Site-specific Analysis Research Articles

Native Cellular Membranes Facilitate Channel Activity of MscL by Enhancing Slow Collective Motions of Its Transmembrane Helices.

Mechanosensitive channels of large conductance (MscL) serve as a mechanoelectrical valve of cells in response to the membrane tension. The influence of membrane environments on the MscL channel activity and the underlying mechanism remains unclear. Herein, we developed a new sample preparation protocol that allows for the detection of high-quality 1H-detected solid-state NMR spectra of MscL in cellular membranes, enabling site-specific analysis of its dynamics. Dipolar order parameters and spin relaxation rates are measured for 51 residues of MscL in synthetic and native membranes. The dynamics data reveal that while MscL maintains a similar rigidity in both membrane environments, it exhibits enhanced slow collective motions in the native cellular membranes. Molecular dynamics simulations demonstrate the critical role of slow motions in the mechanosensitivity of MscL by promoting protein-membrane interactions. This study examines atomic-resolution dynamics of a membrane-protein in cellular membranes and provides novel insights into the functional significance of membrane-protein dynamics.

Quantification and Site-Specific Analysis of Co-occupied N- and O-Glycopeptides.

Protein glycosylation is a complex post-translational modification that is generally classified as N- or O-linked. Site-specific analysis of glycopeptides is accomplished with a variety of fragmentation methods, depending on the type of glycosylation being investigated and the instrumentation available. For instance, collisional dissociation methods are frequently used for N-glycoproteomic analysis with the assumption that one N-sequon exists per tryptic peptide. Alternatively, electron-based methods are preferable for O-glycosite localization. However, the presence of simultaneously N- and O-glycosylated peptides could suggest the necessity of electron-based fragmentation methods for N-glycoproteomics, which is not commonly performed. Thus, we quantified the prevalence of N- and O-glycopeptides in mucins and other glycoproteins. A much higher frequency of co-occupancy within mucins was detected whereas only a negligible occurrence occurred within nonmucin glycoproteins. This was demonstrated from analyses of recombinant and/or purified proteins, as well as more complex samples. Where co-occupancy occurred, O-glycosites were frequently localized to the Ser/Thr within the N-sequon. Additionally, we found that O-glycans in close proximity to the occupied Asn were predominantly unelaborated core 1 structures, while those further away were more extended. Overall, we demonstrate electron-based methods are required for robust site-specific analysis of mucins, wherein co-occupancy is more prevalent. Conversely, collisional methods are generally sufficient for analyses of other types of glycoproteins.

The IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT): multicenter pig study on the effect of ischemic preconditioning.

Numerous cardioprotective interventions have been reported to reduce myocardial infarct size (IS) in pre-clinical studies. However, their translation for the benefit of patients with acute myocardial infarction (AMI) has been largely disappointing. One reason for the lack of translation is the lack of rigor and reproducibility in pre-clinical studies. To address this, we have established the European IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) pig AMI network with centralized randomization and blinded core laboratory IS analysis and validated the network with ischemic preconditioning (IPC) as a positive control. Ten sites in the COST Innovators Grant (IG16225) network participated in the IMPACT network. Three sites were excluded from the final analysis through quality control of infarct images and use of pre-defined exclusion criteria. Using a centrally generated randomization list, pigs were allocated to myocardial ischemia/reperfusion (I/R, N = 5/site) or IPC + I/R (N = 5/site). The primary endpoint was IS [% area-at-risk (AAR)], as quantified by triphenyl-tetrazolium-chloride (TTC) staining in a centralized, blinded core laboratory (5 sites), or IS [% left-ventricular mass (LV)], as quantified by a centralized, blinded cardiac magnetic resonance (CMR) core laboratory (2 sites). In pooled analyses, IPC significantly reduced IS when compared to I/R (57 ± 14 versus 32 ± 19 [%AAR] N = 25 pigs/group; p < 0.001; 25 ± 13 versus 14 ± 8 [%LV]; N = 10 pigs/group; p = 0.021). In site-specific analyses, in 4 of the 5 sites, IS was significantly reduced by IPC when compared to I/R when quantified by TTC and in 1 of 2 sites when quantified by CMR. A pig AMI multicenter European network with centralized randomization and core blinded IS analysis was established and validated with the aim to improve the reproducibility of cardioprotective interventions in pre-clinical studies and the translation of cardioprotection for patient benefit.

