Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP.

Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na+-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor's extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.

A systematic review of circulating predictive and prognostic biomarkers to aid the personalised use of radiotherapy in the radical treatment of patients with oesophageal cancer.

BACKGROUND: The availability of circulating biomarkers that are predictive of treatment response or prognostic of overall outcome could enable the personalised and adaptive use of radiotherapy (RT) in patients with oesophageal adenocarcinoma (OAC) and squamous cell carcinoma (OSCC). METHODS: A systematic review was carried out following Preferred Reporting Items for Systematic Reviews guidance. Medline, EMBASE, PubMed, Cochrane Library, CINAHL, Scopus and the Web of Science databases were searched for studies published between January 2005-February 2023 relating to circulating biomarkers evaluated in the context of neoadjuvant or definitive RT delivered for OAC/OSCC. Study quality was assessed using predefined criteria. RESULTS: A total of 3012 studies were screened and 57 subsequently included, across which 61 biomarkers were reported. A majority (43/57,75.4%) of studies were of Asian origin and retrospective (40/57, 70.2%), with most (52/57, 91.2%) biomarkers reported in the context of patients with OSCC. There was marked inter-study heterogeneity in patient populations, treatment characteristics, biomarker measurement and the cut points used to define biomarker positivity. Nevertheless, there is evidence for the prognostic and predictive value of circulating tumour DNA and numerous miRNAs in OAC and OSCC, as well as for the prognostic and predictive value of circulating levels of CYFRA21.1 in OSCC. CONCLUSIONS: There is consistent evidence for the potential predictive and prognostic value of a small number of biomarkers in OSCC and OAC, though these data are insufficient for translation to current clinical practice. Well-designed prospective studies are now required to validate their role in stratified and personalised RT treatment approaches.

One advantageous reflection of iron metabolism in context of normal physiology and pathological phases.

PURPOSE (BACKGROUND): The presented review is an updating of Iron metabolism in context of normal physiology and pathological phases. Iron is one of the vital elements in humans and associated into proteins as a component of heme (e.g. hemoglobin, myoglobin, cytochromes proteins, myeloperoxidase, nitric oxide synthetases), iron sulfur clusters (e.g. respiratory complexes I-III, coenzyme Q10, mitochondrial aconitase, DNA primase), or other functional groups (e.g. hypoxia inducible factor prolyl hydroxylases). All these entire iron-containing proteins ar e needed for vital cellular and organismal functions together with oxygen transport, mitochondrial respiration, intermediary and xenobiotic metabolism, nucleic acid replication and repair, host defense, and cell signaling. METHODS (METABOLIC STRATEGIES): Cells have developed metabolic strategies to import and employ iron safely. Regulatory process of iron uptake, storage, intracellular trafficking and utilization is vital for the maintenance of cellular iron homeostasis. Cellular iron utilization and intracellular iron trafficking pathways are not well established and very little knowledge about this. The predominant organs, which are associated in the metabolism of iron, are intestine, liver, bone marrow and spleen. Iron is conserved, recycled and stored. The reduced bioavailability of iron in humans has developed extremely efficient mechanisms for iron conservation. Prominently, the losses of iron cannot considerably enhance through physiologic mechanisms, even if iron intake and stores become excessive. Loss of iron is balanced or maintained from dietary sources. RESULTS (OUTCOMES): Numerous physiological abnormalities are associated with impaired iron metabolism. These abnormalities are appeared in the form of several diseases. There are duodenal ulcer, inflammatory bowel disease, sideroblastic anaemia, congenital dyserythropoietic anemias and low-grade myelodysplastic syndromes. Hereditary hemochromatosis and anaemia are two chronic diseases, which are responsible for disturbing the iron metabolism in various tissues, including the spleen and the intestine. Impairment in hepatic hepcidin synthesis is responsible for chronic liver disease, which is grounding from alcoholism or viral hepatitis. This condition directs to iron overload that can cause further hepatic damage. Iron has important role in several infectious diseases are tuberculosis, malaria trypanosomatid diseases and acquired immunodeficiency syndrome (AIDS). Iron is also associated with Systemic lupus erythematosus [SLE], cancer, Alzheimer's disease (AD) and post-traumatic epilepsy. CONCLUSION: Recently, numerous research studies are gradually more dedicated in the field of iron metabolism, but a number of burning questions are still waiting for answer. Cellular iron utilization and intracellular iron trafficking pathways are not well established and very little knowledge about this. Increased information of the physiology of iron homeostasis will support considerate of the pathology of iron disorders and also make available the support to advance treatment.

