Immuno-informatics analysis predicts B and T cell consensus epitopes for designing peptide vaccine against SARS-CoV-2 with 99.82% global population coverage.

The current global pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken a substantial number of lives across the world. Although few vaccines have been rolled-out, a number of vaccine candidates are still under clinical trials at various pharmaceutical companies and laboratories around the world. Considering the intrinsic nature of viruses in mutating and evolving over time, persistent efforts are needed to develop better vaccine candidates. In this study, various immuno-informatics tools and bioinformatics databases were deployed to derive consensus B-cell and T-cell epitope sequences of SARS-CoV-2 spike glycoprotein. This approach has identified four potential epitopes which have the capability to initiate both antibody and cell-mediated immune responses, are non-allergenic and do not trigger autoimmunity. These peptide sequences were also evaluated to show 99.82% of global population coverage based on the genotypic frequencies of HLA binding alleles for both MHC class-I and class-II and are unique for SARS-CoV-2 isolated from human as a host species. Epitope number 2 alone had a global population coverage of 98.2%. Therefore, we further validated binding and interaction of its constituent T-cell epitopes with their corresponding HLA proteins using molecular docking and molecular dynamics simulation experiments, followed by binding free energy calculations with molecular mechanics Poisson-Boltzmann surface area, essential dynamics analysis and free energy landscape analysis. The immuno-informatics pipeline described and the candidate epitopes discovered herein could have significant impact upon efforts to develop globally effective SARS-CoV-2 vaccines.

An Investigation of Surface EMG Shorts-Derived Training Load during Treadmill Running.

The purpose of this study was two-fold: (1) to determine the sensitivity of the sEMG shorts-derived training load (sEMG-TL) during different running speeds; and (2) to investigate the relationship between the oxygen consumption, heart rate (HR), rating of perceived exertion (RPE), accelerometry-based PlayerLoadTM (PL), and sEMG-TL during a running maximum oxygen uptake (V˙O2max) test. The study investigated ten healthy participants. On day one, participants performed a three-speed treadmill test at 8, 10, and 12 km·h-1 for 2 min at each speed. On day two, participants performed a V˙O2max test. Analysis of variance found significant differences in sEMG-TL at all three speeds (p < 0.05). A significantly weak positive relationship between sEMG-TL and %V˙O2max (r = 0.31, p < 0.05) was established, while significantly strong relationships for 8 out of 10 participants at the individual level (r = 0.72-0.97, p < 0.05) were found. Meanwhile, the accelerometry PL was not significantly related to %V˙O2max (p > 0.05) and only demonstrated significant correlations in 3 out of 10 participants at the individual level. Therefore, the sEMG shorts-derived training load was sensitive in detecting a work rate difference of at least 2 km·h-1. sEMG-TL may be an acceptable metric for the measurement of internal loads and could potentially be used as a surrogate for oxygen consumption.

Hardware acceleration of genomics data analysis: challenges and opportunities.

The significant decline in the cost of genome sequencing has dramatically changed the typical bioinformatics pipeline for analysing sequencing data. Where traditionally, the computational challenge of sequencing is now secondary to genomic data analysis. Short read alignment (SRA) is a ubiquitous process within every modern bioinformatics pipeline in the field of genomics and is often regarded as the principal computational bottleneck. Many hardware and software approaches have been provided to solve the challenge of acceleration. However, previous attempts to increase throughput using many-core processing strategies have enjoyed limited success, mainly due to a dependence on global memory for each computational block. The limited scalability and high energy costs of many-core SRA implementations pose a significant constraint in maintaining acceleration. The Networks-On-Chip (NoC) hardware interconnect mechanism has advanced the scalability of many-core computing systems and, more recently, has demonstrated potential in SRA implementations by integrating multiple computational blocks such as pre-alignment filtering and sequence alignment efficiently, while minimizing memory latency and global memory access. This article provides a state of the art review on current hardware acceleration strategies for genomic data analysis, and it establishes the challenges and opportunities of utilizing NoCs as a critical building block in next-generation sequencing (NGS) technologies for advancing the speed of analysis.

Cerina: cognitive-behavioural therapy-based mobile application for managing GAD symptoms among Ulster University Students in Northern Ireland - a protocol for a pilot feasibility randomised controlled trial.

