Guidelines for releasing a variant effect predictor.

Computational methods for assessing the likely impacts of mutations, known as variant effect predictors (VEPs), are widely used in the assessment and interpretation of human genetic variation, as well as in other applications like protein engineering. Many different VEPs have been released to date, and there is tremendous variability in their underlying algorithms and outputs, and in the ways in which the methodologies and predictions are shared. This leads to considerable challenges for end users in knowing which VEPs to use and how to use them. Here, to address these issues, we provide guidelines and recommendations for the release of novel VEPs. Emphasising open-source availability, transparent methodologies, clear variant effect score interpretations, standardised scales, accessible predictions, and rigorous training data disclosure, we aim to improve the usability and interpretability of VEPs, and promote their integration into analysis and evaluation pipelines. We also provide a large, categorised list of currently available VEPs, aiming to facilitate the discovery and encourage the usage of novel methods within the scientific community.

Biopolymeric nanoencapsulation of model drug: Its development and characterisation.

This research aimed to develop the phenytoin-loaded bionanosuspension by utilising the novel biopolymer from Juglans regia andreduce the long-term treatment cost of epilepsy and increase the efficiency of therapy. A novel biopolymer with remarkable inbuilt properties was isolated and used in the development of a nano capsulated dispersed system. The diverse proportions of phenytoin and biopolymer with different ratios 1:2, 1:3, 1:4, 1:5 and 1:8 were taken for the planning of details PJNC1-PJNC5. The bionanosuspension was assessed for dispersibility, pH, % entrapment efficiency, stability study and in vitro drug discharge. The formulation PJNC2 with 1:3 drug biopolymer proportion showed significant outcomes for various assessments with t50% of 16.51 h and r2 estimation of 0.9884. PJNC2 showed 92.07%±2.5 drug delivery in 36h and was stable. The bionanosuspension was found to be stable and safe for the delivery of nanosized phenytoin utilising the biopolymer having a remarkable stabiliser cum retardant property.

A New Horizon in Hip Health: Using an Innovative Variable Loop Curette for Core Decompression and Bone Marrow Aspirate Concentrate in the Management of Pre-collapse Avascular Necrosis of the Hip.

Avascular necrosis (AVN) of the femoral head, or osteonecrosis (ON), is a debilitating condition characterized by disrupted blood supply to the hip joint, leading to subchondral bone necrosis, joint collapse, and arthritis. Emerging evidence suggests that the long-term use of corticosteroids, particularly in the context of COVID-19 treatment, may contribute to AVN development. This case report presents a male in his 50s with bilateral hip pain and a history of corticosteroid use. The patient underwent core decompression (CD) with a bone marrow aspirate concentrate (BMAC) infusion using the innovative curette technique. Postoperatively, he followed a structured rehabilitation protocol and experienced significant pain relief and improved function. Reviewing existing literature, CD with BMAC using innovative curettes emerges as a promising approach for pre-collapse AVN management, preserving hip function, and delaying the necessity for total hip arthroplasty (THA). This case highlights the potential benefits of this technique in early-stage AVN, emphasizing its role in improving functional outcomes and limiting disease progression.

IL-17A Orchestrates Reactive Oxygen Species/HIF1α-Mediated Metabolic Reprogramming in Psoriasis.

