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Exome sequencing (ES) may identify and report secondary findings that are unrelated to the primary disease for which the patient underwent genetic testing, but are of potential value in patient care.In this study, we evaluated 81 American College of Medical Genetics (ACMG) medically actionable genes in 443 patients with various neurological disorders. The variants identified were classified and reported following the 2015 ACMG Standards and Guidelines for the interpretation of sequence variants and the ACMG recommendations for reporting secondary findings (v3.2).We detected a total of 17 variants in 17 patients across 9 different genes as secondary findings. Seven heterozygous variants were found in BRCA1, MSH2, and PALB2 which are part of the cancer phenotype category. Nine heterozygous variants were found in MYH7, TTN, LDLR, DSC2, and DSP which are part of the cardiovascular phenotype category. Finally, one heterozygous variant was found in TTR which is part of the miscellaneous phenotype category. Thirteen of above mentioned variants were classified as known pathogenic and four as expected pathogenic.The information collected in our study may lead to the prevention of severe morbidity and mortality and provides additional insight into the genetic background of the Serbian population. [ABSTRACT FROM AUTHOR]

A nanoplasmonic biosensor for the precise detection of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by leveraging advances in nanostructured sensing materials and highly selective monoclonal antibodies is presented. The sensor integrates plasmonic Au nanostructures optimized for surface‐enhanced Raman scattering (SERS), enhancing sensitivity through unique light interactions at the nanoscale. Coupled with exclusive antibodies that specifically target SARS‐CoV‐2 and its evolving variants, this sensor demonstrates remarkable selectivity and versatility. Validated with 270 clinical samples, it demonstrates a sensitivity of 98.9% and specificity of 100%. More importantly, the virus in nasopharyngeal swab samples collected over 3 years, marking the long‐term, large‐scale clinical validation of the nanoplasmonic biosensor for SARS‐CoV‐2 is been successfully detected. Furthermore, the integration of this sensor with face masks enables the detection of airborne SARS‐CoV‐2, highlighting its potential for routine management of coronavirus disease 2019 (COVID‐19). [ABSTRACT FROM AUTHOR]

Albinism is a phenotypically and genetically heterogeneous condition characterized by a variable degree of hypopigmentation and by ocular features leading to reduced visual acuity. Whereas numerous genotypic studies have been conducted throughout the world, very little is known about the genotypic spectrum of albinism in Africa and especially in sub‐Saharan Western Africa. Here we report the analysis of all known albinism genes in a series a 23 patients originating from Mali. Four were diagnosed with OCA 1 (oculocutaneous albinism type 1), 17 with OCA 2, and two with OCA 4. OCA2 variant NM_000275.3:c.819_822delinsGGTC was most frequently encountered. Four novel variants were identified (two in TYR, two in OCA2). A deep intronic variant was found to alter splicing of the OCA2 RNA by inclusion of a pseudo exon. Of note, the OCA2 exon 7 deletion commonly found in eastern, central, and southern Africa was absent from this series. African patients with OCA 1 and OCA 4 had only been reported twice and once, respectively, in previous publications. This study constitutes the first report of the genotypic spectrum of albinism in a western sub‐Saharan country. [ABSTRACT FROM AUTHOR]

Summary: As a consequence of continuing demand for additional capacity and higher quality data transmission, channel coding as a key component of a digital communication network has progressed from a classical single pair, point‐to‐point information theoretic application to a class of coding techniques with diverse parameters. The heterogeneous requirements of B5G/6G networks technology have made flexibility of code parameters the main desired feature while designing channel codes. Owing to this, channel coding techniques have evolved to support enabling applications that depend on different factors such as latency, reliability, energy efficiency and throughput. We review and discuss the application of new techniques, modifications in the design and construction of modern channel coding schemes, including block, convolutional, rateless and space‐time codes. Further, the error correction performance of mainstream channel decoders for LDPC, polar and turbo codes is compared and analysed for their attainable error rate. The aim of this study is to highlight the adaptability of the discussed coding schemes for the forthcoming cellular network landscape. This article also addresses the implementational challenges of high throughput, low latency and machine type communication scenarios. Moreover, some recent studies exploring the role of machine learning for optimisation of B5G/6G networks are classified and discussed. Concluding, research areas pertaining to the scalability of error control coding for next generation networking are addressed. [ABSTRACT FROM AUTHOR]

Exome sequencing (ES) has identified biallelic kinesin family member 12 (KIF12) mutations as underlying neonatal cholestatic liver disease. We collected information on onset and progression of this entity. Among consecutively referred pediatric patients at our centers, diagnostic ES identified 4 patients with novel, biallelic KIF12 variants using the human GRCh38 reference sequence, as KIF12 remains incompletely annotated in the older reference sequence GRCh37. A review of these and of 21 reported patients with KIF12 variants found that presentation with elevated serum transaminase activity in the context of trivial respiratory infection, without clinical features of liver disease, was more common (n = 18) than manifest cholestatic disease progressing rapidly to liver transplantation (LT; n = 7). Onset of liver disease was at age <1 year in 15 patients; LT was more common in this group. Serum gamma‐glutamyl transpeptidase activity (GGT) was elevated in all patients, and total bilirubin was elevated in 15 patients. Liver fibrosis or cirrhosis was present in 14 of 18 patients who were biopsied. The 16 different pathogenic variants and 11 different KIF12 genotypes found were not correlated with age of onset or progression to LT. Identification of biallelic pathogenic KIF12 variants distinguishes KIF12‐related disease from other entities with elevated GGT. [ABSTRACT FROM AUTHOR]

Piscine orthoreovirus‐1 (PRV‐1) is a prevalent agent in Atlantic salmon (Salmo salar) and the causative agent of heart and skeletal muscle inflammation (HSMI), an important disease in farmed Atlantic salmon. Investigations into the introduction and dissemination routes of PRV‐1 in a field setting have been limited. This study aimed to better understand PRV‐1 infections and HSMI‐associated mortality under field conditions. We tracked introduction and spread of PRV‐1 over one production cycle in a geographically isolated region in Norwegian aquaculture. From five sites, a total of 32 virus isolates were sequenced and genogrouped. The results indicated multiple introductions of PRV‐1 to the area, but also revealed a high level of genetic homogeneity among the virus variants. The variants differed from that of the previous production cycle at two out of three sites investigated, suggesting that synchronized fallowing can be a useful tool for preventing dissemination of PRV‐1 between generations of fish. Exposure to PRV‐1 at the freshwater stage was identified as a potential source of introduction. A low level of HSMI‐associated mortality was observed at all sites, with the onset of mortality showing some variation across PRV‐1 genogroups. However, the study highlighted the complexity of associating viral genogroups with mortality in a field setting. Overall, this study contributes valuable insights into PRV‐1 dynamics in a real‐world aquaculture setting, offering potential strategies for disease management and prevention. [ABSTRACT FROM AUTHOR]

Background and Purpose: Small‐fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337‐18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group. Methods: In this retrospective single‐center study, we analyzed the frequency of the c.76G>A and c.337‐18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database. Results: We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337‐18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database. Conclusions: The c.76G>A and c.337‐18G>C TTR gene variants are not associated with SFN. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2DM) is characterised by insulin resistance and a relative shortage of insulin secretion. Tumour necrosis factor‐α (TNF‐α) plays an important role in insulin resistance by impairing insulin signal transduction. The variants of the TNF‐α promoter region are considered to influence its transcription and are associated with the TNF‐α level. Therefore, it is worth detecting the association of the variants in the TNF‐α gene with the development of T2DM. The aim of this study was to investigate the association of five variants (rs1799964, rs1800630, rs1799724, rs1800629 and rs361525) in the TNF‐α gene promoter region with T2DM in a Chinese Han population. A total of 713 subjects with T2DM and 751 nondiabetic subjects were genotyped using the TaqMan method. The associations of the five variants with the development of T2DM were evaluated. The associations of the five variant genotypes with metabolic traits in nondiabetic subjects were analysed. Our data showed that the A allele of rs1800629 could increase the risk of developing T2DM (p =.002, OR = 1.563; 95% CI: 1.18–2.08). According to inheritance mode analysis, compared with the G/G genotype, the G/A+2A/A genotype of rs1800629 showed a risk effect on T2DM in the log‐additive mode (p =.002, OR = 1.56; 95% CI: 1.17–2.07). The haplotypes analysis identified that the rs1799724‐rs1800629CA was associated with high risk of the development of T2DM (p =.002, OR = 1.559, 95% CI: 1.173–2.072). Conversely, the rs1799724‐rs1800629CG was a protective haplotype of T2DM (p =.001, OR = 0.732, 95% CI: 0.607–0.884). Moreover, compared with the rs1799964 (T/T+C/T) genotype, the rs1799964 C/C genotype was associated with higher glycosylated haemoglobin (HbA1c) levels in nondiabetic subjects (p =.017). Our results revealed that the rs1800629 in the TNF‐α gene promoter region was associated with T2DM in a Chinese Han population. [ABSTRACT FROM AUTHOR]