INTRODUCTION: University students are one of the most vulnerable populations for anxiety disorders worldwide. In Northern Ireland, anxiety disorders appear to be more common among the university student population due to the population demographics across the region. Despite the need, these students show less inclination to access the widely available on-campus well-being services and other external professional services. Digital cognitive-behavioural therapy (CBT) aims to bridge this gap between the need for psychological help and access to it. However, challenges such as limited reach, low adoption, implementation barriers and poor long-term maintenance are mainstay issues resulting in reduced uptake of digital CBT. As a result, the potential impact of digital CBT is currently restricted. The proposed intervention 'Cerina' is a scalable CBT-based mobile app with an interactive user interface that can be implemented in university settings if found to be feasible and effective. METHODS AND ANALYSIS: The study is a single-blind pilot feasibility randomised controlled trial aiming to test the feasibility and preliminary effects of Cerina in reducing Generalised Anxiety Disorder (GAD) symptoms. Participants are 90 Ulster University students aged 18 and above with self-reported GAD symptoms. They will be allocated to two conditions: treatment (ie, access to Cerina for 6 weeks) and a wait-list control group (ie, optional on-campus well-being services for 6 weeks). Participants in the wait-list will access Cerina 6 weeks after their randomisation and participants in both conditions will be assessed at baseline, at 3 (mid-assessment) and 6 weeks (postassessment). The primary outcome is the feasibility of Cerina (ie, adherence to the intervention, its usability and the potential to deliver a full trial in the future). The secondary outcomes include generalised anxiety, depression, worry and quality of life. Additionally, participants in both conditions will be invited to semistructured interviews for process evaluation. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the Ulster University Research Ethics Committee (ID: FCPSY-22-084). The results of the study will be disseminated through publications in scientific articles and presentations at relevant conferences and/or public events. TRIAL REGISTRATION NUMBER: NCT06146530.

Self-Management of Subclinical Common Mental Health Disorders (Anxiety, Depression and Sleep Disorders) Using Wearable Devices.

RATIONALE: Common mental health disorders (CMD) (anxiety, depression, and sleep disorders) are among the leading causes of disease burden globally. The economic burden associated with such disorders is estimated at $2.4 trillion as of 2010 and is expected to reach $16 trillion by 2030. The UK has observed a 21-fold increase in the economic burden associated with CMD over the past decade. The recent COVID-19 pandemic was a catalyst for adopting technologies for mental health support and services, thereby increasing the reception of personal health data and wearables. Wearables hold considerable promise to empower users concerning the management of subclinical common mental health disorders. However, there are significant challenges to adopting wearables as a tool for the self-management of the symptoms of common mental health disorders. AIMS: This review aims to evaluate the potential utility of wearables for the self-management of sub-clinical anxiety and depressive mental health disorders. Furthermore, we seek to understand the potential of wearables to reduce the burden on the healthcare system. METHODOLOGY: a systematic review of research papers was conducted, focusing on wearable devices for the self-management of CMD released between 2018-2022, focusing primarily on mental health management using technology. RESULTS: We screened 445 papers and analysed the reports from 12 wearable devices concerning their device type, year, biometrics used, and machine learning algorithm deployed. Electrodermal activity (EDA/GSR/SC/Skin Temperature), physical activity, and heart rate (HR) are the most common biometrics with nine, six and six reference counts, respectively. Additionally, while smartwatches have greater penetration and integration within the marketplace, fitness trackers have the most significant public value benefit of £513.9 M, likely due to greater retention.

Revisiting Bromohexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy.

Bromohexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structure-activity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window by rational drug design or by using a prodrug approach to exploit differences between tumour physiology and healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromohexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs.

Dihydroxylation of 4-substituted 1,2-dioxines: a concise route to branched erythro sugars.

The synthesis of 2-C-branched erythritol derivatives, including the plant sugar (+/-)-2-C-methylerythritol 2, was achieved through a dihydroxylation/reduction sequence on a series of 4-substituted 1,2-dioxines 3. The asymmetric dihydroxylation of 1,2-dioxines was examined, providing access to optically enriched dihydroxy 1,2-dioxanes 4. The synthesized 1,2-dioxanes were converted to other erythro sugar analogues and tetrahydrofurans through controlled cleavage of the endoperoxide linkage.

A concise route to branched erythrono-gamma-lactones. Synthesis of the leaf-closing substance potassium (+/-)-(2R,3R)-2,3,4-trihydroxy-2-methylbutanoate.

A series of 1,2-dioxanes 3 were ring-opened with Co(SALEN)(2) to furnish lactol regioisomers 4 and 5 (86-99% yield). The lactols were oxidized to gamma-lactones 8 and 9 (72-96% yield) and deprotected to afford the 2-C- and 3-C-alkyl and aryl branched erythrono-gamma-lactones 1, 6, and 7 (65-94% yield), including the natural plant lactone (+/-)-2-C-d-methylerythrono-1,4-lactone 1. The latter compound was treated with aqueous potassium hydroxide to afford potassium (+/-)-(2R,3R)-2,3,4-trihydroxy-2-methylbutanoate 2, which is a leaf-closing substance of Leucaena leucocephalam.

2-C-Cyclo-hexyl-2,3-O-isopropyl-idene-erythrofuran-ose.

