Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion.

Coronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5' genomic leader and upstream of each body open reading frame. In SARS-CoV-2, the TRS has the consensus AAACGAAC; upon searching for emergence of this motif in the global SARS-CoV-2 sequences, we find that it evolves frequently, especially in the 3' end of the genome. We show well-supported examples upstream of the Spike gene-within the nsp16 coding region of ORF1b-which is expressed during human infection, and upstream of the canonical Envelope gene TRS, both of which have evolved convergently in multiple lineages.

Interaction of human gut microbiota and local immune system in progression of colorectal adenoma (MIMICA-1): a protocol for a prospective, observational cohort study.

Introduction: The current understanding of colorectal carcinogenesis is based on the adenoma-carcinoma sequence, where genetics, intestinal microbiota changes and local immunity shifts seem to play the key roles. Despite the emerging evidence of dysbiotic intestinal state and immune-cell infiltration changes in patients with colorectal adenocarcinoma, early and advanced adenoma as precursors of colorectal cancer, and carcinoma as the following progression, are rather less studied. The newly colon-site adapted AI-based analysis of immune infiltrates is able to predict long-term outcomes of colon carcinoma.

Viral niche-partitioning: comparative genomics of giant viruses across environmental gradients in a high Arctic freshwater-saltwater lake.

Giant viruses (GVs; ) impact the biology and ecology of a wide range of eukaryotic hosts, with implications for global biogeochemical cycles. Here, we investigated GV niche separation in highly stratified Lake A at the northern coast of Ellesmere Island, Nunavut, Canada. This lake is composed of a layer of ice-covered freshwater that overlies saltwater derived from the ancient Arctic Ocean, and it therefore provides a broad gradient of environmental conditions and ecological habitats, each with a distinct protist community and rich assemblages of associated GVs.

Synthesis and Investigation of Peptide-Drug Conjugates Comprising Camptothecin and a Human Protein-Derived Cell-Penetrating Peptide.

Drug targeting strategies, such as peptide-drug conjugates (PDCs), have arisen to combat the issue of off-target toxicity that is commonly associated with chemotherapeutic small molecule drugs. Here we investigated the ability of PDCs comprising a human protein-derived cell-penetrating peptide-platelet factor 4-derived internalization peptide (PDIP)-as a targeting strategy to improve the selectivity of camptothecin (CPT), a topoisomerase I inhibitor that suffers from off-target toxicity. The intranuclear target of CPT allowed exploration of PDC design features required for optimal potency.

Real-world satisfaction and experience with injection and autoinjector device for ofatumumab indicated for multiple sclerosis.

Background: To evaluate the overall satisfaction, device usability, and injection experience of MS patients self-administering ofatumumab using the Sensoready autoinjector device in the United States (US).

Methods: This US-based, cross-sectional survey study included patients with MS (≥ 18 years) who self-administered ofatumumab using the Sensoready device within the previous 12 months of the survey. Eligible patients were administered a 30-item de novo questionnaire that focused on overall device satisfaction, device usability, convenience/flexibility for travel with the device, user confidence, injection experience, and time to administer the injection.

Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes.

Purpose: Corneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood.

Physiochemical and functional evaluation of the first-in-class anti-cancer IgE antibody drug, MOv18, through process development and good manufacturing practice production.

Antibodies used for cancer therapy are monoclonal IgGs, but tumor-targeting IgE antibodies have shown enhanced effector cell potency against cancer in preclinical models. Research-grade recombinant IgE antibodies have been generated and studied for several decades. The recent Phase 1 clinical trial of the first-in-class MOv18 IgE, however, necessitated the inaugural process development and scaled manufacture of a recombinant IgE to clinical quality standards.

Comparing microCT Staining and Scanning Methodology for Brain Studies in Various Sizes of Spiders.

Recent advances in microCT are facilitating the investigation of microstructures in spiders and insects leading to an increased number of studies investigating their neuroanatomy. Although microCT is a powerful tool, its effectiveness depends on appropriate tissue preparation and scan settings, particularly for soft, non-sclerotized tissues, such as muscles, organs, and neural tissues. As the application of microCT in spiders is only in its infancy, published protocols are often difficult to implement due to substantial size variation of the specimens.