Evaluation of hypofractionated adaptive radiotherapy using the MR Linac in localised pancreatic cancer: protocol summary of the Emerald-Pancreas phase 1/expansion study located at Oxford University Hospital, UK.

INTRODUCTION: Online adaptive MR-guided radiotherapy allows for dose escalation to pancreatic cancer while sparing surrounding critical organs. We seek to evaluate the safety of delivering hypofractionated five-fraction, three-fraction and single-fraction MR-guided stereotactic ablative radiotherapy (SABR) to the pancreas. METHODS AND ANALYSIS: This is a single-centre three-arm phase 1 non-randomised safety study. Patients with localised pancreatic cancer will receive either 50 Gy in five (biological equivalent dose (BED10)=100 Gy), 39 Gy in three (BED10=90 Gy) or 25 Gy in a single fraction (BED10=87.5 Gy) MR-guided daily online adaptive radiotherapy. Each fractionation regimen will be assessed as independent cohorts to determine tolerability, assessed continuously using Bayesian conjugate posterior beta distributions. The primary endpoint of the study is to establish the safety of five-fraction, three-fraction and single-fraction MR-guided hypofractionation SABR in localised pancreatic cancer by assessing dose-limiting toxicities. Secondary endpoints include overall survival, progression-free survival, local control rates, overall control rate, resection rates, long-term toxicities and freedom from second-line chemotherapy. This study plans to also explore imaging and immune biomarkers that may be useful to predict outcome and personalise treatment. The trial will recruit up to 60 patients with a safety run-in. ETHICS AND DISSEMINATION: The trial is approved by the West Midlands-Black Country Research Ethics Committee 22/WM/0122. The results will be disseminated via conference presentations, peer-reviewed scientific journals and submission to regulatory authorities. The data collected for the study, including individual participant data, will be made available to researchers on request to the study team and with appropriate reason, via octo-enquiries@oncology.ox.ac.uk. The shared data will be deidentified participant data and will be available for 3 years following publication of the study. Data will be shared with investigator support, after approval of a proposal and with a signed data access agreement. TRIAL REGISTRATION NUMBER: ISRCTN10557832.

Structure of human drug transporters OATP1B1 and OATP1B3.

The organic anion transporting polypeptides OATP1B1 and OATP1B3 are membrane proteins that mediate uptake of drugs into the liver for subsequent conjugation and biliary excretion, a key step in drug elimination from the human body. Polymorphic variants of these transporters can cause reduced drug clearance and adverse drug effects such as statin-induced rhabdomyolysis, and co-administration of OATP substrates can lead to damaging drug-drug interaction. Despite their clinical relevance in drug disposition and pharmacokinetics, the structure and mechanism of OATPs are unknown. Here we present cryo-EM structures of human OATP1B1 and OATP1B3 bound to synthetic Fab fragments and in functionally distinct states. A single estrone-3-sulfate molecule is bound in a pocket located in the C-terminal half of OATP1B1. The shape and chemical nature of the pocket rationalize the preference for diverse organic anions and allow in silico docking of statins. The structure of OATP1B3 is determined in a drug-free state but reveals a bicarbonate molecule bound to the conserved signature motif and a histidine residue that is prevalent in OATPs exhibiting pH-dependent activity.

Knowledge, attitudes and practices of resident doctors and interns on safe blood transfusion practices: a survey-based study

ABSTRACT Introduction: The knowledge of clinicians regarding blood transfusion services may impact patient care and transfusion outcome. The wide variation in transfusion practices among clinicians leads to inappropriate blood product usage and jeopardizes patient safety. Hence, this survey study aimed to assess knowledge, attitude and practice among the residents and interns of safe blood transfusion. Methods: The online survey was based on self-administered questionnaires of three sections: 1. Demography; 2. Knowledge, and; 3. Attitude and Practice. One point was assigned for the correct response of each question in every section. The knowledge score was further categorized into three categories, depending on the points obtained. The participants were also divided into four groups, depending on their experience. The Kruskal-Wallis test was applied to determine the difference of knowledge and practice scores in three designated groups of residents and interns. A p-value of less than 0.05 was considered to be significant. Result: A total of 247 residents and interns participated in this study. Thirteen participants had an incomplete response. Out of 234 participants, Senior Residents (SR), Junior Residents (JR), and interns were 70, 96 and 68 participants, respectively. The knowledge scores of interns were significantly low, as compared to SRs and JRs. Practice scores of interns were also significantly low, compared to the JRs. However, most of the residents and interns (85%) were aware of the pre-transfusion testing. Conclusion: Therefore, the mandatory incorporation of the transfusion medicine subject in the undergraduate curriculum can help the young budding doctors to better implement the patient blood management.