Innovative multi-generation system producing liquid hydrogen and oxygen: Thermo-economic analysis and optimization using machine learning optimization technique

This research investigates the multi-objective optimization of a geothermal-driven multi-generation system designed to produce liquid hydrogen and oxygen as its primary outputs. The system incorporates a Proton Exchange Membrane (PEM) Electrolyzer alongside a modified ejector-based Organic Rankine Cycle to generate the required Energy (heating bar, cooling bar, electricity and hydrogen). Case studies were conducted in three distinct locations: Zanjan in Iran, Aarhus in Denmark, and San Bernardino in the United States, utilizing actual geological and meteorological data for accuracy. Simulations were executed applied Engineering Equation Solver & optimization of the system was carried out to enhance performance by focusing on the objective functions of system exergy efficiency and cost reduction. This was accomplished by utilizing response surface methodology (RSM) along with Minitab software (MS).To optimize the system, six decision variables were identified as critical parameters influencing performance. The optimization results indicated that the system can achieve an exergy efficiency of 53.74 % while maintaining a cost rate of $31.56 per hour. The overall cost rate for the geothermal system was determined to be $54.50 per hour, with $10.10 per hour allocated to hydrogen production and $44.40 per hour to electricity generation. Site-specific analyses highlighted San Bernardino as the most favorable location for implementing this system, projecting an annual production of 90.8 tons of liquid hydrogen and 208.3 kg of oxygen. In August, the geothermal system in San Bernardino can produce up to 7691.6 kg/h of liquid hydrogen, while in December, production decreases to 7402.8 kg/h, marking the lowest output for the year. In contrast, Zanjan and Aarhus demonstrated lower production capacities, underscoring the system's feasibility as dependent on site-specific conditions.

Road-traffic noise exposure and coronary atherosclerosis in the Swedish CArdioPulmonary bioImage Study (SCAPIS).

Road-traffic noise may influence the development of cardiovascular events such as stroke and myocardial infarction, but etiological mechanisms remain unclear. This study aimed to assess the relationship between long-term road-traffic noise exposure and coronary atherosclerosis in Sweden. In the Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort, including 30,154 subjects aged 50-65 years, recruited between 2013 and 2018, coronary atherosclerosis was measured based on computer tomography (CT) scans as coronary artery calcium score, segment involvement score (SIS), and non-calcified plaques (NCP) at enrollment. Based on modified Nordic model, road-traffic noise exposure was modeled for 2000, 2013, and 2018 with interpolation for intermediate years. We investigated the association between time-weighted long-term exposure to road-traffic noise (Lden) and the prevalence of atherosclerosis using ordinal logistic regression models adjusting for potential socioeconomic, behavioral, and environmental confounders, including air pollution. No clear associations were found between road-traffic noise and coronary atherosclerosis. The odds ratio for coronary artery calcium score was 1.00 (95% confidence interval [CI] = 0.96, 1.04), SIS 0.99 (0.96, 1.03), and NCP 0.98 (0.90, 1.03) per interquartile range (9.4 dB Lden) for road-traffic noise exposure during 10 years before enrollment. No consistent associations were observed in site-specific analyses or using shorter exposure periods. Furthermore, exposure-response analyses revealed no clear trends, and there were no strong interactions between road-traffic noise and cardiovascular risk factors in relation to the atherosclerosis markers. Long-term exposure to road-traffic noise was not linked to coronary atherosclerosis or calcification in relatively healthy, middle-aged populations in Sweden.

Hot Spots of Site-Specific Integration into the Sinorhizobium meliloti Chromosome.