In the title compound, C(13)H(22)O(4), the acetonide ring adopts an envelope conformation with one of the O atoms as the flap atom, whereas a twisted conformation is found for the furan-ose ring. Centrosymmetric eight-membered {⋯OCOH}(2) synthons involving the hydr-oxy H and acetonide O atoms are found in the crystal structure. These are linked into a supra-molecular chain in the a-axis direction via C-H⋯O contacts.

2,3-O-Isopropyl-idene-3-C-phenyl-erythrofuran-ose.

The title compound, C(13)H(16)O, comprises two fused five-membered rings. Each ring has an envelope conformation, with the ether O atom in the furan-ose ring, and the CMe(2) atom in the acetonide ring as the flap atoms. In the crystal, centrosymmetrically related mol-ecules associate via hydr-oxy-ether O-H⋯O hydrogen bonds and the resulting dimers are linked into a supra-molecular chain with a flattened topology via C-H⋯O(hydr-oxy) contacts, and aligned in the a-axis direction.

2-C-Phenyl-erythrono-1,4-lactone.

THE TITLE COMPOUND (SYSTEMATIC NAME: 3,4-dihydr-oxy-3-phenyl-furan-2-one), C(10)H(10)O(4), features a five-membered γ-lactone ring with an envelope conformation at the C atom carrying the hydr-oxy group without the phenyl substituent. In the crystal, supra-molecular chains mediated by O-H⋯O hydrogen bonding are formed along the a-axis direction. These are consolidated in the crystal structure by C-H⋯O contacts.

5-Bromo-spiro-[1,2-dioxane-4,4'-tricyclo-[4.3.1.1]undeca-ne]-3'-ol.

The title compound, C(14)H(21)BrO(3), comprises a seven- (C(7)) and three six-membered (1 × O(2)C(4) and 2 × C(6)) rings, and each adopts a conformation based on a chair. Stability to the mol-ecular structure is afforded by an intra-molecular O-H⋯Br hydrogen bond. In the crystal structure, mol-ecules are arranged into a helical supra-molecular chain along the b axis, linked by C-H⋯O inter-actions, where the O-atom acceptor is one of the dioxane O atoms. The crystal studied was found to be a racemic twin. The major component was present 94% of the time.

A Case of Propylthiouracil-Induced Hepatitis during Pregnancy.

A 32-year-old with no pre-existing liver disease was diagnosed with Graves' disease at week 4 of pregnancy. Thyroid-stimulating hormone was undetectable with elevated free thyroxine levels and positive thyroid receptor antibodies. She was started on a reducing regime of propylthiouracil (PTU). At week 20 in pregnancy, she became jaundiced. Initial bloods revealed: bilirubin 91 µmol/l, alanine aminotransferase 1,796 IU/l, alkaline phosphatase 200 IU/l, international normalized ratio 1.2, and albumin 33 g/l. A presumptive diagnosis of PTU-induced hepatitis was made. PTU was immediately discontinued and best supportive care instigated. Serum markers for autoimmune and viral hepatitis were negative, abdomen ultrasound, ferritin and caeruloplasmin were normal. Although her alanine aminotransferase began to fall, her bilirubin continued to rise, peaking at 378. Two weeks after PTU cessation she became thyrotoxic and was started on a reducing regime of carbimazole. Her thyroid function stabilized and liver function tests continued to improve with carbimazole stopped at week 32. Growth scans remained normal with delivery of a healthy baby at 38 weeks. This report highlights that good outcomes can be achieved in PTU-induced hepatitis in pregnancy. Patients on PTU should be warned of the potential risk of hepatic failure and advised to seek medical advice immediately if they develop jaundice.

Artemisinin and a series of novel endoperoxide antimalarials exert early effects on digestive vacuole morphology.

Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.

Design of endoperoxides with anti-Candida activity.

Broad antifungal structure-activity relationships governing epoxy-endoperoxides 2 and 3 and their parent endoperoxides 1 are reported. Their inhibitory activity against Candida albicans in conjunction with hemolytic activity and/or growth inhibition of cultured mammalian cells are reported. This information provided guidance for the further development of endoperoxide and epoxy-endoperoxides as topical antifungal agents.

Osmium catalyzed dihydroxylation of 1,2-dioxines: a new entry for stereoselective sugar synthesis.

A series of 3,6-substituted 3,6-dihydro-1,2-dioxines were dihydroxylated with osmium tetroxide to furnish 1,2-dioxane-4,5-diols (peroxy diols) in yields ranging from 33% to 98% and with de values not less than 90%. The peroxy diols were then reduced to generate a stereospecific tetraol core with R,R,S,S or "allitol" stereochemistry. The peroxy diols and their acetonide derivatives were also ring-opened with Co(II) salen complexes to give novel hydroxy ketones in 77-100% yield, including the natural sugar psicose. Importantly, preliminary work on the catalytic asymmetric ring-opening of meso-peroxy diols using the Co(II) Jacobsens's catalyst indicates that asymmetric sugar synthesis from 1,2-dioxines is possible.