Genome editing for primary immunodeficiencies: A therapeutic perspective on Wiskott-Aldrich syndrome

Primary immunodeficiency diseases (PIDs) are a group of rare inherited disorders affecting the immune system that can be conventionally treated with allogeneic hematopoietic stem cell transplantation and with experimental autologous gene therapy. With both approaches still facing important challenges, gene editing has recently emerged as a potential valuable alternative for the treatment of genetic disorders and within a relatively short period from its initial development, has already entered some landmark clinical trials aimed at tackling several life-threatening diseases. In this review, we discuss the progress made towards the development of gene editing-based therapeutic strategies for PIDs with a special focus on Wiskott - Aldrich syndrome and outline their main challenges as well as future directions with respect to already established treatments

Role of arbuscular mycorrhizal fungi in phytoremediation of heavy metals and effects on growth and biochemical activities of wheat (Triticum aestivum L.) plants in Zn contaminated soils

The increase of metals pollution in soil is a worldwide problem that affects the health of humans and environment. The use of green technology such as phytoremediation is one of the environmental friendly techniques, in which plants and other microbes are used to reduce the level of metals contaminants in soil and lower its uptake towards plants tissues. Studies report that a number of cereal crops such as wheat accumulates heavy metals in their tissues at higher concentrations. In the present study, we investigated the effect of arbuscular mycorrhizal fungi (AMF) on wheat plants with the increase of three different zinc (Zn) concentrations (0, 100, 300 and 900 mgkg-1) in soil. After eight weeks of pot experiment, roots colonization, shoot and root biomass, growth, heavy metals contents and other biochemical parameters were assessed. The results indicate mycorrhizal inoculated (M) plants performed better at moderate Zn concentrations (300 mgkg-1). In AMF associated plants, Zn contents were lower in shoot part of plants as compared to roots. In addition, higher P contents were observed in M treated plants as compared to NM plants. The decrease of nutrient contents, growth and antioxidant enzymatic activities were found at the highest applied Zn concentrations (900 mgkg-1). Results indicate that AMF inoculum exhibit different tolerance strategies to reduce metals toxicity in host plants. The effective mycorrhizal symbiosis was observed with wheat plants and can be useful for phytostabilization of Zn contaminated soils which can play a vital role in the increase of food productivity and safety.Key words: Wheat, arbuscular mycorrhizal fungi, phosphorus, nutrient contents, antioxidant enzymes

SARS-CoV-2 Syncytium under the Radar: Molecular Insights of the Spike-Induced Syncytia and Potential Strategies to Limit SARS-CoV-2 Replication

SARS-CoV-2 infection induces non-physiological syncytia when its spike fusogenic protein on the surface of the host cells interacts with the ACE2 receptor on adjacent cells. Spike-induced syncytia are beneficial for virus replication, transmission, and immune evasion, and contribute to the progression of COVID-19. In this review, we highlight the properties of viral fusion proteins, mainly the SARS-CoV-2 spike, and the involvement of the host factors in the fusion process. We also highlight the possible use of anti-fusogenic factors as an antiviral for the development of therapeutics against newly emerging SARS-CoV-2 variants and how the fusogenic property of the spike could be exploited for biomedical applications

Double Action p-n Junction Fabrication and Investigation for Solar cell and LED Application

Today, energy is fundamental agenda of the world. For electricity energy generation, price analysis factor is most crucial as cost of energy generation is increasing day by day throughout the world. This research describes some studies on low cost device with double action p-n junction. Thin films of ITO, n-type ZnS and Zn doped GaAs (1:2) are deposited on glass substrate by RF magnetron sputtering. Spectroscopic Ellipsometer is used for optical measurements of extracts. Under illumination (AM 1.5), device acts as solar cell with PCE of 2.4%. By applying reverse bias voltage radiative recombination also takes place in active region (Eg= 2.2ev) and device act as green color LED (with low band width) in wavelength range of 520-523nm. However, it is possible to improve emission capability and band width, by decreasing non-radiative recombination.