The diversity of phage-related sequences (PRSs) and their site-specific integration into the genomes of nonpathogenic, agriculturally valuable, nitrogen-fixing root nodule bacteria, such as Sinorhizobium meliloti, were evaluated in this study. A total of 314 PRSs, ranging in size from 3.24 kb to 88.98 kb, were identified in the genomes of 27 S. meliloti strains. The amount of genetic information foreign to S. meliloti accumulated in all identified PRSs was 6.30 Mb. However, more than 53% of this information was contained in prophages (Phs) and genomic islands (GIs) integrated into genes encoding tRNAs (tRNA genes) located on the chromosomes of the rhizobial strains studied. It was found that phiLM21-like Phs were predominantly abundant in the genomes of S. meliloti strains of distant geographical origin, whereas RR1-A- and 16-3-like Phs were much less common. In addition, GIs predominantly contained fragments of phages infecting bacteria of distant taxa, while rhizobiophage-like sequences were unique. A site-specific integration analysis revealed that not all tRNA genes in S. meliloti are integration sites, but among those in which integration occurred, there were "hot spots" of integration into which either Phs or GIs were predominantly inserted. For the first time, it is shown that at these integration "hot spots", not only is the homology of attP and attB strictly preserved, but integrases in PRSs similar to those of phages infecting the Proteobacteria genera Azospirillum or Pseudomonas are also present. The data presented greatly expand the understanding of the fate of phage-related sequences in host bacterial genomes and also raise new questions about the role of phages in bacterial-phage coevolution.

Uncovering missing glycans and unexpected fragments with pGlycoNovo for site-specific glycosylation analysis across species

Precision mapping of site-specific glycans using mass spectrometry is vital in glycoproteomics. However, the diversity of glycan compositions across species often exceeds database capacity, hindering the identification of rare glycans. Here, we introduce pGlycoNovo, a software within the pGlyco3 software environment, which employs a glycan first-based full-range Y-ion dynamic searching strategy. pGlycoNovo enables de novo identification of intact glycopeptides with rare glycans by considering all possible monosaccharide combinations, expanding the glycan search space to 16~1000 times compared to non-open search methods, while maintaining accuracy, sensitivity and speed. Reanalysis of SARS Covid-2 spike protein glycosylation data revealed 230 additional site-specific N-glycans and 30 previously unreported O-glycans. pGlycoNovo demonstrated high complementarity to six other tools and superior search speed. It enables characterization of site-specific N-glycosylation across five evolutionarily distant species, contributing to a dataset of 32,549 site-specific glycans on 4602 proteins, including 2409 site-specific rare glycans, and uncovering unexpected glycan fragments.

Amplification factors of intensity measures for site-specific PSHA using spectrally equivalent pulse-like and non-pulse-like ground motion records

Proper representations of ground motion characteristics and prediction of rock-to-ground amplification factors (AFs) of intensity measures (IMs) are crucial in site-specific probabilistic seismic hazard analysis (PSHA). By using spectrally equivalent pulse-like and non-pulse-like ground motion suites within the convolution-based PSHA framework, this paper aims to (i) investigate the amplification patterns and AF prediction efficiency for 16 typical IMs; and (ii) evaluate the sensitivities of AF and PSHA to the pulse-characteristic, rock-IM type, and AF functional form. The results reveal that IMs are generally amplified, whereas de-amplification occurs at soft sites for IMs largely dominated by high-frequency content (e.g., Arias intensity). Specific rock-IMs for predicting AFs are recommended through efficiency criterion. The results for pulse-like and non-pulse-like suites are found to be not significantly different; hence, including pulse-like records is generally not essential in convolution-based PSHA as long as the bedrock spectra designed with pulse-type features have been matched. Meanwhile, the similar AF predictions from the linear and nonlinear models indicate that the choice of functional form is of secondary importance. Instead, the selection of rock-IM is of higher importance, especially for soft sites and high-frequency dominated IMs. This study could provide useful insights into ground motion selection and AF prediction for site-specific PSHA.

Quantitative and Site-specific Analysis of Adenosine-to-inosine RNA Editing by Ligation-assisted qPCR

Quantitative and Site-specific Analysis of Adenosine-to-inosine RNA Editing by Ligation-assisted qPCR

Analysis and Visualization of Quantitative Proteomics Data Using FragPipe-Analyst.