This study aimed to investigate functional variants in chromosome 14 (BTA14) and its impact in genomic selection for birth weight (BW), weaning weight (WW), and yearling weight (YW) in Nellore cattle. Genetic parameter estimation and the weighted single‐step genomic best linear unbiased prediction (WssGBLUP) analyses were performed. Direct additive heritability estimates were high for WW and YW, and moderate for BW. Trait‐associated variants distributed across multiple regions on BTA14 were observed in the weighted single‐step genome‐wide association studies (WssGWAS) results, implying a polygenic genetic architecture for weight in different ages. Several genes have been found in association with the weight traits, including the CUB And Sushi multiple domains 3 (CSMD3), thyroglobulin (TG), and diacylglycerol O‐acyltransferase 1 (DGAT1) genes. The variance explained per SNP was higher in six functional classes of gene regulatory regions (5UTR, CpG islands, downstream, upstream, long non‐coding RNA, and transcription factor binding sites (TFBS)), highlighting their importance for weight traits in Nellore cattle. A marginal increase in accuracy was observed when the selected functional variants (SV) information was considered in the WssGBLUP method, probably because of the small number of SV available on BTA14. The identified genes, pathways, and functions contribute to a better understanding of the genetic and physiological mechanisms regulating weight traits in the Nellore breed. [ABSTRACT FROM AUTHOR]

Summary: Iron‐refractory iron deficiency anaemia (IRIDA) is a rare autosomal recessive disorder, distinguished by hypochromic microcytic anaemia, low transferrin levels and inappropriately elevated hepcidin (HEPC) levels. It is caused by mutations in TMPRSS6 gene. Systematic screening of 500 pregnant women with iron deficiency anaemia having moderate to severe microcytosis with no other causes of anaemia were enrolled to rule out oral iron refractoriness. It identified a final cohort of 10 (2.15% prevalence) individuals with IRIDA phenotype. Haematological and biochemical analysis revealed significant differences between iron responders and iron non‐responders, with iron non‐responders showing lower haemoglobin, red blood cell count, serum iron and serum ferritin levels, along with elevated HEPC (9.47 ± 2.75 ng/mL, p = 0.0009) and erythropoietin (4.58 ± 4.07 µ/mL, p = 0.0196) levels. Genetic sequencing of the TMPRSS6 gene in this final cohort identified 10 novel variants, including seven missense and three frame‐shift mutations, with four missense variants showing high functional impact defining the IRIDA phenotype. Structural analysis revealed significant damage caused by two variants (p.L83R and p.S235R). This study provides valuable insights into IRIDA among pregnant women in the Indian subcontinent, unveiling its underlying causes of unresponsiveness, genetic mechanisms and prevalence. Furthermore, research collaboration is essential to validate these findings and develop effective treatments. [ABSTRACT FROM AUTHOR]

In a study conducted in India, 50 Fusarium isolates were collected from pigeonpea growing regions and extensively examined for their cultural and morphological characteristics. These isolates exhibited significant variations in traits including growth rate, mycelial growth patterns, color, zonation, pigmentation, spore size, and septation. Subsequently, 30 isolates were chosen for pathogenicity testing on eight pigeonpea genotypes. Results showed distinct reactions, with four genotypes displaying differential responses (ICP8858, ICP8859, ICP8862, and BDN‐2), while ICP9174 and ICP8863 consistently exhibited resistance and ICP2376 and BAHAR remained susceptible to wilt disease. To study the interaction between Fusarium isolates and pigeonpea host differentials (HDs), an additive main effects and multiplicative interaction analysis was conducted. The majority of disease incidence variation (75.54%) was attributed to HD effects, while Fusarium isolate effects accounted for only 1.99%. The interaction between Isolates and HDs (I × HD) contributed 21.95% to the total variation, being smaller than HD but larger than I. Based on HD reactions, isolates were classified into nine variants, showing varying distributions across pigeonpea growing states, with variants 2 and 3 being prevalent in several regions. This diversity underscores the need for location‐specific wilt‐resistant pigeonpea cultivars. Furthermore, genetic analysis of 23 representative isolates, through internal transcribed spacer region of ribosomal DNA and translation elongation factor 1‐α gene sequencing, revealed three major clusters: Fusarium udum, Fusarium solani, and Fusarium equiseti. These findings hold potential for developing location‐specific wilt‐resistant pigeonpea cultivars and enhancing disease management strategies. [ABSTRACT FROM AUTHOR]

Background: Since severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was first reported in Wuhan, China, in December 2019, it has spread rapidly, and many coronavirus disease (COVID‐19) cases have occurred in Gwangju, South Korea. Viral mutations following the COVID‐19 epidemic have increased interest in the characteristics of epidemics in this region, and pathogen genetic analysis is required for infection control and prevention. Methods: In this study, SARS‐CoV‐2 whole‐genome analysis was performed on samples from patients with COVID‐19 in Gwangju from 2020 to 2022 to identify the trends in COVID‐19 prevalence and to analyze the phylogenetic relationships of dominant variants. B.41 and B.1.497 prevailed in 2020, the early stage of the COVID‐19 outbreak; then, B.1.619.1 mainly occurred until June 2021. B.1.617.2, classified as sublineages AY.69 and AY.122, occurred continuously from July to December 2021. Since strict measures to strengthen national quarantine management had been implemented in South Korea until this time, the analysis of mutations was also able to infer the epidemiological relationship between infection transmission routes. Since the first identification of the Omicron variant in late December 2021, the spread of infection has been very rapid, and weekly whole‐genome analysis of specimens has enabled us to monitor new Omicron sublineages occurring in Gwangju. Conclusions: Our study suggests that conducting regional surveillance in addition to nation‐level genomic surveillance will enable more rapid and detailed variant surveillance, which will be helpful in the overall prevention and management of infectious diseases. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome‐related coronavirus 2 (SARS‐CoV‐2) seriously threatens public health and safety. Genetic variants determine the expression of SARS‐CoV‐2 structural proteins, which are associated with enhanced transmissibility, enhanced virulence, and immune escape. Vaccination is encouraged as a public health intervention, and different types of vaccines are used worldwide. However, new variants continue to emerge, especially the Omicron complex, and the neutralizing antibody responses are diminished significantly. In this review, we outlined the uniqueness of SARS‐CoV‐2 from three perspectives. First, we described the detailed structure of the spike (S) protein, which is highly susceptible to mutations and contributes to the distinct infection cycle of the virus. Second, we systematically summarized the immunoglobulin G epitopes of SARS‐CoV‐2 and highlighted the central role of the nonconserved regions of the S protein in adaptive immune escape. Third, we provided an overview of the vaccines targeting the S protein and discussed the impact of the nonconserved regions on vaccine effectiveness. The characterization and identification of the structure and genomic organization of SARS‐CoV‐2 will help elucidate its mechanisms of viral mutation and infection and provide a basis for the selection of optimal treatments. The leaps in advancements regarding improved diagnosis, targeted vaccines and therapeutic remedies provide sound evidence showing that scientific understanding, research, and technology evolved at the pace of the pandemic. [ABSTRACT FROM AUTHOR]