The exclusion of anti-D alloantibody in a suspected anti-G antibody in a pregnant 28-year-old Odiya Indian woman.

The Rh-D negative pregnancy is commonly associated with alloimmunization against D-antigen. It can be prevented by anti-D prophylaxis in pregnant patients with negative results on antibody screening. Hence, it is essential to exclude alloantibody-D in the presence of multiple alloantibodies. Anti-G antibody is formed after exposure to G antigen in neonate RBCs. Blood-group discrepancy was noted in reverse grouping, and antibody-screening results were positive in our case individual, a 28-year old Odiya Indian woman. We performed antibody identification on serum specimens from this patient, which revealed the pattern of anti-D + anti-C antibody specificity. Blood-group discrepancy was solved using rr (ce/ce)-phenotype pooled cells for reverse grouping. We identified anti-G antibodies by themselves without anti-D and anti-C after performing sequential adsorption of serum with r'r' (Ce/Ce) and R2R2 (DcE/DcE) group-O RBCs in the mother, who had rr phenotype and primigravida designation. After completing antibody screening at the first antenatal check-up, we recommended prophylactic anti-D for the mother in any future pregnancies she may have.

Yoga Programme for Type 2 Diabetes Prevention (YOGA-DP): A Qualitative Study Exploring the Trial Team's Facilitators and Challenges in Conducting a Feasibility Trial in India.

BACKGROUND: In India, around 77 million people are at high risk of developing type 2 diabetes mellitus (T2DM). Yoga interventions can be effective in preventing T2DM. We conducted a feasibility randomized controlled trial (RCT) in India, and the intervention was the Yoga Programme for T2DM Prevention (YOGA-DP). This study aimed to identify and explore the facilitators and challenges in conducting the feasibility trial in India, and more specifically, to explore the perceptions and experiences of trial staff in relation to running the feasibility trial and Yoga instructors in relation to delivering the intervention. METHODS: An exploratory qualitative study was conducted at two trial sites in India (Yoga centers in New Delhi and Bengaluru). Semi-structured interviews were conducted with ten participants (six trial staff and four Yoga instructors) to explore their perceptions and experiences related to the study's aim. Data were analyzed using deductive as well as inductive logic and an interpretative phenomenological approach. RESULTS: Feasibility-trial-related facilitators were useful participant recruitment strategies and help and support received from the trial coordination center. Intervention-related facilitators were strengths of the intervention content, structure, and delivery (including materials) and competencies of Yoga instructors. Feasibility-trial-related challenges were lack of awareness about T2DM among potential participants, stigma and fear associated with T2DM among potential participants, difficulties in explaining the research and obtaining written informed consent from potential participants, expectations and demands of potential participants and control-group participants, gender and language issues in participant recruitment, other participant recruitment-related challenges, issues in participant follow-up, and issues in data collection and trial documentation. Intervention-related challenges were the limited interest of participants in Yoga, participants' time constraints on practicing Yoga, participants' health issues hindered Yoga practice, beginners' difficulties with practicing Yoga, participants' demotivation to practice Yoga at home, issues with the Yoga practice venue, confusion regarding the intervention structure, issues with intervention materials, and the incompetence of Yoga instructors. CONCLUSIONS: The perceptions and experiences of trial staff and Yoga instructors helped us to understand the facilitators and challenges in running a feasibility trial and delivering the intervention for T2DM prevention, respectively. These findings and their suggestions will be used when designing the definitive RCT for evaluating YOGA-DP's effectiveness, and may be helpful to researchers planning similar trials. TRIAL REGISTRATION NUMBER: India (CTRI) CTRI/2019/05/018893.

Leukoreduction of red blood cell units decreases dysregulatory micro RNAs during routine storage: An observational study with In-silico analysis.