The FragPipe computational proteomics platform is gaining widespread popularity among the proteomics research community because of its fast processing speed and user-friendly graphical interface. Although FragPipe produces well-formatted output tables that are ready for analysis, there is still a need for an easy-to-use and user-friendly downstream statistical analysis and visualization tool. FragPipe-Analyst addresses this need by providing an R shiny web server to assist FragPipe users in conducting downstream analyses of the resulting quantitative proteomics data. It supports major quantification workflows, including label-free quantification, tandem mass tags, and data-independent acquisition. FragPipe-Analyst offers a range of useful functionalities, such as various missing value imputation options, data quality control, unsupervised clustering, differential expression (DE) analysis using Limma, and gene ontology and pathway enrichment analysis using Enrichr. To support advanced analysis and customized visualizations, we also developed FragPipeAnalystR, an R package encompassing all FragPipe-Analyst functionalities that is extended to support site-specific analysis of post-translational modifications (PTMs). FragPipe-Analyst and FragPipeAnalystR are both open-source and freely available.

Seismic site characterization baseline data for microzonation and site response analysis of Otuasega Town, Bayelsa State, Niger Delta region of Nigeria

This study presents the findings of a comprehensive geotechnical and seismic site investigation conducted at Otuasega Town located in Bayelsa State within the Niger Delta region of Nigeria. Subsurface exploration involved advancing 10 boreholes to 30 m depth using hollow stem auger drilling. Continuous disturbed and undisturbed soil sampling was performed at 1.5 m intervals for detailed geotechnical testing. Laboratory tests on the recovered soil samples established the index properties, classification, densities and consistency limits of the stratified deposits. The subsurface profile comprised alternating layers of clay, silt and sand typical of deltaic sediments, with the clay fractions exhibiting medium to high plasticity. Shear wave velocity (Vs) profiling using Multichannel Analysis of Surface Waves (WASW) techniques categorised the site predominantly as Site Class C and D based on international standards. The Standard Penetration Test (SPT) N-values ranged from 5 to 10, indicating soft normally consolidated clay conditions typical of the Niger Delta region. Predictive empirical models developed from the field and lab data showed strong correlations for estimating key geotechnical parameters such as SPT blow count, Vs and liquefaction resistance. Ground response analyses using the Vs and SPT data indicated significant site amplification potential, with peak ground accelerations up to 1.5 times the bedrock motion. Liquefaction analysis based on the empirical SPT-based methods revealed a high potential for liquefaction in the sandy layers, especially under strong earthquake shaking. The study characterized the complex sedimentology and provided baseline information for seismic microzonation and site-specific ground response analyses to advance understanding of geohazards in this delta environment.

DEVELOPMENT OF PEAK GROUND ACCELERATION USING A NON-LINEAR APPROACH TO EVALUATE LIQUEFACTION POTENTIAL IN SEI WAMPU BRIDGE, LANGKAT, NORTH SUMATRA, INDONESIA

The design of building structures requires compliance with seismic codes and all their consequences. Based on geotechnical investigation reports, the construction of Sei Wampu Bridge in Langkat, North Sumatra, Indonesia, is located in an area where the soil layers are predominantly sand with shallow water levels because of its proximity to a river and is a high earthquake zone due to the Semangko fault. That condition will affect the potential of liquefaction occurring. This study aims to identify the liquefaction potential in the Sei Wampu Bridge. Based on Indonesian National Standard (SNI) 1726-2019, sites prone to liquefaction are categorized as site class-specific soil (F) and requires site-specific response analysis (SSRA) methods. Non-linear analysis 1-D is chosen to propagate earthquake waves with the software DEEPSOIL V7. The input parameter for soil movement utilizes an average spectral matching method with a minimum of 7 pairs of soil movement selected from the earthquake recording website, PEER Ground Motion Database. The selection of earthquake considers a 1000-year earthquake load return period, or a 7% probability exceeded within 75 years. Site-specific response analysis (SSRA) resulted in a peak ground acceleration (PGA) value for each borehole depth used in liquefaction potential analysis. Using a historical earthquake scenario with a 6.3 Mw shows that the research location has liquefaction potential at 0 m-15 m deep with high vulnerability levels, where the LPI value reaches 36.21.