Aim: To investigate the evolution of clinical symptoms of COVID‐19 in children throughout the pandemic. Methods: In this national prospective surveillance study, symptoms in children hospitalised with COVID‐19 were collected from all paediatric hospitals in Switzerland between March 2020 and March 2023. Data was analysed across four time periods, according to the predominantly circulating SARS‐CoV‐2 variant: T1 (wild‐type), T2 (Alpha), T3 (Delta) and T4 (Omicron), as well as by age group. Results: The study included 1323 children. The proportion of children admitted to an intensive care unit remained stable throughout the pandemic. However, the pattern and frequency of clinical manifestations changed over time. Respiratory symptoms were less prevalent during T1 (wild‐type), fever during T2 (Alpha) and rash during T4 (Omicron). In contrast, fever and neurological symptoms were more prevalent during T4 (Omicron). Newly described symptoms during T4 (Omicron) included conjunctivitis, laryngotracheitis and seizures. Fever was more prevalent among neonates and infants whereas respiratory symptoms were more common among infants. Gastrointestinal symptoms were more frequent among toddlers, while both toddlers and school‐aged children presented with neurological symptoms more often than other age groups. Conclusion: Continuous surveillance is required to detect changes in manifestations and there by be prepared for the optimal management of complications in children with COVID‐19. [ABSTRACT FROM AUTHOR]

Over 70,000 DNA lesions occur in the cell every day, and the inability to properly repair them can lead to mutations and destabilize the genome, resulting in carcinogenesis. The base excision repair (BER) pathway is critical for maintaining genomic integrity by repairing small base lesions, abasic sites and single‐stranded breaks. Monofunctional and bifunctional glycosylases initiate the first step of BER by recognizing and excising specific base lesions, followed by DNA end processing, gap filling, and finally nick sealing. The Nei‐like 2 (NEIL2) enzyme is a critical bifunctional DNA glycosylase in BER that preferentially excises cytosine oxidation products and abasic sites from single‐stranded, double‐stranded, and bubble‐structured DNA. NEIL2 has been implicated to have important roles in several cellular functions, including genome maintenance, participation in active demethylation, and modulation of the immune response. Several germline and somatic variants of NEIL2 with altered expression and enzymatic activity have been reported in the literature linking them to cancers. In this review, we provide an overview of NEIL2 cellular functions and summarize current findings on NEIL2 variants and their relationship to cancer. [ABSTRACT FROM AUTHOR]

Calmodulin‐binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long‐term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift‐7, nonsense‐6, splicing‐1, initiation codon‐1, missense‐5, and intragenic deletions‐3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait, hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under‐reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals. [ABSTRACT FROM AUTHOR]

Background: Alport syndrome (AS) is a genetically heterogeneous disorder resulting from mutations in the collagen IV genes COL4A3, COL4A4, and COL4A5. The genetic diagnosis of AS is very important to make precise diagnosis and achieve optimal outcomes. Methods: In this study, 16 Chinese families with suspected AS were recruited after pedigree analysis, and the clinical presentations were analyzed by a nephrologist. The genetic diagnosis was performed by whole‐exome sequencing (WES) and the disease‐causing variants were confirmed by Sanger sequencing. Results: The cohort of probands included seven men and nine women, with a mean age of 19.9 years. Pathological analysis showed slight‐to‐moderate mesangial proliferation, and thin basement membrane was the main findings. Pathogenic variants were revealed by WES in each family, and the co‐segregation with renal presentation was confirmed by PCR. In addition, RT‐PCR analysis showed that the intronic variant led to aberrant splicing. Conclusion: Our findings expand the spectrum of AS gene variation, which will inform genetic diagnosis and add to the theoretical basis for the prevention of AS. Pathogenic variants were revealed by WES in each family, and the co‐segregation with renal presentation was confirmed by PCR. Our findings expand the spectrum of gene variation. [ABSTRACT FROM AUTHOR]

Invasive lobular carcinoma (ILC) is a special breast cancer type characterized by noncohesive growth and E‐cadherin loss. Focal activation of P‐cadherin expression in tumor cells that are deficient for E‐cadherin occurs in a subset of ILCs. Switching from an E‐cadherin deficient to P‐cadherin proficient status (EPS) partially restores cell–cell adhesion leading to the formation of cohesive tubular elements. It is unknown what conditions control EPS. Here, we report on EPS in ILC metastases in the large bowel. We reviewed endoscopic colon biopsies and colectomy specimens from a 52‐year‐old female (index patient) and of 18 additional patients (reference series) diagnosed with metastatic ILC in the colon. EPS was assessed by immunohistochemistry for E‐cadherin and P‐cadherin. CDH1/E‐cadherin mutations were determined by next‐generation sequencing. The index patient's colectomy showed transmural metastatic ILC harboring a CDH1/E‐cadherin p.Q610* mutation. ILC cells displayed different growth patterns in different anatomic layers of the colon wall. In the tunica muscularis propria and the tela submucosa, ILC cells featured noncohesive growth and were E‐cadherin‐negative and P‐cadherin‐negative. However, ILC cells invading the mucosa formed cohesive tubular elements in the intercryptal stroma of the lamina propria mucosae. Inter‐cryptal ILC cells switched to a P‐cadherin‐positive phenotype in this microenvironmental niche. In the reference series, colon mucosa infiltration was evident in 13 of 18 patients, one of which showed intercryptal EPS and conversion to cohesive growth as described in the index patient. The large bowel is a common metastatic site in ILC. In endoscopic colon biopsies, the typical noncohesive growth of ILC may be concealed by microenvironment‐induced EPS and conversion to cohesive growth. [ABSTRACT FROM AUTHOR]

Complement inhibition has shown promise in various disorders, including COVID‐19. A prediction tool including complement genetic variants is vital. This study aims to identify crucial complement‐related variants and determine an optimal pattern for accurate disease outcome prediction. Genetic data from 204 COVID‐19 patients hospitalized between April 2020 and April 2021 at three referral centres were analysed using an artificial intelligence‐based algorithm to predict disease outcome (ICU vs. non‐ICU admission). A recently introduced alpha‐index identified the 30 most predictive genetic variants. DERGA algorithm, which employs multiple classification algorithms, determined the optimal pattern of these key variants, resulting in 97% accuracy for predicting disease outcome. Individual variations ranged from 40 to 161 variants per patient, with 977 total variants detected. This study demonstrates the utility of alpha‐index in ranking a substantial number of genetic variants. This approach enables the implementation of well‐established classification algorithms that effectively determine the relevance of genetic variants in predicting outcomes with high accuracy. [ABSTRACT FROM AUTHOR]

The recurrent multiwave nature of coronavirus disease 2019 (COVID‐19) necessitates updating its symptomatology. We characterize the effect of variants on symptom presentation, identify the symptoms predictive and protective of death, and quantify the effect of vaccination on symptom development. With the COVID‐19 cases reported up to August 25, 2022 in Hong Kong, an iterative multitier text‐matching algorithm was developed to identify symptoms from free text. Multivariate regression was used to measure associations between variants, symptom development, death, and vaccination status. A least absolute shrinkage and selection operator technique was used to identify a parsimonious set of symptoms jointly associated with death. Overall, 70.9% (54 450/76 762) of cases were symptomatic with 102 symptoms identified. Intrinsically, the wild‐type and delta variant caused similar symptoms among unvaccinated symptomatic cases, whereas the wild‐type and omicron BA.2 subvariant had heterogeneous patterns, with seven symptoms (fatigue, fever, chest pain, runny nose, sputum production, nausea/vomiting, and sore throat) more frequent in the BA.2 cohort. With ≥2 vaccine doses, BA.2 was more likely than delta to cause fever among symptomatic cases. Fever, blocked nose, pneumonia, and shortness of breath remained jointly predictive of death among unvaccinated symptomatic elderly in the wild‐type‐to‐omicron transition. Number of vaccine doses required for reducing occurrence varied by symptoms. We substantiate that omicron has a different clinical presentation compared to previous variants. Syndromic surveillance can be bettered with reduced reliance on symptom‐based case identification, increased weighing on symptoms predictive of death in outcome prediction, individual‐based risk assessment in care homes, and incorporating free‐text symptom reporting. [ABSTRACT FROM AUTHOR]