BACKGROUND: Red Blood cells (RBCs) bring about harmful consequences during storage. MicroRNA (miRNA) dysregulation in stored RBCs could represent potential biomarkers of storage lesions. Although leukoreduction prevents damage to RBCs, it is uncertain whether leukoreduction of RBCs would impact the dysregulation of miRNAs during storage. This study evaluated the potential role of miRNAs for any alteration of leukoreduced (LR) and non-leukoreduced (NLR) RBCs till 21 days of storage. STUDY DESIGN AND METHODS: In this prospective study, thirty male volunteers' blood was equally divided into leukoreduced RBCs (LR) and NLR RBC (NLR) bags and stored till Day 21 at 4-60c. Selected miRNAs were quantified on Days 0 and 21. Further, bioinformatic tools were used to analyze the selected miRNAs and their predicted target genes (mRNAs) and identify the miRNA-mRNA regulatory relationships. RESULTS: A significantly higher fold change values of three miRNAs (miR-96-5p, miR-197-3p, miR-769-3p) were observed in NLR RBCs (p < .05). A significantly higher (p < .05) expression levels of miR-150-5p and miR-197-3p were observed in NLR RBCs till 21 days of storage. Further, the correlation with mRNA quantification confirmed the regulatory role of these miRNAs upon functional pathway enrichment analysis. DISCUSSION: A higher level of dysregulation of miRNAs was observed in NLR RBCs. Validation from In-Silico analysis suggested the regulatory role of miRNAs in cell apoptosis, senescence, and RBC-related signaling pathways. This indicated that stored LR RBCs would likely have better in vivo survival and function following transfusion. However, an in vivo study of miRNA in RBCs is warranted for conclusive evidence.

ACKR3-arrestin2/3 complexes reveal molecular consequences of GRK-dependent barcoding.

Atypical chemokine receptor 3 (ACKR3, also known as CXCR7) is a scavenger receptor that regulates extracellular levels of the chemokine CXCL12 to maintain responsiveness of its partner, the G protein-coupled receptor (GPCR), CXCR4. ACKR3 is notable because it does not couple to G proteins and instead is completely biased towards arrestins. Our previous studies revealed that GRK2 and GRK5 install distinct distributions of phosphates (or "barcodes") on the ACKR3 carboxy terminal tail, but how these unique barcodes drive different cellular outcomes is not understood. It is also not known if arrestin2 (Arr2) and 3 (Arr3) bind to these barcodes in distinct ways. Here we report cryo-electron microscopy structures of Arr2 and Arr3 in complex with ACKR3 phosphorylated by either GRK2 or GRK5. Unexpectedly, the finger loops of Arr2 and 3 directly insert into the detergent/membrane instead of the transmembrane core of ACKR3, in contrast to previously reported "core" GPCR-arrestin complexes. The distance between the phosphorylation barcode and the receptor transmembrane core regulates the interaction mode of arrestin, alternating between a tighter complex for GRK5 sites and heterogenous primarily "tail only" complexes for GRK2 sites. Arr2 and 3 bind at different angles relative to the core of ACKR3, likely due to differences in membrane/micelle anchoring at their C-edge loops. Our structural investigations were facilitated by Fab7, a novel Fab that binds both Arr2 and 3 in their activated states irrespective of receptor or phosphorylation status, rendering it a potentially useful tool to aid structure determination of any native GPCR-arrestin complex. The structures provide unprecedented insight into how different phosphorylation barcodes and arrestin isoforms can globally affect the configuration of receptor-arrestin complexes. These differences may promote unique downstream intracellular interactions and cellular responses. Our structures also suggest that the 100% bias of ACKR3 for arrestins is driven by the ability of arrestins, but not G proteins, to bind GRK-phosphorylated ACKR3 even when excluded from the receptor cytoplasmic binding pocket.

Site-Specific Glycation of Human Heat Shock Protein (Hsp27) Enhances Its Chaperone Activity.

Non-enzymatic posttranslational modifications are believed to affect at least 30% of human proteins, commonly termed glycation. Many of these modifications are implicated in various pathological conditions, e.g., cataract, diabetes, neurodegenerative diseases, and cancer. Chemical protein synthesis enables access to full-length proteins carrying site-specific modifications. One such modification, argpyrimidine (Apy), has been detected in human small heat shock protein Hsp27 and closely related proteins in patient-derived tissues. Thus far, studies have looked into only artificial mixtures of Apy modifications, and only one has analyzed Apy188. We were interested in understanding the impact of such individual Apy modifications on five different arginine sites within the crucial N-terminal domain of Hsp27. By combining protein semisynthesis with biochemical assays on semisynthetic Hsp27 analogues with single-point Apy modification at those sites, we have shown how a seemingly minimal modification within this region results in dramatically altered functional attributes.