Comparative analysis of phosphorylated proteomes between plerocercoid and adult Spirometra mansoni reveals phosphoproteomic profiles of the medical tapeworm

BackgroundPlerocercoid larvae of the tapeworm Spirometra mansoni can infect both humans and animals, leading to severe parasitic zoonosis worldwide. Despite ongoing research efforts, our understanding of the developmental process of S. mansoni remains inadequate. To better characterize posttranslational regulation associated with parasite growth, development, and reproduction, a comparative phosphoproteomic study was conducted on the plerocercoid and adult stages of S. mansoni.MethodsIn this study, site-specific phosphoproteomic analysis was conducted via 4D label-free quantitative analysis technology to obtain primary information about the overall phosphorylation status of plerocercoids and adults.ResultsA total of 778 differentially abundant proteins (DAPs) were detected between adults and plerocercoids, of which 704 DAPs were upregulated and only 74 were downregulated. DAPs involved in metabolic activity were upregulated in plerocercoid larvae compared with adults, whereas DAPs associated with binding were upregulated in adults. Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analyses indicated that most DAPs involved in signal transduction and environmental information processing pathways were highly active in adults. DAPs upregulated in the plerocercoid group were enriched mainly in metabolic activities. The kinases PKACA, GSK3B, and smMLCK closely interact, suggesting potential active roles in the growth and development of S. mansoni.ConclusionsThe dataset presented in this study offers a valuable resource for forthcoming research on signaling pathways as well as new insights into functional studies on the molecular mechanisms of S. mansoni.Graphical abstract

Ground-motions site and event specificity: Insights from assessing a suite of simulated ground motions in the San Francisco Bay Area

This article presents the results of a research that is part of a larger collaborative effort between the Lawrence Berkeley National Laboratory and the Pacific Earthquake Engineering Research Center, funded by the US Department of Energy Office of Cybersecurity, Energy Security and Emergency Response. The main objective of this study is to assess a suite of near and far-field simulated ground motions obtained from 20 realizations of an M7 Hayward Fault earthquake in the San Francisco Bay Area, California USA, and inform the selection of rupture simulation parameters leading to strong motions. To this aim, comparisons are conducted with NGA-W2 and directivity ground-motion models and a selected population of records. An archetypal steel moment-resisting frame is utilized to assess infrastructure response distributions. The analyses carried out for each simulated event and subdomain with consistent properties in terms of shallow shear-wave velocity proved to be instrumental for better interpreting the differences between simulated motions and empirical models. The main reasons identified for variances between simulations and empirical relationships included (1) directivity effects fully captured by the simulations across the full breadth of rupture models; (2) site vicinity to ruptures that incorporate large-slip patches, particularly if these are in the forward-directivity direction; and (3) presence of geologic structures that can “trap” seismic waves and produce ground motions with large amplitude and long signal duration. The analyses carried out in this work provide a path for interpreting ground-motion site and event specificity obtained from a suite of physics-based simulations, differing only in the rupture model characterization, to inform the selection of simulation scenarios for site-specific engineering analyses under strong excitations. Evidence from this work points to the possibility that current hazard models may underestimate ground-motion intensities in areas where the combined effect of directivity and site conditions results in large ground-motion amplitudes.

GRable Version 1.0: A Software Tool for Site-Specific Glycoform Analysis With Improved MS1-Based Glycopeptide Detection With Parallel Clustering and Confidence Evaluation With MS2 Information

High-throughput intact glycopeptide analysis is crucial for elucidating the physiological and pathological status of the glycans attached to each glycoprotein. Mass spectrometry-based glycoproteomic methods are challenging because of the diversity and heterogeneity of glycan structures. Therefore, we developed an MS1-based site-specific glycoform analysis method named "Glycan heterogeneity-based Relational IDentification of Glycopeptide signals on Elution profile (Glyco-RIDGE)" for a more comprehensive analysis. This method detects glycopeptide signals as a cluster based on the mass and chromatographic properties of glycopeptides and then searches for each combination of core peptides and glycan compositions by matching their mass and retention time differences. Here, we developed a novel browser-based software named GRable for semi-automated Glyco-RIDGE analysis with significant improvements in glycopeptide detection algorithms, including "parallel clustering." This unique function improved the comprehensiveness of glycopeptide detection and allowed the analysis to focus on specific glycan structures, such as pauci-mannose. The other notable improvement is evaluating the "confidence level" of the GRable results, especially using MS2 information. This function facilitated reduced misassignment of the core peptide and glycan composition and improved the interpretation of the results. Additional improved points of the algorithms are "correction function" for accurate monoisotopic peak picking; one-to-one correspondence of clusters and core peptides even for multiply sialylated glycopeptides; and "inter-cluster analysis" function for understanding the reason for detected but unmatched clusters. The significance of these improvements was demonstrated using purified and crude glycoprotein samples, showing that GRable allowed site-specific glycoform analysis of intact sialylated glycoproteins on a large-scale and in-depth. Therefore, this software will help us analyze the status and changes in glycans to obtain biological and clinical insights into protein glycosylation by complementing the comprehensiveness of MS2-based glycoproteomics. GRable can be freely run online using a web browser via the GlyCosmos Portal (https://glycosmos.org/grable).