Immune cell-derived IL-17A is one of the key pathogenic cytokines in psoriasis, an immunometabolic disorder. Although IL-17A is an established regulator of cutaneous immune cell biology, its functional and metabolic effects on nonimmune cells of the skin, particularly keratinocytes, have not been comprehensively explored. Using multiomics profiling and systems biology-based approaches, we systematically uncover significant roles for IL-17A in the metabolic reprogramming of human primary keratinocytes (HPKs). High-throughput liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy revealed IL-17A-dependent regulation of multiple HPK proteins and metabolites of carbohydrate and lipid metabolism. Systems-level MitoCore modeling using flux-balance analysis identified IL-17A-mediated increases in HPK glycolysis, glutaminolysis, and lipid uptake, which were validated using biochemical cell-based assays and stable isotope-resolved metabolomics. IL-17A treatment triggered downstream mitochondrial reactive oxygen species and HIF1α expression and resultant HPK proliferation, consistent with the observed elevation of these downstream effectors in the epidermis of patients with psoriasis. Pharmacological inhibition of HIF1α or reactive oxygen species reversed IL-17A-mediated glycolysis, glutaminolysis, lipid uptake, and HPK hyperproliferation. These results identify keratinocytes as important target cells of IL-17A and reveal its involvement in multiple downstream metabolic reprogramming pathways in human skin.

Restoring Wrist Harmony: A Case Report of Ulnar Osteotomy for Correcting the Radius Malunion.

A 41-year-old female patient sought medical attention due to a malunited distal radius fracture with a positive ulnar variance, experiencing wrist pain and limited range of motion. The patient was successfully treated with an isolated ulnar osteotomy and bone grafting, resulting in significant alleviation of symptoms and improved wrist mobility. Various surgical methods have been proposed to address malunited radius fractures, and ulnar osteotomy has shown promise as an effective technique for such cases.

Intraoperative Identification and Mosaicplasty in a Case of Femur Subchondral Osteoid Osteoma.

Osteoid osteomas (OOs) are non-malignant primary bone abnormalities marked by a central nidus surrounded by reactive sclerosis. They typically manifest as aggravated nocturnal pain that responds to non-steroidal anti-inflammatory drugs (NSAIDs). These growths are most frequently found within the intracortical bone and the diaphysis of elongated bones. Within the realm of uncommon conditions, intra-articular OOs (IAOOs) exhibit distinctive presentations, often leading to postponed or inaccurate diagnoses. We present a patient with OO at the distal femur, accessible through the knee joint, which was intraoperatively identified and localized using a needle pricking technique and treated by arthrotomy and mosaicplasty.

A computational study on mitogenome-encoded proteins of Pavo cristatus and Pavo muticus identifies key genetic variations with functional implications.

BACKGROUND: The Pavo cristatus population, native to the Indian subcontinent, is thriving well in India. However, the Pavo muticus population, native to the tropical forests of Southeast Asia, has reduced drastically and has been categorised as an endangered group. To understand the probable genetic factors associated with the decline of P. muticus, we compared the mitogenome-encoded proteins (13 proteins) between these two species. RESULTS: Our data revealed that the most frequent variant between these two species was mtND1, which had an alteration in 9.57% residues, followed by mtND5 and mtATP6. We extended our study on the rest of the proteins and observed that cytochrome c oxidase subunits 1, 2, and 3 do not have any change. The 3-dimensional structure of all 13 proteins was modeled using the Phyre2 programme. Our data show that most of the proteins are alpha helical, and the variations observed in P. muticus reside on the surface of the respective proteins. The effect of variation on protein function was also predicted, and our results show that amino acid substitution in mtND1 at 14 sites could be deleterious. Similarly, destabilising changes were observed in mtND1, 2, 3, 4, 5, and 6 and mtATP6-8 due to amino acid substitution in P. muticus. Furthermore, protein disorder scores were considerably altered in mtND1, 2, and 5 of P. muticus. CONCLUSIONS: The results presented here strongly suggest that variations in mitogenome-encoded proteins of P. cristatus and P. muticus may alter their structure and functions. Subsequently, these variations could alter energy production and may correlate with the decline in the population of P. muticus.

Minor intron splicing is critical for survival of lethal prostate cancer.