Efficacy of early PET-CT directed switch to carboplatin and paclitaxel based definitive chemoradiotherapy in patients with oesophageal cancer who have a poor early response to induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial.

Background: The utility of early metabolic response assessment to guide selection of the systemic component of definitive chemoradiotherapy (dCRT) for oesophageal cancer is uncertain. Methods: In this multi-centre, randomised, open-label, phase II substudy of the radiotherapy dose-escalation SCOPE2 trial we evaluated the role of 18F-Fluorodeoxyglucose positron emission tomography (PET) at day 14 of cycle 1 of three-weekly induction cis/cap (cisplatin (60 mg/m2)/capecitabine (625 mg/m2 days 1-21)) in patients with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC). Non-responders, who had a less than 35% reduction in maximum standardised uptake value (SUVmax) from pre-treatment baseline, were randomly assigned to continue cis/cap or switch to car/pac (carboplatin AUC 5/paclitaxel 175 mg/m2) for a further induction cycle, then concurrently with radiotherapy over 25 fractions. Responders continued cis/cap for the duration of treatment. All patients (including responders) were randomised to standard (50Gy) or high (60Gy) dose radiation as part of the main study. Primary endpoint for the substudy was treatment failure-free survival (TFFS) at week 24. The trial was registered with International Standard Randomized Controlled Trial Number 97125464 and ClinicalTrials.govNCT02741856. Findings: This substudy was closed on 1st August 2021 by the Independent Data Monitoring Committee on the grounds of futility and possible harm. To this point from 22nd November 2016, 103 patients from 16 UK centres had participated in the PET-CT substudy; 63 (61.2%; 52/83 OSCC, 11/20 OAC) of whom were non-responders. Of these, 31 were randomised to car/pac and 32 to remain on cis/cap. All patients were followed up until at least 24 weeks, at which point in OSCC both TFFS (25/27 (92.6%) vs 17/25 (68%); p = 0.028) and overall survival (42.5 vs. 20.4 months, adjusted HR 0.36; p = 0.018) favoured cis/cap over car/pac. There was a trend towards worse survival in OSCC + OAC cis/cap responders (33.6 months; 95%CI 23.1-nr) vs. non-responders (42.5 (95%CI 27.0-nr) months; HR = 1.43; 95%CI 0.67-3.08; p = 0.35). Interpretation: In OSCC, early metabolic response assessment is not prognostic for TFFS or overall survival and should not be used to personalise systemic therapy in patients receiving dCRT. Funding: Cancer Research UK.

Chain-like Structures Facilitate Li+ Transport in Concentrated Aqueous Electrolytes: Insights from Ultrafast Infrared Spectroscopy and Molecular Dynamics Simulations.

Highly concentrated aqueous electrolytes have attracted attention due to their unique applications in lithium ion batteries (LIBs). However, the solvation structure and transport mechanism of Li+ cations at concentrated concentrations remain largely unexplored. To address this gap in knowledge, we employ ultrafast infrared spectroscopy and molecular dynamics (MD) simulations to reveal the dynamic and spatial structural heterogeneity in aqueous lithium chloride (LiCl) solutions. The coupling between the reorientation dynamics of the extrinsic probe and the macroscopic viscosity in aqueous LiCl solutions was analyzed using the Stokes-Einstein-Debye (SED) equations. MD simulations reveal that the Cl- and Li+ form chain-like structures through electrostatic interactions, supporting the vehicular migration of Li+ through the chain-like structure. The concentration dependent conductivity of the LiCl solution is well reproduced, where Li(H2O)2+ and Li(H2O)3+ are the dominant species that contribute to the conduction of Li+. This study is expected to establish correlations between ion pair structures and macroscopic properties.

Crystal structure of a mycobacterial secretory protein Rv0398c and in silico prediction of its export pathway.