Background and Aim: In late 2021, the world faced the rapid spread of the SARS‐CoV‐2 Omicron variant, which quickly became the variant of concern. In April 2022, two new lineages of Omicron (BA.4/BA.5) emerged from Africa, where they caused the fifth wave of infection. Method: We searched PubMed, Google Scholar, and Scopus online databases up to December 2023 for founding relevant studies. Results: BA.4 and BA.5 subgroups, with changes in the spike protein, have a greater ability to escape from the immune system, which was possible with the help of L452R and F486V mutations. Epidemiologically, these evolving subtypes show similarities to seasonal influenza but with higher mortality rates. The symptoms of these subgroups are different from the previous types in the form of upper respiratory symptoms. Antiviral treatments, the use of antibodies such as bebtelovimab, and the development of vaccines are promising. Conclusion: Consequently, we must continue to be vigilant in our joint surveillance efforts against COVID‐19 in diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Dilated cardiomyopathy (DCM) is a major cause of heart failure and sudden cardiac death. As DCM is a genetically heterogeneous disease, genetic variants of cardiac transcription factor genes may play an important role. Transcription factor TBX20, an indispensable factor in normal heart development, is involved in the regulation of cardiac structure and function. Although the TBX20 gene is associated with the occurrence and development of DCM, the influence of genetic variants of the TBX20 gene promoter region on DCM has not been reported. Methods: We conducted a case–control study consisting of 107 DCM patients and 210 healthy controls. Genetic variants within TBX20 gene promoter region were identified using sequencing techniques and were functionally analyzed by dual‐luciferase reporting assay. Electrophoretic mobility shift assay (EMSA) was used to investigate DNA‐protein interactions. Results: In this study cohort (n = 317), we identified eight variants within TBX20 gene promoter. One novel DNA sequence variants (DSV) (g.4275G>T) and four single‐nucleotide polymorphisms (SNPs) [g.4169G>A (rs1263874255), g.4949C>T (rs1191745927), g.5114G>A (rs112076877), g.5252C>T (rs1356932911)] were identified in DCM patients, but in none of controls. Among them, the DSV (g.4275G>T) and three SNPs [g.4949C>T (rs1191745927), g.5114G>A (rs112076877) and g.5252C>T (rs1356932911)] significantly altered the transcription activity of TBX20 gene promoter by dual‐luciferase reporting assay (p < 0.05). Further, EMSA assay indicated that the DSV (g.4275G>T) and three SNPs [g.4949C>T (rs1191745927), g.5114G>A (rs112076877) and g.5252C>T (rs1356932911)] affected the binding of transcription factors. Conclusions: These data indicate that the DSV (g.4275G>T) and three SNPs [g.4949C>T (rs1191745927), g.5114G>A (rs112076877) and g.5252C>T (rs1356932911)] increase transcription activity of TBX20 gene promoter in both HEK‐293 and neonatal rat cardiomyocytes (NRCMs) cell lines by affecting the binding of transcription factors. But the mechanism remains to be verified in vivo. [ABSTRACT FROM AUTHOR]

Background and aims: Abnormal metabolism of vitamin D was the primary mechanism in many pregnancy diseases. Our study was the first to examine the hypothesis that VDR gene polymorphisms contribute to the risk of gestational diabetes mellitus (GDM) in the Chinese population at high altitudes. Materials and methods: One hundred and eighteen women with GDM and 104 women with normal glucose tolerance (NGT) were included in this study using a case‐control design. Four single nucleotide polymorphisms (g.47879112G > A, g.47846052C > T, g.47844974A > G, and g.47845054C > A) of mother and fetus were genotyped. Results: Maternal and fetal frequency of the A allele of g.47879112G > A was significantly increased in women with GDM than in those with NGT (p <.05). A correlation between the AA homozygous genotype of g.47879112G > A and GDM was noted. Compared with non‐carriers, A allele carriers showed higher fasting plasma insulin and two‐hour post‐challenge plasma glucose (2h‐PPG), and lower levels of vitamin D. Furthermore, both maternal and fetal 4‐marker haplotype ACCG were found to be significantly associated with GDM (p <.05). Conclusions: Association and haplotype analysis indicated that the A allele of g.47879112G > A could be a risk factor for GDM development in the Chinese population at high altitudes. Additionally, the VDR gene polymorphism of the fetus and mother may have a synergistic effect. The VDR polymorphism is associated with an increased risk of GDM and may be useful for predicting the development of the disease. [ABSTRACT FROM AUTHOR]

Severe coronavirus disease 2019 (COVID‐19) is related to dysregulated immune responses. We aimed to explore the effect of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants on the immune response by nasopharyngeal transcriptomic in critically‐ill patients. This prospective monocentric study included COVID‐19 patients requiring intensive care unit (ICU) admission between March 2020 and 2022. Patients were classified according to VOC (ancestral, Alpha, Delta, and Omicron). Eighty‐eight patients with severe COVID‐19 were included after matching (on prespecified clinical criteria). Profiling of gene expression markers of innate and adaptive immune responses were investigated by respiratory transcriptomics at ICU admission. Eighty‐eight patients were included in the study after matching (ancestral [n = 24], Alpha [n = 24], Delta [n = 22], and Omicron [n = 18] variants). Respiratory transcriptomic analysis revealed distinct innate and adaptive immune profiling between variants. In comparison with the ancestral variant, there was a reduced expression of neutrophil degranulation, T cell activation, cytokines signalling pathways in patients infected with Alpha and Delta variants. In contrast, there was a higher expression of neutrophil degranulation, T and B cells activation, and inflammatory interleukins pathways in patients infected with Omicron. To conclude, Omicron induced distinct immune respiratory transcriptomics signatures compared to pre‐existing variants in patients with severe COVID‐19, pointing to an evolving pathophysiology of severe COVID‐19 in the Omicron era. [ABSTRACT FROM AUTHOR]

Identification of cancer‐associated variants, especially those in functional regions of long noncoding RNAs (lncRNAs), has become an essential task in tumor etiology. However, the genetic function of lncRNA variants involved in bladder cancer susceptibility remains poorly understood. Herein, it is identified that the rs62483508 G > A variant in microRNA response elements (MREs) of lncRNA Bladder cancer Cell Cytoplasm‐Enriched abundant transcript 4 (BCCE4) is significantly associated with decreased bladder cancer risk (odds ratio = 0.84, P = 7.33 × 10−8) in the Chinese population (3603 cases and 4986 controls) but not in the European population. The protective genetic effect of the rs62483508 A allele is found in smokers or cigarette smoke‐related carcinogen 4‐aminobiphenyl (4‐ABP) exposure. Subsequent biological experiments reveal that the A allele of rs62483508 disrupts the binding affinity of miR‐328‐3p to facilitate USP18 from miRNA‐mediated degradation and thus specifically attenuates the downstream PD‐L1/PD‐1 interaction. LncRNA BCCE4 is also enriched in exosomes from bladder cancer plasma, tissues, and cells. This comprehensive study clarifies the genetic mechanism of lncRNA BCCE4 in bladder cancer susceptibility and its role in the regulation of the immune response in tumorigenesis. The findings provide a valuable predictor of bladder cancer risk that can facilitate diagnosis and prevention. [ABSTRACT FROM AUTHOR]

Precise spatiotemporal control of gene expression during normal development and cell differentiation is achieved by the combined action of proximal (promoters) and distal (enhancers) cis‐regulatory elements. Recent studies have reported that a subset of promoters, termed Epromoters, works also as enhancers to regulate distal genes. This new paradigm opened novel questions regarding the complexity of our genome and raises the possibility that genetic variation within Epromoters has pleiotropic effects on various physiological and pathological traits by differentially impacting multiple proximal and distal genes. Here, we discuss the different observations pointing to an important role of Epromoters in the regulatory landscape and summarize the evidence supporting a pleiotropic impact of these elements in disease. We further hypothesize that Epromoter might represent a major contributor to phenotypic variation and disease. [ABSTRACT FROM AUTHOR]