The evolutionarily conserved minor spliceosome (MiS) is required for protein expression of ∼714 minor intron-containing genes (MIGs) crucial for cell-cycle regulation, DNA repair, and MAP-kinase signaling. We explored the role of MIGs and MiS in cancer, taking prostate cancer (PCa) as an exemplar. Both androgen receptor signaling and elevated levels of U6atac, a MiS small nuclear RNA, regulate MiS activity, which is highest in advanced metastatic PCa. siU6atac-mediated MiS inhibition in PCa in vitro model systems resulted in aberrant minor intron splicing leading to cell-cycle G1 arrest. Small interfering RNA knocking down U6atac was ∼50% more efficient in lowering tumor burden in models of advanced therapy-resistant PCa compared with standard antiandrogen therapy. In lethal PCa, siU6atac disrupted the splicing of a crucial lineage dependency factor, the RE1-silencing factor (REST). Taken together, we have nominated MiS as a vulnerability for lethal PCa and potentially other cancers.

An immunoinformatics approach to study the epitopes of SARS-CoV-2 helicase, Nsp13.

Introduction and objective: Vaccines are administered worldwide to control on-going coronavirus disease-19 (COVID-19) pandemic caused by SARS-CoV-2. Vaccine efficacy is largely contributed by the epitopes present on the viral proteins and their alteration might help emerging variants to escape host immune surveillance. Therefore, this study was designed to study SARS-CoV-2 Nsp13 protein, its epitopes and evolution. Methods: Clustal Omega was used to identify mutations in Nsp13 protein. Secondary structure and disorder score was predicted by CFSSP and PONDR-VSL2 webservers. Protein stability was predicted by DynaMut webserver. B cell epitopes were predicted by IEDB DiscoTope 2.0 tools and their 3D structures were represented by discovery studio. Antigenicity and allergenicity of epitopes were predicted by Vaxijen2.0 and AllergenFPv.1.0. Physiochemical properties of epitopes were predicted by Toxinpred, HLP webserver tool. Results: Our data revealed 182 mutations in Nsp13 among Indian SARS-CoV-2 isolates, which were characterised by secondary structure and per-residue disorderness, stability and dynamicity predictions. To correlate the functional impact of these mutations, we characterised the most prominent B cell and T cell epitopes contributed by Nsp13. Our data revealed twenty-one epitopes, which exhibited antigenicity, stability and interactions with MHC class-I and class-II molecules. Subsequently, the physiochemical properties of these epitopes were analysed. Furthermore, eighteen mutations reside in these Nsp13 epitopes. Conclusions: We report appearance of eighteen mutations in the predicted twenty-one epitopes of Nsp13. Among these, at least seven epitopes closely matches with the functionally validated epitopes. Altogether, our study shows the pattern of evolution of Nsp13 epitopes and their probable implications.

Introducción y objetivo: Las vacunas se administran a nivel mundial para controlar la pandemia en curso de la enfermedad por coronavirus de 2019 (COVID-19) causada por SARS-CoV-2. A la eficacia de la vacuna contribuyen ampliamente los epítopes presentes en las proteínas virales, y su alteración puede contribuir a que las variantes emergentes se escapen de la vigilancia inmunológica del huésped. Por tanto, este estudio fue diseñado para estudiar la proteína Nsp13 de SARS-CoV-2, sus epítopes y su evolución. Métodos: Se utilizó Clustal Omega para identificar las mutaciones de la proteína Nsp13. La estructura secundaria y la tasa de desorden se predijeron mediante los servidores web CFSSP y PONDR-VSL2. La estabilidad de la proteína fue predicha mediante el servidor web DynaMut. Los epítopes de las células B fueron predichos mediante las herramientas DiscoTope 2.0 de IEDB, y sus estructuras en 3D fueron representadas mediante Discovery Studio.La antigenicidad y alergenicidad de los epítopes fueron predichas mediante Vaxijen2.0 y AlergenFPv.1.0. Las propiedades fisioquímicas de los epítopes fueron predichas mediante Toxinpred, la herramienta del servidor web HLP. Resultados: Nuestros datos revelaron 182 mutaciones en Nsp13 entre los aislados indios de SARS-CoV-2, que fueron caracterizadas mediante las predicciones de la estructura secundaria y la capacidad de desorden por residuo, la estabilidad y la dinamicidad. Para correlacionar el impacto funcional de estas mutaciones, caracterizamos los epítopes más prominentes de las células B y las células T a los que contribuyó Nsp13. Nuestros datos revelaron veintiún epítopes, que exhibieron antigenicidad, estabilidad e interacciones con las moléculas MHC de clase I y clase II. Seguidamente se analizaron las propiedades fisioquímicas de estos epítopes. Además, en estos epítopes de Nsp13 residen ocho mutaciones. Conclusiones: Reportamos el aspecto de ocho mutaciones en los veintiún epítopes de Nsp13 predichos. Entre estos, al menos siete epítopes concuerdan estrechamente con los epítopes funcionalmente validados. En su conjunto, nuestro estudio refleja el patrón evolutivo de los epítopes de Nsp13 y sus implicaciones probables.