Secretory proteins are used by pathogenic bacteria to manipulate the host systems and compete with other microorganisms, thereby enabling their survival in their host. Similar to other bacteria, secretory proteins of Mycobacterium tuberculosis also play a pivotal role in evading immune response within hosts, thereby leading to acute and latent tuberculosis infection. Prokaryotes have several classes of bacterial secretory systems out of which the Sec and Tat pathways are the most conserved in Mtb to transport proteins across the cytoplasmic membrane. Here, we report the crystal structure of a secretory protein, Rv0398c determined to 1.9 Å resolution. The protein comprises a core of antiparallel ß sheets surrounded by α helices adopting a unique ß sandwich fold. Structural comparison with other secretory proteins in Mtb and other pathogenic bacteria reveals that Rv0398c may be secreted via the Sec pathway. Our structural and in silico analyses thus provide mechanistic insights into the pathway adopted by Mtb to transport out secretory protein, Rv0398c which will facilitate the invasion to the host immune system.

A comparative evaluation of the quality of cryoprecipitate prepared from 350 ml versus 450 ml of whole blood and different methods of thawing of plasma: A prospective observational study.

INTRODUCTION: Cryoprecipitate is used in conditions like hypofibrinogenemia, massive transfusion with bleeding, and factor XIII deficiency. The current guidelines support the preparation of cryoprecipitate from 450 ml whole blood. But 350 ml of whole blood collection is expected from low body weight (<55 kg) donors. However, no standardized criteria exist for preparing cryoprecipitate from 350 ml of whole blood. AIM OF THE STUDY: This study compared the fibrinogen and factor VIII levels in cryoprecipitate units prepared from 350 ml versus 450 ml whole blood collection. The study also compared the fibrinogen and factor VIII levels prepared by circulating water bath versus blood bank refrigerator (BBR) thawing method. METHODOLOGY: A total of 128 blood bags were equally divided into groups A and B for 450 and 350 ml whole blood collection further subdivided into subgroups based on thawing methods. The fibrinogen and factor VIII yield were analyzed in the cryoprecipitates prepared from both groups. RESULTS: The factor VIII levels were significantly higher in cryoprecipitate made from 450 ml whole blood collection (P = 0.02). The BBR method of plasma thawing resulted in better fibrinogen recovery than the cryo bath method. Whereas vice versa in the case of factor VIII recovery. A weak but significant positive correlation was noted in factor VIII levels with the plasma volume. CONCLUSION: Over 75% of the cryoprecipitates prepared from 350 ml whole blood passed the fibrinogen and factor VIII quality control criteria. So, 350 ml whole blood collection from low body weight (<55 kg) donors could be utilized to prepare cryoprcipitates. However, future clinical studies should focus on the cryoprecipitate's clinical efficacy prepared from 350 ml of whole blood.

Impact of dose and storage duration of platelet concentrates on platelet recovery between ABO identical and ABO non-identical random donor platelet transfusions in hemato-oncology patients.

INTRODUCTION AND OBJECTIVES: It is challenging to adopt a policy of ABO identical platelet transfusion in hemato-oncological patients because of the high demand. Moreover, there are no global standards for the management of ABO non-identical platelet transfusions due to limited evidence. The current study compared the impact of dose and storage duration of platelets on percent platelet recovery (PPR) at 1 h and 24 h between ABO identical and ABO non-identical platelet transfusions in hemato-oncological conditions. The other objectives were to assess the clinical efficacy and compare adverse reactions between the two groups. METHODS: A total of 130 random donor platelet transfusion episodes (81 ABO identical and 49 ABO non-identical) were evaluated in 60 eligible patients with different malignant, as well as non-malignant, hematological conditions. All analysis was performed using two-sided tests, and p-values <0.05 were considered significant. RESULTS: The PPR at 1 h and 24 h was significantly higher in ABO identical platelet transfusion. Platelet recovery and survival were not affected by the gender, dose or storage duration of platelet concentrate. Aplastic anemia and myelodysplastic syndrome (MDS) disease conditions were observed to be independent risk predictors for 1-h post-transfusion refractoriness. CONCLUSION: ABO identical platelets have higher platelet recovery and survival. Both ABO identical and ABO non-identical platelet transfusions have similar efficacy in controlling bleeding episodes up to World Health Organization (WHO) grade two. Assessment of other factors, such as platelet functional properties in the donor, anti-HLA and anti-HPA antibodies, may be needed to better understand the platelet efficacy of platelet transfusions.

Structural basis for assembly and lipid-mediated gating of LRRC8A:C volume-regulated anion channels.