Weak molecular interactions play an important role in protein structure and function. Computational tools that identify weak molecular interactions are, therefore, valuable for the study of proteins. Here, we present AQcalc, a web server (https://aqcalcbiocomputing.com/) that can be used to identify anion–quadrupole (AQ) interactions, which are weak interactions involving aromatic residue (Trp, Tyr, and Phe) ring edges and anions (Asp, Glu, and phosphate ion) both within proteins and at their interfaces (protein–protein, protein‐nucleic acids, and protein–lipid bilayer). AQcalc identifies AQ interactions as well as clusters involving AQ, cation–π, and salt bridges, among others. Utilizing AQcalc we analyzed weak interactions in protein models, even in the absence of experimental structures, to understand the contributions of weak interactions to deleterious structural changes, including those associated with oncogenic and germline disease variants. We identified several deleterious variants with disrupted AQ interactions (comparable in frequency to cation–π disruptions). Amyloid fibrils utilize AQ to bury anions at frequencies that far exceed those observed for globular proteins. AQ interactions were detected three and five times more frequently than the hydrogen‐bonded AQ (HBAQ) in fibril structures and protein–lipid bilayer interfaces, respectively. By contrast, AQ and HBAQ interactions were detected with similar frequencies in globular proteins. Collectively, these findings suggest AQcalc will be effective in facilitating fine structural analysis. As other web utilities designed to identify protein residue interaction networks do not report AQ interactions, wide use of AQcalc will enrich our understanding of residue interaction networks and facilitate hypothesis testing by identifying and experimentally characterizing these comparably weak but important interactions. [ABSTRACT FROM AUTHOR]

BRCA1 variants are extensively associated with increased risk of breast cancer. Early detection and screening of variants is still rare in developing countries. Here, we investigated six BRCA1 variants in 300 subjects from Pakistani population using tetra amplification‐refractory mutation system (T‐ARMS) PCR. Our results indicate significant association of BRCA1 variants rs8176237 (AA; OR 8.2, 95% CI 3.02–22.64, p < 0.0001), rs1060915 (CC; OR 4.29, 95% CI 1.94–9.48, p = 0.0003), and rs799912 (TT; OR 3.16, 95% CI 1.44–6.94, p = 0.004) with up to 8‐fold increased odds of breast cancer under recessive model. Furthermore, BRCA1 haplotypes AGCACG and AGCCCT were associated with up to 18% breast cancer cases (p < 0.05). Additionally, we found association of these variants with up to 11‐fold increased odds of benign breast tumors. Linkage disequilibrium (LD) block‐wise analysis revealed haplotypes GCAC and ATAC were associated with significantly increased risk. To our knowledge, this is the first study that identifies the association of these BRCA1 variants with breast tumors in Pakistani population. In conclusion, BRCA1 variants investigated in the present study are associated with high odds of benign‐ and malignant breast tumors. Studies with bigger sample size may help early detection and screening to reduce the odds of breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: This study is the first study in which demographic, laboratory data, and outcomes of coronavirus disease‐2019 (COVID‐19) patients due to the circulating SARS‐CoV‐2 infections caused by different variants (Alpha, Delta, and Omicron) are compared in Iran. Methods: We conducted a retrospective study of confirmed hospitalized COVID‐19 cases from April 9, 2021, to May 22, 2022. Demographic data and laboratory findings were extracted from patients' electronic medical records on the first day of admission to the hospital. All patients were followed up for outcomes related to COVID‐19 including intensive care unit (ICU) admission and mortality rate. Results: Of 760 confirmed hospitalized COVID‐19 cases, 362, 298, and 100 represented patients during waves 4–6, respectively. During the Omicron wave, hospitalized patients were older than the other two waves and had a lower median level of C‐reactive protein (CRP), alanine transaminase (ALT), aspartate transaminase (AST), and erythrocyte sedimentation rate (ESR). The median length of hospital stay during waves 4–6 was 5 days (interquartile range [IQR]: 4.0–8.0), 7 days (IQR: 6.0–11), and 6 days (IQR: 5.0–9.0), respectively (p < 0.001). The rate of ICU admission during waves 4–6 significantly increased. Conclusions: Although the Omicron variant caused less severe disease, in older patients who were hospitalized due to Omicron infection, longer hospital and ICU stays were reported, which could be attributed to their old age. In particular, elderly patients are more vulnerable to severe COVID‐19; otherwise, as expected, other laboratory parameters and clinical outcomes were in accordance with differences in pathogenicity and infectivity of these variants. [ABSTRACT FROM AUTHOR]

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron variant is undergoing continuous evolution and convergent mutation. These new subvariants are raising concerns that they may evade neutralizing monoclonal antibodies (mAbs). We investigated the serum neutralization efficacy of Evusheld (cilgavimab and tixagevimab) against SARS‐CoV‐2 Omicron BA.2, BA.2.75, BA.2.76, BA.5, BF.7, BQ.1.1, and XBB.1.5. A total of 90 serum samples from healthy individuals were collected in Shanghai. Anti‐RBD antibodies were measured and symptoms of infection with COVID‐19 were compared among those individuals. The neutralizing activity of serum against Omicron variants was analyzed by pseudovirus neutralization assays in 22 samples. Evusheld retained neutralizing activity against BA.2, BA.2.75, and BA.5, albeit with somewhat reduced titers. However, the neutralizing activity of Evusheld against BA.2.76, BF.7, BQ.1.1, and XBB.1.5 significantly decreased, with XBB.1.5 showing the greatest escape activity among the subvariants. We also observed that Evusheld recipients displayed elevated antibody levels in their serum, which efficiently neutralized the original variant, and exhibited different characteristics of infection than those who did not receive Evusheld. The mAb has partial neutralization activity against Omicron sublineages. However, the increasing doses of mAb and a larger size of population should be further investigated. [ABSTRACT FROM AUTHOR]

Background: Occipital encephaloceles is a rare congenital defect in which meninges and the brain protrude out as a sac‐like structure through opening in the skull. The condition can result in neurologic complications as well as structural abnormalities of the skull. To the best of our knowledge, no genetic variant has been identified as an underlying cause of non‐syndromic occipital encephaloceles. Methods: In this study, I report a family with 2 individuals having large occipital encephalocele. Clinical and radiological examination did not reveal any other neurological or skeletal manifestations in both affected individuals. Results: Exome sequencing detected the previously unreported homozygous single nucleotide duplication (NM_002318.3:c.64dupC) in LOXL2 gene. This is a nonsense variant (NP_002309.1:p.Leu22Profs*7) leading to a premature truncation and loss‐of‐function of the lysyl oxidase‐like 2 protein. The variant is segregating in an autosomal recessive manner in a family. Both parents are heterozygous carriers for the variant while unaffected sibs have wild type sequence. Conclusion: We hypothesize that LOXL2 is a potential candidate gene for occipital encephalocele due to the established role of LOXL3, a close paralog of LOXL2, in craniofacial development. This case illustrates the power of exome sequencing to establish genetic diagnosis and expands the spectrum of genetic defects in occipital encephalocele and related disorders. [ABSTRACT FROM AUTHOR]

For phase transformations within polycrystalline materials, the connection between the crystal orientations of parent grains and those of child grains is usually expressed in terms of (theoretical or measured) orientation relationships. This paper introduces a new approach to various problems associated with orientation relationships: (i) estimation, (ii) whether or not a single orientation relationship fits the data adequately, (iii) whether or not a set of children comes from a common parent, and (iv) reconstruction of a parent or of grain boundaries. The approach is an extension to the crystallographic context of the well established embedding approach to directional statistics. It is inherently statistical, producing precise probabilistic statements. Explicit coordinate systems are not used and arbitrary thresholds are avoided. [ABSTRACT FROM AUTHOR]

Introduction: This study examines the associations between asthma and nitric oxide (NO) synthase (NOS) gene polymorphisms. Methods: After a systematic literature search in electronic databases, studies were selected based on eligibility criteria. Data were extracted from research articles and were synthesized and tabulated. Where a particular polymorphism data were reported by multiple studies, meta‐analyses of odds ratios were performed, or odds ratios reported by individual studies were pooled. Results: Twenty studies (4450 asthma patients and 5306 non‐asthmatic individuals) were identified. Many studies did not find any association between CCTTT repeat polymorphism in NOS2 gene and asthma. However, a study reported that pretreatment mean exhaled NO levels in asthmatics were found to be significantly higher in genotypes with higher number of CCTTT repeats. Also, alleles with <11 CCTTT repeats were associated with poor asthma treatment outcomes. A single nucleotide polymorphism, G894T, in NOS3 gene was not found to be significantly associated with asthma by at least four studies. However, a T allele at this locus was associated with lower NO levels. Also, G894T frequency was significantly higher in asthmatic children who responded to inhaled corticosteroids along with long‐lasting beta2‐agonists. A T allele of NOS3 786C/T polymorphism increased the probability of bronchial asthma with comorbid essential hypertension in asthma patients. Asthma severity also differed for different Ser608Leu exon 16 variants of NOS2 gene. Conclusions: Several polymorph NOS gene variants are identified, some of which appear to have influence on asthma prevalence or outcomes. However, data are varying depending on the nature of variant, ethnicity, study design, and disease parameters. [ABSTRACT FROM AUTHOR]