An improved medium formulation for efficient ex vivo gene editing, expansion and engraftment of hematopoietic stem and progenitor cell populations

Gene editing has emerged as a powerful tool for the therapeutic correction of monogenic diseases. CRISPR/Cas9 applied to hematopoietic stem and progenitor cells (HSPCs) has shown great promise in proof-of-principle preclinical studies to treat hematological disorders, and clinical trials using these tools are now underway. Nonetheless, there remain important challenges that need to be addressed, such as the efficiency of targeting primitive, long-term repopulating HSPCs and their in vitro expansion for clinical application. In this study, we assessed the effect of different culture medium compositions on the ability of HSPCs to proliferate and undergo homology directed repair-mediated knock-in of a reporter gene, while preserving their stemness features during ex vivo culture. We demonstrated that by supplementing the culture medium with stem cell agonists and by fine-tuning its cytokine composition it is possible to achieve high levels of gene targeting in long-term repopulating HSPCs both in vitro and in vivo, with a beneficial balance between preservation of stemness and cell expansion. Overall, the implementation of this optimized ex vivo HSPC culture protocol can improve the efficacy, feasibility and applicability of gene editing as a key step to unlocking the full therapeutic potential of this powerful technology

Serpin Inhibition Mechanism: A Delicate Balance between Native Metastable State and Polymerization

The serpins (serine proteinase inhibitors) are structurally similar but functionally diverse proteins that fold into a conserved structure and employ a unique suicide substrate-like inhibitory mechanism. Serpins play absolutely critical role in the control of proteases involved in the inflammatory, complement, coagulation and fibrinolytic pathways and are associated with many conformational diseases. Serpin's native state is a metastable state which transforms to a more stable state during its inhibitory mechanism. Serpin in the native form is in the stressed (S) conformation that undergoes a transition to a relaxed (R) conformation for the protease inhibition. During this transition the region called as reactive center loop which interacts with target proteases, inserts itself into the center of β-sheet A to form an extra strand. Serpin is delicately balanced to perform its function with many critical residues involved in maintaining metastability. However due to its typical mechanism of inhibition, naturally occurring serpin variants produces conformational instability that allows insertion of RCL of one molecule into the β-sheet A of another to form a loop-sheet linkage leading to its polymerization and aggregation. Thus understanding the molecular basis and amino acid involved in serpin polymerization mechanism is critical to devising strategies for its cure

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

Seasonal Differences in Expression of Neuropeptide Y (NPY) in Visual Centers of Spotted Munia (Lonchura punctulata)

The visual perception of birds is an incredibly exciting subject of research. Birds have significantly higher visual acuity than most other animals, which helps them stay safe in flight and detect their prey. Understanding how the eyes send information to the brain for additional processing is crucial. The brain has sections (nuclei) that accept input from the retina. The key areas where information is processed are the hyperpallium apicale (HA), hippocampus (HP), optic tectum (TeO), nucleus rotundus (RoT), and the geniculatus lateralis ventralis (Glv); among these, the RoT is one of the most investigated nuclei for vision. This study looked at how the visual centers of non-photoperiodic songbirds (Spotted Munia) adapt in different life history stages by looking at NPY expression. We immunohistochemically quantified NPY expression in four different seasons, including pre-breeding (June), breeding (September), post-breeding (December), and regressed (March) in the brain of Spotted Munia. We evaluated changes in the expression levels of the peptide throughout the year, by determining the expression at four different periods throughout the year. Peptide expression levels were projected to fluctuate within photoperiod-induced seasons. It was discovered that the parts of the brain related to vision (RoT, HA, and HP) have a higher number of immunoreactive cells during their mating season, i.e., during the summer. The appearance of NPY, a non-photic marker, in brain areas linked with light perception, was fascinating. Indirectly, NPY aids avian reproduction in a variety of ways. These findings demonstrate the importance of these nuclei in the process of reproduction, as well as the involvement of NPY in the visual brain areas of Spotted Munia

SARS-CoV-2 Syncytium under the Radar: Molecular Insights of the Spike-Induced Syncytia and Potential Strategies to Limit SARS-CoV-2 Replication

Peer reviewed: TrueSARS-CoV-2 infection induces non-physiological syncytia when its spike fusogenic protein on the surface of the host cells interacts with the ACE2 receptor on adjacent cells. Spike-induced syncytia are beneficial for virus replication, transmission, and immune evasion, and contribute to the progression of COVID-19. In this review, we highlight the properties of viral fusion proteins, mainly the SARS-CoV-2 spike, and the involvement of the host factors in the fusion process. We also highlight the possible use of anti-fusogenic factors as an antiviral for the development of therapeutics against newly emerging SARS-CoV-2 variants and how the fusogenic property of the spike could be exploited for biomedical applications