Time-lapse analysis of embryos classified as euploid, mosaic, and aneuploid after embryonic trophectoderm biopsy.

Purpose: Analyze morphokinetic, morphology, and KIDscore™Day5 in different PGT-A classes, focusing on putative mosaicism level and type.

Methods: The single-center retrospective study analyzed 832 embryoscope-cultured blastocysts from cycles with at least one putative mosaic, conducted from 2020 to 2022. A P-value < 0.

Aging-Induced Discrepant Response of Fracture Healing is Initiated from the Organization and Mineralization of Collagen Fibrils in Callus.

Fracture healing is a complex process during which the bone restores its structural and mechanical integrity. Collagen networks and minerals are the fundamental components to rebuild the bone matrix in callus. It has been recognized that bone quality could be impaired during aging.

Histopathologic Progression and Metastatic Relapse Outcomes in Small Cell Neuroendocrine Carcinomas of the Urinary Tract.

Introduction: Small cell neuroendocrine carcinoma of the urinary tract (SCNEC-URO) has an inferior prognosis compared to conventional urothelial carcinoma (UC). Here, we evaluate the predictors and patterns of relapse after surgery.

Materials And Methods: We identified a definitive-surgery cohort (n = 224) from an institutional database of patients with cT1-T4NxM0 SCNEC-URO treated in 1985-2021.

Immunogenicity and vaccine efficacy of -derived extracellular vesicles as a novel vaccine candidate.

(APP) is a significant pathogen in the swine industry, leading to substantial economic losses and highlighting the need for effective vaccines. This study evaluates the potential of APP-derived extracellular vesicles (APP-EVs) as a vaccine candidate compared to the commercial Coglapix vaccine. APP-EVs, isolated using tangential flow filtration (TFF) and cushioned ultracentrifugation, exhibited an average size of 105 nm and a zeta potential of -17.

scRNA-seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with uncomplicated malaria.

Malaria causes significant morbidity and mortality worldwide, disproportionately impacting sub-Saharan Africa. Disease phenotypes associated with infection can vary widely, from asymptomatic to life-threatening. To date, prevention efforts, particularly those related to vaccine development, have been hindered by an incomplete understanding of which factors impact host immune responses resulting in these divergent outcomes.

Engineering of CRISPR-Cas PAM recognition using deep learning of vast evolutionary data.

CRISPR-Cas enzymes must recognize a protospacer-adjacent motif (PAM) to edit a genomic site, significantly limiting the range of targetable sequences in a genome. Machine learning-based protein engineering provides a powerful solution to efficiently generate Cas protein variants tailored to recognize specific PAMs. Here, we present Protein2PAM, an evolution-informed deep learning model trained on a dataset of over 45,000 CRISPR-Cas PAMs.

Influence of solvent, sex, and age on pharmacokinetic and acute behavioral effects of vaporized cannabis extract in mice.

The legalization of cannabis in several states across the US has increased the need to better understand its effects on the body, brain, and behavior, particularly in different populations. Rodent models are particularly valuable in this respect because they provide precise control over external variables. Previous rodent studies have found age and sex differences in response to injected Δ-tetrahydrocannabinol (THC), the major psychoactive component of cannabis.

Comparative study of inactivation efficacy of far-UVC (222 nm) and germicidal UVC (254 nm) radiation against virus-laden aerosols of artificial human saliva.

Virus-laden aerosols play a substantial role in the spread of numerous infectious diseases, particularly in enclosed indoor settings. Ultraviolet-C (UVC) disinfection is known to be a highly efficient method for disinfecting pathogenic airborne viruses. Recent recommendations suggest using far-UVC radiation (222 nm) emitted by KrCl* (krypton-chloride) excimer lamps to disinfect high-risk public spaces due to lower exposure risks than low-pressure (LP) mercury lamps (254 nm).