Background: SARS‐CoV‐2 genomic surveillance is necessary for the detection, monitoring, and evaluation of virus variants, which can have increased transmissibility, disease severity, or other adverse effects. We sequenced 330 SARS‐CoV‐2 genomes during the sixth wave of the COVID pandemic in Iran and compared them with five previous waves, for identifying SARS‐CoV‐2 variants, the genomic behavior of the virus, and understanding its characteristics. Methods: After viral RNA extraction from clinical samples collected during the COVID‐19 pandemic, next generation sequencing was performed using the Nextseq and Nanopore platforms. The sequencing data were analyzed and compared with reference sequences. Results: In Iran during the first wave, V and L clades were detected. The second wave was recognized by G, GH, and GR clades. Circulating clades during the third wave were GH and GR. In the fourth wave, GRY (alpha variant), GK (delta variant), and one GH clade (beta variant) were detected. All viruses in the fifth wave were in GK clade (delta variant). In the sixth wave, Omicron variant (GRA clade) was circulating. Conclusions: Genome sequencing, a key strategy in genomic surveillance systems, helps to detect and monitor the prevalence of SARS‐CoV‐2 variants, monitor the viral evolution of SARS‐CoV‐2, identify new variants for disease prevention, control, and treatment, and also provide information for and conduct public health measures in this area. With this system, Iran could be ready for surveillance of other respiratory virus diseases besides influenza and SARS‐CoV‐2. [ABSTRACT FROM AUTHOR]

Coronavirus Disease‐19 (COVID‐19) is an infectious disease caused by severe acute respiratory syndrome‐coronaviruses‐2 (SARS‐CoV‐2), a highly pathogenic and transmissible coronavirus. Most cases of COVID‐19 have mild to moderate symptoms, including cough, fever, myalgias, and headache. On the other hand, this coronavirus can lead to severe complications and death in some cases. Therefore, vaccination is the most effective tool to prevent and eradicate COVID‐19 disease. Also, rapid and effective diagnostic tests are critical in identifying cases of COVID‐19. The COVID‐19 pandemic has a dynamic structure on the agenda and contains up‐to‐date developments. This article has comprehensively discussed the most up‐to‐date pandemic situation since it first appeared. For the first time, not only the structure, replication mechanism, and variants of SARS‐CoV‐2 (Alpha, Beta, Gamma, Omicron, Delta, Epsilon, Kappa, Mu, Eta, Zeta, Theta, lota, Lambda) but also all the details of the pandemic, such as how it came out, how it spread, current cases, what precautions should be taken, prevention strategies, the vaccines produced, the tests developed, and the drugs used are reviewed in every aspect. Herein, the comparison of diagnostic tests for SARS‐CoV‐2 in terms of procedure, accuracy, cost, and time has been presented. The mechanism, safety, efficacy, and effectiveness of COVID‐19 vaccines against SARS‐CoV‐2 variants have been evaluated. Drug studies, therapeutic targets, various immunomodulators, and antiviral molecules applied to patients with COVID‐19 have been reviewed. [ABSTRACT FROM AUTHOR]

Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder; however, the known FEVR‐associated variants account for approximately only 50% cases. Currently, the pathogenesis of most reported variants is not well studied, we aim to identify novel variants from FEVR‐associated genes and perform a comprehensive functional analysis to uncover the pathogenesis of variants that cause FEVR. Using targeted gene panel and Sanger sequencing, we identified six novel and three known variants in TSPAN12 and NDP. These variants were demonstrated to cause significant inhibition of Norrin/β‐catenin pathway by dual‐luciferase reporter assay and western blot analysis. Structural analysis and co‐immunoprecipitation revealed compromised interactions between missense variants and binding partners in the Norrin/β‐catenin pathway. Immunofluorescence and subcellular protein extraction were performed to reveal the abnormal subcellular trafficking. Additionally, over‐expression of TSPAN12 successfully enhanced the Norrin/β‐catenin signaling activity by strengthening the binding affinity of mutant Norrin with FZD4 or LRP5. Together, these observations expanded the spectrum of FEVR‐associated variants for the genetic counseling and prenatal diagnosis of FEVR, as well providing a potential therapeutic strategy for the treatment of FEVR. [ABSTRACT FROM AUTHOR]

Peptides are promising therapeutic agents for COVID‐19 because of their specificity, easy synthesis, and ability to be fine‐tuned. We previously demonstrated that a cell‐permeable peptide corresponding to the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Spike C‐terminal domain (CD) inhibits the interaction between viral spike and nucleocapsid proteins that results in SARS‐CoV‐2 replication in vitro. Here, we used docking studies to design R‐t‐Spike CD(D), a more potent short cell‐penetrating peptide composed of all D‐form amino acids and evaluated its inhibitory effect against the replication of SARS‐CoV‐2 S clade and other variants. R‐t‐Spike CD(D) was internalized into Vero cells and Calu‐3 cells and suppressed the replication of SARS‐CoV‐2 S clade, delta variant, and omicron variant with higher potency than the original peptide. In hemizygous K18‐hACE2 mice, intratracheal administration of R‐t‐Spike CD(D) effectively delivered the peptide to the trachea and lungs, whereas intranasal administration delivered the peptide mostly to the upper respiratory system and stomach, and a small amount to the lungs. Administration by either route reduced viral loads in mouse lungs and turbinates. Furthermore, intranasally administered R‐t‐Spike CD(D) mitigated pathological change in the lungs and increased the survival of mice after infection with the SARS‐CoV‐2 S clade or delta variant. Our data suggest that R‐t‐Spike CD(D) has potential as a therapeutic agent against SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Background: COVID‐19 prevalence has remained high throughout the pandemic with intermittent surges, due largely to the emergence of genetic variants, demonstrating the need for more accessible sequencing technologies for strain typing. Methods: A ligation‐based typing assay was developed to detect known variants of severe acute respiratory syndrome virus 2 (SARS‐CoV‐2) by identifying the presence of characteristic single‐nucleotide polymorphisms (SNPs). General principles for extending the strategy to new variants and alternate diseases with SNPs of interest are described. Of note, this strategy leverages commercially available reagents for assay preparation, as well as standard real‐time polymerase chain reaction (PCR) instrumentation for assay performance. Results: The assay demonstrated a combined sensitivity and specificity of 96.6% and 99.5%, respectively, for the classification of 88 clinical samples of the Alpha, Delta, and Omicron variants relative to the gold standard of viral genome sequencing. It achieved an average limit of detection of 7.4 × 104 genome copies/mL in contrived nasopharyngeal samples. The ligation‐based strategy performed robustly in the presence of additional polymorphisms in the targeted regions of interest as shown by the sequence alignment of clinical samples. Conclusions: The assay demonstrates the potential for robust variant typing with performance comparable with next‐generation sequencing without the need for the time delays and resources required for sequencing. The reduced resource dependency and generalizability could expand access to variant classification information for pandemic surveillance. [ABSTRACT FROM AUTHOR]

The nature and dynamics of mutations associated with the emergence, spread, and vanishing of SARS‐CoV‐2 variants causing successive waves are complex. We determined the kinetics of the most common French variant ("Marseille‐4") for 10 months since its onset in July 2020. Here, we analyzed and classified into subvariants and lineages 7453 genomes obtained by next‐generation sequencing. We identified two subvariants, Marseille‐4A, which contains 22 different lineages of at least 50 genomes, and Marseille‐4B. Their average lifetime was 4.1 ± 1.4 months, during which 4.1 ± 2.6 mutations accumulated. Growth rate was 0.079 ± 0.045, varying from 0.010 to 0.173. Most of the lineages exhibited a bell‐shaped distribution. Several beneficial mutations at unpredicted sites initiated a new outbreak, while the accumulation of other mutations resulted in more viral heterogenicity, increased diversity and vanishing of the lineages. Marseille‐4B emerged when the other Marseille‐4 lineages vanished. Its ORF8 gene was knocked out by a stop codon, as reported in SARS‐CoV‐2 of mink and in the Alpha variant. This subvariant was associated with increased hospitalization and death rates, suggesting that ORF8 is a nonvirulence gene. We speculate that the observed heterogenicity of a lineage may predict the end of the outbreak. [ABSTRACT FROM AUTHOR]

