modification: Modification of the sugar chain in the endoplasmic reticulum involves the removal of the terminal 3 molecules of glucose

The terminal mannose of b branch and b branch, after entering the endoplasmic reticulum, forms n-sugar chain of complex type, hybrid type and high mannose type after cutting and processing various glycosyltransferases and glycosidases. In plants, complex sugars and hybrid sugars the second n-acetylglucosamine is also linked to a xylose, forming a complex n-sugar type characteristic of plants.

Function: According to the current research results, it can be determined that the N- glycosylation modification of protein plays an important role in the process of protein folding, transportation and other processes. More specific relevant studies on N-glycan analysis need to be further studied.

The third: O-Glycan

O-Glycan profiling is different from N-glycan profiling. O-linked glycosylation is the transfer of the sugar chain to the oxygen atoms of serine, threonine, or hydroxyl lysine of the polypeptide chain. O-linked glycosylation is catalyzed by different glycosyltransferases, with one monosaccharide added at a time. As with complex n-linked glycosylation, the final step is to add sialic acid residues, which occur in the golgi body anti-mask capsule and TGN.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can damage multiple organs and tissues such as kidney, cardiovascular, respiratory system, digestive system, blood system,  and eyes, with an increasing death risk in patients.

It’s reported that SLE affects over 5 million people worldwide, 90% of whom are female. An Increased expression of interferon-induced genes is observed in 60% to 80% of adult patients, which results in the overproduction of the immune protein type I interferon. Human type I interferons that can fight against cancer and modulate immune system include IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω, all of which share a group of receptor complexes on the cell surface, the IFNα/β receptor, including two transmembrane protein subunits, IFNAR1 and IFNAR2. Both are essential for the functional realization of type I interferons.

As is known, SLE still remains incurable and current treatments only achieve a disease remission. According to European League Against Rheumatism (EULAR) 2019, the goal of treatment of SLE is to relieve disease symptoms and reduce disease relapse. At the same time, the toxic side effects of drugs should be controlled, thereby reducing the cumulative damage to tissues and organs and improving the life quality of patients.

Commonly used drugs for SLE mainly include glucocorticoids, immunosuppressive agents, antimalarials and non-steroidal anti-inflammatory drugs. The traditional drugs for SLE treatment usually have drug toxicity that may lead to liver damage, bone marrow suppression, etc. Fortunately, the novel immunotherapy that utilizes various monoclonal antibodies, such as rituximab and bevacizumab, turns out to be a promising solution.

Rituximab is a human-mouse chimeric monoclonal antibody against CD20 of B lymphocytes that effectively removes dysplastic B lymphocytes in vivo. The American Rheumatism Association (ARA) Guideline has recommended that rituximab may be considered in patients with LN whose nephritis has not improved or even worsened after 6 months of induction therapy, or in patients who have failed both cyclophosphamide (CTX) and mycophenolate mofetil (MMF).

Belimumab, the first new drug approved during the last 50 years for the treatment of systemic lupus erythematosus, is a monoclonal antibody drug that binds to and inhibits a protein called B-lymphocyte stimulating factor (BLyS), and blocking BLyS can cause B cells to self-destroy and stop the body's immune system from attacking its own tissues. Belimumab reduces the number of abnormal B lymphocytes that make the immune system produce cells to mistakenly attack blood vessels and other healthy tissues.

Recently, another novel drug, called anifrolumab, has been proved effective to treat SLE in an international phase III trial called TULIP 2 to evaluate the role of anifrolumab in reducing disease activity. The results showed that anifrolumab contributed to a statistically and clinically significant reduction in the amount of disease activity. After 52 weeks of trial initiation, more patients in the anifrolumab treatment group achieved reducing overall disease activity in all active organs, improving lupus skin disease, decreasing steroid drug dose and flare rate per year.

There is no doubt that great progresses have been made to relieve the symptoms of SLE during last decades. However, a more effective and curable method is still in need for patients suffering from SLE.

Introduction

Peptide synthesis is a solid phase synthesis process generally from the n-terminal (amino terminal) to the c-terminal (carboxyl terminal) synthesis. In the past it was carried out in solution called liquid phase synthesis.  in 1963, Merrifield proposed solid-phase peptide synthesis (SPPS). The process of synthesis was convenient, rapid so that it became the preferred method and brought about a revolution of the peptides in organic synthesis. Afterwards through continuous improvement and efforts, today solid-phase method has become a common technique in peptide and protein synthesis while showing unparalleled advantages compared with the classic liquid phase synthesis. For example, greatly reducing the difficulty of purifying product in each step.

The synthesis of cyclic peptides

Development

Nowadays, according to different requirements of customers, such as sequence, purity, molecular weight, etc., polypeptides can be processed and synthesized to meet these specific needs. This is custom peptide synthesis which is a type of peptide synthesis service.

Customized synthesized peptide is crucial to a great number of fields，so let’s have a look .

Application Fields

Peptide synthesis service and custom peptide synthesis service mainly include these three aspects :

1. Peptide Synthesis
2. Peptide Modifications
3. Peptide Library Services

In fact, peptide synthesis service is much closer to our real-life situation than we imagined. Here are some examples:

Cancer immunotherapy: Cancer immunotherapy uses the body’s own immune system to attack cancer cells. Peptide-based vaccines use tumor-associated antigens that associate with T cells to target cancer.

Self-assembling peptide: Self-assembling peptides are short, synthetic peptides characterized by amphipathic sequences. These peptides are able to spontaneously self-assemble in aqueous solution to form highly organized structures such as hydrogels.

Peptide Venom Peptides: Bioactive peptides are the most dominant component of animal venoms. Venom peptides can vary in length and complexity, thus their synthesis requires a combination of chemical and recombinant synthesis.

Peptide Natriuretic Peptides: Functioning in the induction of natriuresis, (the excretion of large amounts of sodium in the urine), natriuretic peptides have been touted as useful biomarkers for the purpose of personalized heart failure treatments and are involved in maintaining heart pressure and volume, as well as regulating cardiovascular remodeling pathways.

Neurodegenerative Disease Peptides: A pathological hallmark of neurodegenerative diseases is the abnormal aggregation of extracellular or intracellular peptides and proteins such as beta amyloid, tau, prions, and polyQ-hHtt. Custom peptides can be used to study aggregation, and develop aggregative inhibitors and vaccines.

Antimicrobial Peptides: The prevalence of antibiotic-resistant microbes continues to hinder the treatment of a variety of diseases. Custom peptides can be used to develop intelligently designed antimicrobial drugs

Milk-derived peptide therapies: Nutrition aside, milk has gained recognition as a rich source of potentially therapeutic proteins and peptides that have a variety of functions, such as antimicrobial, antiviral, antioxidant, immunostimulant, and anti-hypertension activities.

Summary

The development of semi-automatic and automatic peptide synthesizer has brought the technology of peptide and protein synthesis to a peak. So far, people have achieved the synthesis of linear polypeptides composed of hundreds of amino acids (or more) and the yield is quite high. As the exploration of the life phenomenon and protein function becomes deeper and deeper, with the growing demand for a variety of functional materials, people pay more attention to special shapes and features of peptides such as cyclic peptide, peptide, peptide sample library, etc.