Challenges in illumination analysis and design for Martian surface-level habitation

It is needless to say that travel to and settlement on Mars are associated with extreme levels of scientific and engineering issues. This will only be amplified with the long-term duration of the mission, not only due to scarcity of resources, but also as the psychological aspects of the dynamics among the crew increase drastically. It should be emphasized that this is a scientific crew, who have undergone high levels of confinement during space travel to Mars, O (102 Earth days), are living in semi-solitude and partial confinement conditions for durations of O (103 Earth days), and even at the nominal termination of the mission, foresee a high-risk and arduous travel time of O (102 Earth days) back to the Earth. The mental weight of the described mission with its slow pace and tardy episodes, puts the crew under severe psychological issues. Minimal and conservative design of spaces, lack of constant access to the exterior, and social solitude are among major factors contributing to the psychological well-being of the crew. Furthermore, the overall lower levels of natural light, accompanied by the minimum possible area of transparent facades, protecting the crew from harmful radiations and cold exterior, burden the mental conditions of the crew even more. Given the limited availability of data from the surface of Mars, study of the effects linked to the lighting and illumination design of the habitats is challenging. The current manuscript hopes to shed light on the illumination and lighting design and simulation procedure, required data, assumptions, and final results for the surface-level habitats on Mars.•Mars / Sub orbital configuration allows for limited natural lighting, however, upon site-specific analysis, it might be considerable as a base passive source.•Current simulation tools are design based on Earth-bound design requirements. These need to be re-oriented to match available planetary data.

Cannabis Use and Head and Neck Cancer

Cannabis is the most commonly used illicit substance worldwide. Whether cannabis use is associated with head and neck cancer (HNC) is unclear. To assess the clinical association between cannabis use and HNC. This large multicenter cohort study used clinical records from a database that included 20 years of data (through April 2024) from 64 health care organizations. A database was searched for medical records for US adults with and without cannabis-related disorder who had recorded outpatient hospital clinic visits and no prior history of HNC. Propensity score matching was performed for demographic characteristics, alcohol-related disorders, and tobacco use. Subsequently, relative risks (RRs) were calculated to explore risk of HNC, including HNC subsites. This analysis was repeated among those younger than 60 years and 60 years or older. Cannabis-related disorder. Diagnosis of HNC and any HNC subsite. The cannabis-related disorder cohort included 116 076 individuals (51 646 women [44.5%]) with a mean (SD) age of 46.4 (16.8) years. The non-cannabis-related disorder cohort included 3 985 286 individuals (2 173 684 women [54.5%]) with a mean (SD) age of 60.8 (20.6) years. The rate of new HNC diagnosis in all sites was higher in the cannabis-related disorder cohort. After matching (n = 115 865 per group), patients with cannabis-related disorder had a higher risk of any HNC (RR, 3.49; 95% CI, 2.78-4.39) than those without HNC. A site-specific analysis yielded that those with cannabis-related disorder had a higher risk of oral (RR, 2.51; 95% CI, 1.81-3.47), oropharyngeal (RR, 4.90; 95% CI, 2.99-8.02), and laryngeal (RR, 8.39; 95% CI, 4.72-14.90) cancer. Results were consistent when stratifying by older and younger age group. This cohort study highlights an association between cannabis-related disorder and the development of HNC in adult patients. Given the limitations of the database, future research should examine the mechanism of this association and analyze dose response with strong controls to further support evidence of cannabis use as a risk factor for HNCs.