We evaluated the kinetics of antibody responses to Two years into the COVID‐19 pandemic and 1 year after the start of vaccination rollout, the world faced a peak of cases associated with the highly contagious Omicron variant of concern (VoC) of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike (S) and nucleocapsid (N) antigens over five cross‐sectional visits (January–November 2021), and the determinants of pre‐booster immunoglobulin levels, in a prospective cohort of vaccinated primary health care workers in Catalonia, Spain. Antibodies against S antigens after a full primary vaccination course, mostly with BNT162b2, decreased steadily over time and were higher in pre‐exposed (n = 247) than naïve (n = 200) individuals, but seropositivity was maintained at 100% (100% IgG, 95.5% IgA, 30.6% IgM) up to 319 days after the first dose. Antibody binding to variants of concern was highly maintained for IgG compared to wild type but significantly reduced for IgA and IgM, particularly for Beta and Gamma. Factors significantly associated with longer‐term antibodies included age, sex, occupation, smoking, adverse reaction to vaccination, levels of pre‐vaccination SARS‐CoV‐2 antibodies, interval between disease onset and vaccination, hospitalization, oxygen supply, post COVID and symptomatology. Earlier morning vaccination hours were associated with higher IgG responses in pre‐exposed participants. Symptomatic breakthroughs occurred in 9/447 (2.01%) individuals, all among naïve (9/200, 4.5%) and generally boosted antibody responses. Additionally, an increase in IgA and/or IgM seropositivity to variants, and N seroconversion at later time points (6.54%), indicated asymptomatic breakthrough infections, even among pre‐exposed. Seropositivity remained highly stable over almost a year after vaccination. However, gradually waning of anti‐S IgGs that correlate with neutralizing activity, coupled to evidence of an increase in breakthrough infections during the Delta and Omicron predominance, provides a rationale for booster immunization. [ABSTRACT FROM AUTHOR]

This short report documented cystic fibrosis transmembrane conductance regulator (CFTR) variants in 37 patients with cystic fibrosis (CF) in the Rio Grande do Norte region of Northeast Brazil. The high‐throughput sequencing technology (HTS) genetic testing provided a definitive molecular diagnosis in 31 patients (83.8%). Among them, 25 patients' carriers of the c.1521_1523delCTT variant, categorized as a class 2 mutation, can be currently treated with CFTR modulator drugs. Five children aged 2–5 years could benefit from double lumacaftor/ivacaftor therapy, and 20 patients aged >6 years could be treated with the triple‐combination elexacaftor/tezacaftor/ivacaftor therapy. Thus, the identification of pathogenic variants associated with the development of this disease allows for the introduction of therapy with CFTR modulators that favour better patient management. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study was to evaluate the in vitro virucidal activity of commercial mouthwashes against SARS‐CoV‐2 and variants of concern. Materials and Methods: Antiviral activity was assessed at different time intervals, based on common use of these products by titrating residual viral infectivity on Vero E6 cells. Results: All the mouthwashes were effective to reduce the infectious titers of SARS‐CoV‐2 and its tested variants. Mouthwashes Listerine® Cool Mint milder taste and Listerine® Cavity Protection milder taste reduced the infectious viral titer by up to 3.9 log10 after 30 s, while mouthwash Cetilsan® Sugar Free was able to reduce the viral titer by 2.2–2.9 log10 at all tested time intervals. Mouthwash Curasept® ADS DNA Intensive treatment was less effective to decrease viral infectivity (0.7–2.2 log10 TCID50/ml at all tested time intervals). Interestingly, the Gamma variant appeared more resistant to treatment in vitro with the different mouthwashes. Conclusions: In this study, we were able to assess the ability of different mouthwashes to in vitro decrease the infectivity of SARS‐CoV‐2 and its variants, and we observed that Gamma variant of concern was more resistant to treatment with mouthwashes. [ABSTRACT FROM AUTHOR]

Background and purpose: Tic disorders (TDs) are childhood onset neuropsychiatric disorders characterized by single or multiple sudden, rapid, recurrent, and motor tics and/or vocal tics. Several nuclear genes that are involved in mitochondrial functions suggest a potential role of mitochondria in TDs. Methods: To evaluate the association of mitochondrial DNA (mtDNA) variants with TDs, we screened the whole mitochondrial genomes in 493 TD patients and 109 age‐ and sex‐matched healthy controls using next generation sequencing technology. Results: A total of 1918 mtDNA variants including 1220 variants in patients only, 154 variants in controls only, and 544 variants shared by both cases and controls were identified. We found a higher number of overall mtDNA variants in TD patients (p = 0.00028). The variant density in MT‐ATP6/8 and MT‐CYB coding regions showed a significant difference between TD patients and controls (p = 0.0025 and p = 0.003, respectively). Furthermore, we observed a significant association of 15 common variants with TD based on an additive model, including m.14766C > T, m.14783 T > C, m.14905G > A, and m.15301G > A in MT‐CYB; m.4769A > G, m.10398A > G, m.12705C > T, and m.12850A > G in MT‐ND genes; m.7028C > T in MT‐CO1; m.8701A > G in MT‐ATP6; two variants with m.16223C > T, m.5580 T > C in noncoding regions; and three rRNA variants with m.1438A > G and m.750A > G in RNR1, and m.2352 T > C in RNR2. Conclusions: Our data provide evidence of mtDNA variants associated with TDs. The accumulation of the heteroplasmic levels may increase the risk of TDs. Replication studies with larger samples are necessary to understand the pathogenesis of TDs. [ABSTRACT FROM AUTHOR]

Hypertension is one of the major issues worldwide and one of the main factors involved in heart and kidney failure. Angiotensinogen and renin are key components of the renin–angiotensin–aldosterone system, which plays an indispensable role in hypertension. The aim of this study was to find out the non‐synonymous mutations and structure‐based mutation‐function correlation in the renin–AGT complex and reveal the most deleterious mutations to accelerated hypertension. In the current study, we employed computational modeling and molecular simulation approaches to demonstrate the impact of specific mutations in the REN‐AGT interface in hypertension. Computational algorithms, that is, PhD‐SNP, PolyPhen‐1, MAPP, Sorting Intolerant from Tolerant, Screening of non‐acceptable polymorphism, PredictSNP, PolyPhen‐2, and Protein Analysis Through Evolutionary Relationships predicted 20 mutations as deleterious in AGT while only five mutations were confirmed as deleterious in the renin protein. Investigation of the bonding analysis revealed that two mutations S107L and V193F in renin altered the hydrogen‐bonding paradigm at the interface site. Furthermore, exploration of structural‐dynamic behaviors demonstrated by that these mutations also increases the structural stability to regulate the expression of disease pathway. The flexibility index of each residues and structural compactness analysis further validated the findings by portraying the difference in the dynamic behavior in contrast to the wild type. Binding energy calculations based on molecular mechanics/generalized Born surface area methods were used which further established the binding differences between the wild type, S107L, and V193F mutant variants. The total binding energy for wild type, S107L, and V193F was reported to be −27.79, −47.72, and −38.25, respectively. In conclusion, these two mutations increase the binding free energy alongside the docking score to enhance the binding between renin and AGT to overexpress this pathway in a hypertension disease condition. Patients with these mutations may be screened for potential therapeutic intervention. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) 16 exhibits different variants that may differ in their carcinogenic risk. To identify some high‐risk variants, we sequenced and compared HPV16 whole genomes obtained from a longitudinal cohort of 34 HPV16‐infected women who had either spontaneously cleared their infection (clearance group or "C"), or developed cervical high‐grade lesions following a viral persistence (group persistence or "P"). Phylogenetic analysis of paired samples obtained at the beginning (C0 or P0) and at the end (C2 or P2) of the follow‐up (median intervals between C0–C2 and between P0–P2 were 16 and 36.5 months, respectively) revealed a low genetic variability within the host compared to the genetic interhost diversity. By comparing our HPV16 sequences to a reference sequence, we observed 301 different substitutions, more often transitions (60.9%) than transversions (39.1%), that occurred throughout the viral genome, but with a low frequency in E6 and E7 oncogenes (10 and 9 substitutions), suggesting a high conservation of these genes. Deletions and insertions were mostly observed in intergenic regions of the virus. The only significant substitution found between the subgroups C2 and P2 was observed in the L2 gene (L330F), with an unclear biological relevance. Our results suggest a low longitudinal intrahost evolution of HPV16 sequences and no correlation between genetic variations and clinical evolution. [ABSTRACT FROM AUTHOR]