An At-labeled alpha-melanocyte stimulating hormone peptide analog for targeted alpha therapy of metastatic melanoma.

Purpose: Patients who develop metastatic melanoma have a very poor prognosis, and new treatments are needed to improve the response rates. Melanocortin-1 receptor (MC1R) is a promising target for radionuclide therapy of metastatic melanoma, and alpha-melanocyte stimulating hormone (α-MSH) peptide analogs show high affinities to MC1Rs. Because targeted alpha therapy (TAT) can be a desirable treatment for metastatic melanoma, this study aimed to develop an At-labeled α-MSH peptide analog for TAT of metastatic melanoma.

Dexamethasone Delivery via Amphiphilic, Low-swelling Hydrogels Treats Postoperative Inflammation in Cervical Spine Applications.

Anterior cervical spine surgeries are often complicated by difficulty swallowing due to local postoperative swelling, pain, scarring, and tissue dysfunction. These postoperative events lead to systemic steroid and narcotic use. Local, sustained drug delivery may address these problems, but current materials are unsafe for tight surgical spaces due to high biomaterial swelling, especially upon degradation.

The Linda Kizazi study: a comparison of morbidity and mortality from birth to 2 years between children who are HIV-unexposed and HIV-exposed, uninfected in the era of universal antiretroviral therapy.

Background: Historically, children who are HIV-exposed, uninfected (CHEU) have been found to have greater morbidity and mortality than children who are HIV-unexposed, uninfected (CHUU). To assess whether this difference persists in the era of universal antiretroviral therapy (ART), we conducted a cohort study to compare the risk of acute diarrhoea, respiratory tract infections (RTI), malaria, hospitalisation, and all-cause mortality between Kenyan CHEU and CHUU from birth to 2 years.

Methods: From December 2018 to March 2020 at Mathare North Health Centre in Nairobi, we recruited pregnant women living with HIV on ART for ≥6 months and pregnant women without HIV from the same community.

Antimicrobial efficacy of alternative root canal disinfection strategies: An evaluation on multiple working models.

Researching disinfection strategies is pivotal because effectively eliminating bacteria and their byproducts during root canal treatment (RCT) remains a challenge. This study investigated the antimicrobial efficacy of natural antimicrobial compounds, propolis (PRO) and copaiba oil-resin (COR), compared to conventional agents in Endodontics. Antimicrobials were tested against endodontic pathogens via macrodilution with standardized inoculums to determine the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC).

Adjuvant Cytotoxic Chemotherapy may not be Associated with a Survival Advantage for Resected Intrahepatic Cholangiocarcinoma.

Background: Randomized data suggest improved survival with adjuvant chemotherapy for biliary tract cancers; however, subset analyses of intrahepatic cholangiocarcinoma (IHC) show limited survival benefit. This study evaluated the impact of adjuvant chemotherapy on recurrence patterns and overall survival (OS) in patients with resected IHC.

Methods: Patients who underwent curative-intent resection for IHC were identified within a bi-institutional dataset and the National Cancer Database (NCDB).

Metagenomics: a new frontier for routine pathology testing of gastrointestinal pathogens.

Background: Accurate and comprehensive identification of enteropathogens, causing infectious gastroenteritis, is essential for optimal patient treatment and effective isolation processes in health care systems. Traditional diagnostic techniques are well established and optimised in low-cost formats. However, thorough testing for a wider range of causal agents is time consuming and remains limited to a subset of pathogenic organisms.

Consistent direction despite wavering policy: reductions in resident physician extended duration shifts over 20 years.

We examined data from 17,498 physicians-in-training who reported on 92,662 months of work over a 20 year study interval that included three major revisions to work hour limits. Extended duration shifts (≥24 hours; EDS) are much less common than they used to be. On average, first-year resident physicians (PGY1s) currently work a total of 4 EDS per year and 3 EDS per month during months in which any EDS are worked.

Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with the age at which characteristic symptoms manifest strongly influenced by inherited HTT CAG length. Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.

Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells.

Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8 T cells.