Leucine-rich repeat-containing protein 8 (LRRC8) family members form volume-regulated anion channels activated by hypoosmotic cell swelling. LRRC8 channels are ubiquitously expressed in vertebrate cells as heteromeric assemblies of LRRC8A (SWELL1) and LRRC8B-E subunits. Channels of different subunit composition have distinct properties that explain the functional diversity of LRRC8 currents across cell types. However, the basis for heteromeric LRRC8 channel assembly and function is unknown. Here we leverage a fiducial-tagging strategy to determine single-particle cryo-EM structures of heterohexameric LRRC8A:C channels in multiple conformations. Compared to homomers, LRRC8A:C channels show pronounced differences in architecture due to heterotypic LRR interactions that displace subunits away from the conduction axis and poise the channel for activation. Structures and functional studies further reveal that lipids embedded in the channel pore block ion conduction in the closed state. These results provide insight into determinants for heteromeric LRRC8 channel assembly, activity and gating by lipids.

Yoga Programme for Type 2 Diabetes Prevention (YOGA-DP) Among High-Risk People in India: A Multicenter Feasibility Randomized Controlled Trial.

INTRODUCTION: Many Indians are at high risk of type 2 diabetes mellitus (T2DM). The blood glucose level can be improved through a healthy lifestyle (such as physical activity and a healthy diet). Yoga can help in T2DM prevention, being a culturally appropriate approach to improving lifestyle. We developed the Yoga Programme for T2DM Prevention (YOGA-DP), a 24-week structured lifestyle education and exercise (Yoga) program that included 27 group Yoga sessions and self-practice of Yoga at home. In this study, the feasibility of undertaking a definitive randomized controlled trial (RCT) was explored that will evaluate the intervention's effectiveness among high-risk individuals in India. METHODS: A multicenter, two-arm, parallel-group, feasibility RCT was conducted in India. The outcome assessors and data analysts were blinded. Adults with a fasting blood glucose level of 100-125 mg/dL (i.e., at high risk of T2DM) were eligible. Participants were randomized centrally using a computer-generated randomization schedule. In the intervention group, participants received YOGA-DP. In the control group, participants received enhanced standard care. RESULTS: In this feasibility trial, the recruitment of participants took 4 months (from May to September 2019). We screened 711 people and assessed 160 for eligibility. Sixty-five participants (33 in the intervention group and 32 in the control group) were randomized, and 57 (88%) participants were followed up for 6 months (32 in the intervention group and 25 in the control group). In the intervention group, the group Yoga sessions were continuously attended by 32 (97%) participants (median (interquartile range, IQR) number of sessions attended = 27 (3)). In the intervention group, Yoga was self-practiced at home by 30 (91%) participants (median (IQR) number of days per week and minutes per day self-practiced = 2 (2) and 35 (15), respectively). In the control group, one (3%) participant attended external Yoga sessions (on Pranayama) for 1 week during the feasibility trial period. There was no serious adverse event. CONCLUSIONS: The participant recruitment and follow-up and adherence to the intervention were promising in this feasibility study. In the control group, the potential contamination was low. Therefore, it should be feasible to undertake a definitive RCT in the future that will evaluate YOGA-DP's effectiveness among high-risk people in India. FEASIBILITY TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI) CTRI/2019/05/018893; registered on May 1, 2019.

Tracking the Intramolecular Charge Transfer Process of 2,6-Substituted D-A BODIPY Derivatives.

Three 2,6-electron donor-substituted boron dipyrromethene (BODIPY) exhibiting an intramolecular charge transfer (ICT) character with large Stokes shift and moderate fluorescence quantum yields were designed and synthesized. Broadband femtosecond transient absorption (fs-TA) spectroscopy measurements were performed to directly detect the CT state in nonpolar or less polar solvents and the charge separation (CS) state in more polar solvents. A solid foundation for the fs-TA assignment can be found in electrolysis experiments. In addition, the ICT character of the newly designed compounds was investigated by density functional theory (DFT) calculations. Meanwhile, the reference compounds without the donor groups were synthesized, and their photophysical behaviors and ultrafast time-resolved spectra confirmed that no ICT process occurred regardless of the nature of the solvent. This work emphasizes the importance of decorating the BODIPY core with electron-donating substituents at 2,6-positions to efficiently adjust its photofunctional behaviors demonstrating the ICT character. Importantly, the photophysical processes could be easily regulated by changing the solvent with different polarities.