The emergence of SARS‐CoV‐2 variants has exacerbated the COVID‐19 global health crisis. Thus far, all variants carry mutations in the spike glycoprotein, which is a critical determinant of viral transmission being responsible for attachment, receptor engagement and membrane fusion, and an important target of immunity. Variants frequently bear truncations of flexible loops in the N‐terminal domain (NTD) of spike; the functional importance of these modifications has remained poorly characterised. We demonstrate that NTD deletions are important for efficient entry by the Alpha and Omicron variants and that this correlates with spike stability. Phylogenetic analysis reveals extensive NTD loop length polymorphisms across the sarbecoviruses, setting an evolutionary precedent for loop remodelling. Guided by these analyses, we demonstrate that variations in NTD loop length, alone, are sufficient to modulate virus entry. We propose that variations in NTD loop length act to fine‐tune spike; this may provide a mechanism for SARS‐CoV‐2 to navigate a complex selection landscape encompassing optimisation of essential functionality, immune‐driven antigenic variation and ongoing adaptation to a new host. Synopsis: The functional importance of the SARS‐CoV‐2 spike N‐terminal domain is poorly understood. This study demonstrates that length variation in flexible loops within the NTD can modulate spike activity to optimise SARS‐CoV‐2 entry.SARS‐CoV‐2 spike NTD loops are a hotspot of diversity in emergent variants and sarbecoviruses in general.The NTD determines virus entry efficiency by Alpha and Omicron variants, and by Pangolin coronavirus.NTD loops may provide a mechanism for evolutionary fine tuning of spike activity. [ABSTRACT FROM AUTHOR]

Objective: This study looked at differences in the presence of headache as an onset symptom of coronavirus disease 2019 (COVID‐19) and as a post‐COVID‐19 symptom in individuals previously hospitalized owing to infection with the Wuhan, Alpha, or Delta variants of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Background: Headache can be present in up to 50% of individuals during the acute phase of SARS‐CoV‐2 infection and in 10% of subjects during the post‐COVID‐19 phase. There are no data on differences in the occurrence of headache in the acute‐ and post‐COVID‐19 phase according to the SARS‐CoV‐2 variants. Methods: A cross‐sectional cohort study was conducted. Unvaccinated subjects previously hospitalized for COVID‐19 caused by the Wuhan (n = 201), Alpha (n = 211), or Delta (n = 202) SARS‐CoV‐2 variants were scheduled for a telephone interview 6 months after hospital discharge. Hospitalization data were collected from hospital medical records. Results: The presence of headache as a COVID‐19 onset symptom at hospitalization was higher in subjects with the Delta variant (66/202, 32.7%) than in those infected with the Wuhan (42/201, 20.9%; odds ratio [OR] 1.83, 95% confidence interval [CI] 1.17–2.88) or Alpha (25/211, 11.8%; OR 3.61, 95% CI, 2.16–6.01) variants. The prevalence of post‐COVID‐19 headache 6 months after hospital discharge was higher in individuals infected with the Delta variant (26/202, 12.9%) than in those infected with the Wuhan (11/201, 5.5%; OR 2.52, 95% CI 1.22–5.31) or Alpha (eight of 211, 3.8%; OR 3.74, 95% CI 1.65–8.49) variants. The presence of headache as a COVID‐19 onset symptom was associated with post‐COVID‐19 headache in subjects infected with the Wuhan (OR 7.75, 95% CI 2.15–27.93) and Delta variants (OR 2.78, 95% CI 1.20–6.42) but not with the Alpha variant (OR 2.60, 95% CI 0.49–13.69). Conclusion: Headache was a common symptom in both the acute‐ and post‐COVID‐19 phase in subjects infected with the Wuhan, Alpha, and Delta variants but mostly in those infected with the Delta variant. [ABSTRACT FROM AUTHOR]

Neutralizing antibody is an important indicator of vaccine efficacy, of which IgG is the main component. IgG can be divided into four subclasses. Up to now, studies analysing the humoral response to SARS‐CoV‐2 vaccination have mostly focused on measuring total IgG, and the contribution of specific IgG subclasses remains elusive. The aim of this study is to investigate the kinetics of neutralizing antibodies and IgG subclasses, and to explore their relationships in people vaccinated with inactivated COVID‐19 vaccine. We conducted a prospective cohort study in 174 healthy adults aged 18–59 years old who were administrated 2 doses of CoronaVac 14 days apart and a booster dose 1 year after the primary immunization, and followed up for 15 months. Blood samples were collected at various time points after primary and booster immunization. We used live SARS‐CoV‐2 virus neutralizing assay to determine neutralizing ability against the wild‐type strain and 4 variants (Beta, Gamma, Delta and Omicron) and ELISA to quantify SARS‐CoV‐2 RBD‐specific IgG subclasses. The results showed that the 2‐dose primary immunization only achieved low neutralizing ability, while a booster shot can significantly enhance neutralizing ability against the wild‐type strain, Beta, Gamma, Delta and Omicron variants. IgG1 and IgG3 were the most abundant serum antibodies, and IgG2 and IgG4 were hardly detected at any time. The ratio of IgG1/IgG3 was positively associated with the neutralization ability. The underlying mechanism requires further exploration. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been spreading globally for over 2 years, causing serious contagious disease and incalculable damage. The introduction of vaccines has slowed the spread of SARS‐CoV‐2 to some extent, but there remains a need for specific and effective treatment. The high chemical diversity and safety profiles of natural products make them a potential source of effective anti‐SARS‐CoV‐2 drugs. Cotton plant is one of the most important economic and medical crops and is the source of a large number of antiviral phytochemicals. In this work, we used SARS‐CoV‐2 main protein (Mpro) as the target to identify potential anti‐SARS‐CoV‐2 natural products in cotton. An in vitro assay showed that of all cotton tissues examined, cotton flower extracts (CFs) exhibited optimal inhibitory effects against Mpro. We proceeded to use the CF metabolite database to screen natural Mpro inhibitors by combining virtual screening and biochemical assays. We identified that several CF natural products, including astragalin, myricitrin, and astilbin, significantly inhibited Mpro with half‐maximal inhibitory concentrations (IC50s) of 0.13, 10.73, and 7.92 μm, respectively. These findings may serve as a basis for further studies into the suitability of cotton as a source of potential therapeutics for SARS‐CoV‐2. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic has caused an unprecedented health crisis and economic burden worldwide. Its etiological agent SARS‐CoV‐2, a new virus in the coronavirus family, has infected hundreds of millions of people worldwide. SARS‐CoV‐2 has evolved over the past 2 years to increase its transmissibility as well as to evade the immunity established by previous infection and vaccination. Nevertheless, strong immune responses can be elicited by viral infection and vaccination, which have proved to be protective against the emergence of variants, particularly with respect to hospitalization or severe disease. Here, we review our current understanding of how the virus enters the host cell and how our immune system is able to defend against cell entry and infection. Neutralizing antibodies are a major component of our immune defense and have been extensively studied for SARS‐CoV‐2 and its variants. Structures of these neutralizing antibodies have provided valuable insights into epitopes that are protective against the original ancestral virus and the variants that have emerged. The molecular characterization of neutralizing epitopes as well as epitope conservation and resistance are important for design of next‐generation vaccines and antibody therapeutics. [ABSTRACT FROM AUTHOR]