Tartrate-resistant acid phosphatase (TRAP/ACP5) promotes bone length, regulates cortical and trabecular bone mass, and maintains growth plate architecture and width in a sex- and site-specific manner in mice

Tartrate-resistant acid phosphatase (TRAP) serum levels reflect osteoclast number, bone remodeling activity, and fracture risk. Deletion or loss of function of TRAP results in short stature in mice and man. Yet, the impact and mechanisms of TRAP for the site- and sex-specific development of bone and cartilage is not well understood. Here, we use a global TRAP knockout (TRAPKO) and wildtype littermate control (WT) mice of both sexes to investigate TRAP as a possible sex- and site-specific regulator of bone and growth plate development. TRAPKO mice of both sexes weighed less and had shorter tibial length than their WT, features that were more accentuated in male than female TRAPKO mice. These changes were not associated with a general reduction in growth as not all organs displayed a proportionally lower mass, and serum IGF-1 was unchanged. Using μCT and site-specificity analysis of the cortical bone revealed wider proximal tibia, a higher trabecular thickness, and lower trabecular separation in male TRAPKO compared to WT mice, an effect not seen in female mice. Histomorphometric analysis revealed that the growth plate height as well as height of terminal hypertrophic chondrocytes were markedly increased, and the number of columns was decreased in TRAPKO mice of both sexes. These effects were more accentuated in female mice. Proliferation and differentiation of bone marrow derived macrophages into osteoclasts, as well as C-terminal cross links were normal in TRAPKO mice of both sexes. Collectively, our results show that TRAP regulates bone and cartilage development in a sex-and site-specific manner in mice.

Site-Specific Seismic Hazard Analysis for Shallow Tunnel in Nepal

Abstract Several seismic codes are implemented for the design and construction of superstructures in Nepal but there is no seismic guideline for shallow tunnels which are often constructed using conventional engineering approaches. The uniform hazard spectrum was obtained after performing a Probabilistic Seismic Hazard Analysis at Dhulikhel and the target spectrum was estimated by comparing it with the spectrum recommended by the seismic code of Nepal Building Code NBC 105:2020 and Indian standard IS 1893:2016. The average response spectrum from ten recorded earthquake ground motions was selected from a peer ground motion database with the known shear wave velocity obtained from geophysical survey. The comparative analysis revealed that the design spectra for identical soil classes, as determined by this study are slightly higher than those prescribed by the present seismic code provisions. This finding emphasizes the necessity for developing more specific guidelines tailored to the design of shallow tunnels in Nepal to ensure their structural resilience in the event of an earthquake.

Association of Tobacco Use and Cancer Incidence in India: A Systematic Review and Meta-Analysis.

To estimate the strength of the association between tobacco use and cancer incidence among the Indian population. Data from PubMed, Embase, and Virtual Health Library were searched from inception of databases till April 30, 2022. There were no restrictions except for English language and human study. Case-control and cohort studies on cancer incidence in relation to tobacco use were selected. Data were extracted independently by two investigators, and discrepancies were resolved by a third reviewer. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The quality assessment was done using the Newcastle Ottawa Scale. The majority were case-control designs (60, 89.6%), covering diverse geographic regions, with Maharashtra (18, 30%) and Kerala (12, 20%) being the most studied. Pooled effect sizes were calculated using the random-effects model, and forest plots were generated. The risk of any cancer associated with smoked and smokeless tobacco was 2.71 (95% CI, 2.25 to 3.16) and 2.68 (95% CI, 2.22 to 3.14), respectively, indicating similar risks. Gender-wise, smoked tobacco had an association of 2.35 (95% CI, 2.05 to 2.65) for males, whereas for smokeless tobacco, it was 1.77 (95% CI, 1.47 to 2.07) for males and 2.34 (95% CI, 1.26 to 3.42) for females. Regardless of gender, tobacco type, and affected body parts, the risk of cancer due to tobacco use was consistent in the Indian population. Site-specific analysis showed higher risks of respiratory system cancers of 4.97 (95% CI, 3.62 to 6.32) and head and neck cancers of 3.95 (95% CI, 3.48 to 4.42). This study underscores that both smoked and smokeless tobacco are equally harmful to human health among the Indian population, providing insights for stakeholders and policymakers to arrive at tobacco-specific interventions.