Personalized diversification of complementary recommendations with user preference in online grocery.

Complementary recommendations play an important role in surfacing the relevant items to the customers. In the cross-selling scenario, some customers might present more exploratory shopping behaviors and prefer more diverse complements, while other customers show less exploratory (or more conventional) shopping behaviors and want to have a deep dive of less diverse types of complements. The existence of two distinct shopping behaviors reflects users' different shopping intents and requires complementary recommendations to be adaptable based on the user's shopping intent. Although many studies focus on improving the recommendations through post-processing techniques, such as user-item-level personalized ranking and diversification of recommendations, they fail to address such a requirement. First, many user-item-level personalization methods cannot explicitly model the preference of users in two types of shopping behaviors and their intent on the corresponding complementary recommendations. Second, most of the diversification methods increase the heterogeneity of the recommendations. However, users' intent on conventional complementary shopping requires more homogeneity of the recommendations, which is not explicitly modeled. The present study tries attempts to solve these problems by the personalized diversification strategies for complementary recommendations. To address the requirement of modeling heterogenized and homogenized complementary recommendations, we propose two diversification strategies, heterogenization and homogenization, to re-rank complementary recommendations based on the determinantal point process (DPP). We use transaction history to estimate users' intent on more exploratory or more conventional complementary shopping. With the estimated user intent scores and two diversification strategies, we propose an algorithm to personalize the diversification strategies dynamically. We demonstrate the effectiveness of our re-ranking algorithm on the publicly available Instacart dataset.

Unified views on variant impact across many diseases.

Genomic studies of human disorders are often performed by distinct research communities (i.e., focused on rare diseases, common diseases, or cancer). Despite underlying differences in the mechanistic origin of different disease categories, these studies share the goal of identifying causal genomic events that are critical for the clinical manifestation of the disease phenotype. Moreover, these studies face common challenges, including understanding the complex genetic architecture of the disease, deciphering the impact of variants on multiple scales, and interpreting noncoding mutations. Here, we highlight these challenges in depth and argue that properly addressing them will require a more unified vocabulary and approach across disease communities. Toward this goal, we present a unified perspective on relating variant impact to various genomic disorders.

Topological Metal MoP Nanowire for Interconnect.

The increasing resistance of copper (Cu) interconnects for decreasing dimensions is a major challenge in continued downscaling of integrated circuits beyond the 7 nm technology node as it leads to unacceptable signal delays and power consumption in computing. The resistivity of Cu increases due to electron scattering at surfaces and grain boundaries at the nanoscale. Topological semimetals, owing to their topologically protected surface states and suppressed electron backscattering, are promising candidates to potentially replace current Cu interconnects. Here, we report the unprecedented resistivity scaling of topological metal molybdenum phosphide (MoP) nanowires, and it is shown that the resistivity values are superior to those of nanoscale Cu interconnects <500 nm2 cross-section areas. The cohesive energy of MoP suggests better stability against electromigration, enabling a barrier-free design . MoP nanowires are more resistant to surface oxidation than the 20 nm thick Cu. The thermal conductivity of MoP is comparable to those of Ru and Co. Most importantly, it is demonstrated that the dimensional scaling of MoP, in terms of line resistance versus total cross-sectional area, is competitive to those of effective Cu with barrier/liner and barrier-less Ru, suggesting MoP is an attractive alternative for the scaling challenge of Cu interconnects.

FAVOR: functional annotation of variants online resource and annotator for variation across the human genome.

Large biobank-scale whole genome sequencing (WGS) studies are rapidly identifying a multitude of coding and non-coding variants. They provide an unprecedented resource for illuminating the genetic basis of human diseases. Variant functional annotations play a critical role in WGS analysis, result interpretation, and prioritization of disease- or trait-associated causal variants. Existing functional annotation databases have limited scope to perform online queries and functionally annotate the genotype data of large biobank-scale WGS studies. We develop the Functional Annotation of Variants Online Resources (FAVOR) to meet these pressing needs. FAVOR provides a comprehensive multi-faceted variant functional annotation online portal that summarizes and visualizes findings of all possible nine billion single nucleotide variants (SNVs) across the genome. It allows for rapid variant-, gene- and region-level queries of variant functional annotations. FAVOR integrates variant functional information from multiple sources to describe the functional characteristics of variants and facilitates prioritizing plausible causal variants influencing human phenotypes. Furthermore, we provide a scalable annotation tool, FAVORannotator, to functionally annotate large-scale WGS studies and efficiently store the genotype and their variant functional annotation data in a single file using the annotated Genomic Data Structure (aGDS) format, making downstream analysis more convenient. FAVOR and FAVORannotator are available at https://favor.genohub.org.

Photoinduced CO2 and N2 reductions on plasmonically enabled gallium oxide.

Ag-containing ZnO/ ß-Ga2O3 semiconductor, which exhibit reduced bandgap, increased light absorption, and hydrophilicity, have been found to be useful for photocatalytic CO2 reduction and N2 fixation by water. The charge-separation is facilitated by the new interfaces and inherent vacancies. The Ag@GaZn demonstrated the highest photocurrent response, about 20- and 2.27-folds that of the Ga and GaZn samples, respectively. CO, CH4, and H2 formed as products for photo-reduction of CO2. Ag@GaZn catalyst exhibited the highest AQY of 0.121 % at 400 nm (31.2 W/m2). Also, Ag@GaZn generated 740 µmolg-1 of NH4+ ions, which was about 18-folds higher than Ga sample. In situ DRIFTS for isotopic-labelled 13CO2 and 15N2 reaffirmed the photo-activity of as-synthesized catalysts. Density functional theory provided insight into the relative affinity of different planes of heterostructures towards H2O, CO2 and N2 molecules. The structure-photoactivity rationale behind the intriguing Ag@GaZn sample offers a fundamental insight into the role of plasmonic Ag and design principle of heterostructure with improved photoactivity and stability.

Understanding the individuals' motivators and barriers of e-waste recycling: A mixed-method approach.

The increasing amount of e-waste and poor participation of individuals in proper recycling or disposal has become a big concern for policymakers. Therefore, it is essential to understand the factors that may facilitate or inhibit individuals from adopting e-waste recycling. The present research examines the attitude and intentions of individuals by applying the theoretical lens of Behavioral Reasoning Theory (BRT). The study uses a mixed-method approach and has been conducted in two phases: Phase 1- qualitative study (one-to-one interview: 30 respondents) and Phase 2: quantitative study (survey-based questionnaire- 348 responses). The qualitative part employs thematic analysis, and the quantitative study has been analyzed using SEM. Through the qualitative research, the study has identified self-image perceived negative effect and salvage value as the 'reasons for', whereas inconvenience, lack of support system, and emotional attachment have been identified as the 'reasons against' e-waste recycling. The findings show that moral and social norms significantly impact individual reasoning ('reason for'/'reason against') and attitude toward e-waste recycling. The result has also confirmed the moderation effect on self-efficacy among reasoning, attitude, and intention. The findings offer interesting insights to the government and policymakers for increasing individuals' participation in e-waste recycling.

Side-lobe reduction by cascading Bragg grating filters on a Si-photonic chip.

Bragg-grating based cavities and coupler designs present opportunities for flexible allocation of bandwidth and spectrum in silicon photonic devices. Integrated silicon photonic devices are moving toward mainstream, mass adoption, leading to the need for compact Bragg grating based designs. In this work we present a design and experimental validation of a cascaded contra-directional Bragg-grating coupler with a measured main lobe to side-lobe contrast of 12.93 dB. This level of performance is achieved in a more compact size as compared to conventional apodized gratings, and a similar design philosophy can be used to improve side-lobe reduction in grating-based mirror design for on-chip lasers and other cavity-based designs as well.

Behavior of Linear and Nonlinear Dimensionality Reduction for Collective Variable Identification of Small Molecule Solution-Phase Reactions.

Identifying collective variables (CVs) for chemical reactions is essential to reduce the 3N-dimensional energy landscape into lower dimensional basins and barriers of interest. However, in condensed phase processes, the nonmeaningful motions of bulk solvent often overpower the ability of dimensionality reduction methods to identify correlated motions that underpin collective variables. Yet solvent can play important indirect or direct roles in reactivity, and much can be lost through treatments that remove or dampen solvent motion. This has been amply demonstrated within principal component analysis (PCA), although less is known about the behavior of nonlinear dimensionality reduction methods, e.g., uniform manifold approximation and projection (UMAP), that have become recently utilized. The latter presents an interesting alternative to linear methods though often at the expense of interpretability. This work presents distance-attenuated projection methods of atomic coordinates that facilitate the application of both PCA and UMAP to identify collective variables in the presence of explicit solvent and further the specific identity of solvent molecules that participate in chemical reactions. The performance of both methods is examined in detail for two reactions where the explicit solvent plays very different roles within the collective variables. When applied to raw molecular dynamics data in solution, both PCA and UMAP representations are dominated by bulk solvent motions. On the other hand, when applied to data preprocessed by our attenuated projection methods, both PCA and UMAP identify the appropriate collective variables (though varying sensitivity is observed due to the presence of explicit solvent that results from the projection method). Importantly, this approach allows identification of specific solvent molecules that are relevant to the CVs and their importance.

Genetic alterations and oxidative stress in T cell lymphomas.

T cell lymphomas encompass a diverse group of Non-Hodgkin lymphomas with a wide spectrum of clinical, immunological and pathological manifestations. In the last two decades there has been a progress in our understanding of the cell of origin, genetic abnormalities and their impact on behaviour in T cell lymphomas. Genetic alterations are one of the critical drivers of the pathogenesis of T cell lymphoma. Disease progression has been correlated with multiple genetic abnormalities where malignant clones arise primarily out of the host immune surveillance arsenal. There are many cellular processes involved in disease development, and some of them are T cell signaling, differentiation, epigenetic modifications, and immune regulation. Modulation of these crucial pathways via genetic mutations and chromosomal abnormalities possessing either point or copy number mutations helps tumor cells to develop a niche favourable for their growth via metabolic alterations. Several metabolic pathways especially regulation of redox homeostasis is critical in pathogenesis of lymphoma. Disruption of redox potential and induction of oxidative stress renders malignant cells vulnerable to mitochondrial damage and triggers apoptotic pathways causing cell death. Targeting genetic abnormalities and oxidative stress along with current treatment regime have the potential for improved therapeutics and presents new combination approaches towards selective treatment of T cell lymphomas.