Selection Events Research Articles

Interface design of SARS-CoV-2 symmetrical nsp7 dimer and machine learning-guided nsp7 sequence prediction reveals physicochemical properties and hotspots for nsp7 stability, adaptation, and therapeutic design.

The COVID-19 pandemic, driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates a profound understanding of the virus and its lifecycle. As an RNA virus with high mutation rates, SARS-CoV-2 exhibits genetic variability leading to the emergence of variants with potential implications. Among its key proteins, the RNA-dependent RNA polymerase (RdRp) is pivotal for viral replication. Notably, RdRp forms dimers via non-structural protein (nsp) subunits, particularly nsp7, crucial for efficient viral RNA copying. Similar to the main protease (Mpro) of SARS-CoV-2, there is a possibility that the nsp7 might also undergo mutational selection events to generate more stable and adaptable versions of nsp7 dimer during virus evolution. However, efforts to obtain such cohesive and comprehensive information are lacking. To address this, we performed this study focused on deciphering the molecular intricacies of nsp7 dimerization using a multifaceted approach. Leveraging computational protein design (CPD), machine learning (ML), AlphaFold v2.0-based structural analysis, and several related computational approaches, we aimed to identify critical residues and mutations influencing nsp7 dimer stability and adaptation. Our methodology involved identifying potential hotspot residues within the dimeric nsp7 interface using an interface-based CPD approach. Through Rosetta-based symmetrical protein design, we designed and modulated nsp7 dimerization, considering selected interface residues. Analysis of physicochemical features revealed acceptable structural changes and several structural and residue-specific insights emphasizing the intricate nature of such protein-protein complexes. Our ML models, particularly the random forest regressor (RFR), accurately predicted binding affinities and ML-guided sequence predictions corroborated CPD findings, elucidating potential nsp7 mutations and their impact on binding affinity. Validation against clinical sequencing data demonstrated the predictive accuracy of our approach. Moreover, AlphaFold v2.0 structural analyses validated optimal dimeric configurations of affinity-enhancing designs, affirming methodological precision. Affinity-enhancing designs exhibited favourable energetics and higher binding affinity as compared to their counterparts. The obtained physicochemical properties, molecular interactions, and sequence predictions advance our understanding of SARS-CoV-2 evolution and inform potential avenues for therapeutic intervention against COVID-19.

On selection and conditioning in multiple testing and selective inference

Summary We investigate a class of methods for selective inference that condition on a selection event. Such methods follow a two-stage process. First, a data-driven collection of hypotheses is chosen from some large universe of hypotheses. Subsequently, inference takes place within this data-driven collection, conditioned on the information that was used for the selection. Examples of such methods include basic data splitting as well as modern data-carving methods and post-selection inference methods for lasso coefficients based on the polyhedral lemma. In this article, we take a holistic view of such methods, considering the selection, conditioning and final error control steps together as a single method. From this perspective, we demonstrate that multiple testing methods defined directly on the full universe of hypotheses are always at least as powerful as selective inference methods based on selection and conditioning. This result holds true even when the universe is potentially infinite and only implicitly defined, such as in the case of data splitting. We provide general theory and intuition before investigating in detail several case studies where a shift to a nonselective or unconditional perspective can yield a power gain.

Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased Tcell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ Tcells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.

A developmentally controlled cellular decompartmentalization process executes programmed cell death in the Arabidopsis root cap.

Programmed cell death (PCD) is a fundamental cellular process crucial to development, homeostasis, and immunity in multicellular eukaryotes. In contrast to our knowledge on the regulation of diverse animal cell death subroutines, information on execution of PCD in plants remains fragmentary. Here, we make use of the accessibility of the Arabidopsis (Arabidopsis thaliana) root cap to visualize the execution process of developmentally controlled PCD. We identify a succession of selective decompartmentalization events and ion fluxes as part of the terminal differentiation program that is orchestrated by the NO APICAL MERISTEM, ARABIDOPSIS THALIANA ACTIVATING FACTOR, CUP-SHAPED COTYLEDON (NAC) transcription factor SOMBRERO. Surprisingly, the breakdown of the large central vacuole is a relatively late and variable event, preceded by an increase of intracellular calcium levels and acidification, release of mitochondrial matrix proteins, leakage of nuclear and endoplasmic reticulum lumina, and release of fluorescent membrane reporters into the cytosol. In analogy to animal apoptosis, the plasma membrane remains impermeable for proteins during and after PCD execution. Elevated intracellular calcium levels and acidification are sufficient to trigger cell death execution specifically in terminally differentiated root cap cells, suggesting that these ion fluxes act as PCD-triggering signals. This detailed information on the cellular processes occurring during developmental PCD in plants is a pivotal prerequisite for future research into the molecular mechanisms of cell death execution.

Abstract C130: Increasing prostate cancer education and screening for black men in southeastern Michigan: Your prostate, your health

Abstract Background Black Men (BM) have disproportionately higher mortality rates from prostate cancer (PCa) and present with more advanced disease. Early screening may improve outcomes. The aim of our project was to provide education, screening, and provider outreach in efforts to decrease the disproportionate number of PCa deaths in Black men. Methods We conducted focus group discussions with BM to assess their perceptions and understanding of PCa and screening. Focus groups aided in the development of educational materials. Educational materials were distributed at community events. Attendants were asked to participate in a survey to assess their knowledge, interest, and perceptions of prostate cancer screening and diagnosis. Screening was offered, at select events, using prostate-specific antigen (PSA) testing. Men with PSA levels of ≥4 ng/ml were contacted for follow-up. The project included training for Henry Ford Health (HFH) providers and an assessment of their PCa screening practice. Results We completed 4 focus groups and distributed ~1000 PCa educational brochures. To date, 136 men completed the survey. The least common response (n=33, 21.17%) to signs and symptoms associated with prostate cancer was “Prostate cancer can have no symptoms.” while the most common response (n=108, 66.42%) stated that prostate cancer is associated with “Having a hard time passing urine.” The most common response (n=106, 79.1%) to the perceived barrier to prostate cancer screening was “Lack of education around the importance of screening.” Furthermore, when participants were asked why men do not get prostate cancer screening the most common response (n=119, 79.33%) was “Fear of diagnosis.” The greatest number of survey responses (n=90, 69.77%) stated that “Social Media” is how they learned about prostate cancer screening. The largest number of responses (n=83, 57.24%) for the preferred method of communication regarding getting a prostate cancer screening was, “Text message reminder to schedule an appointment.” We participated in 42 community events between March 2022 to May 2023. 323 men were screened. 27 men had an elevated PSA, and 14 of these men did not complete follow-up. The reasons for the lack of follow-up were inability to re-contact (n=10, 71%), lack of insurance (n=2, 14%), no show to appointment (n=1, 7%), fear (n=1, 7%), and unknown (n=1, 7%). HFH provider educational sessions were conducted. Of 129 providers who completed a screening practice assessment, 78 (60%) routinely offered PSA screening to men between ages 55-69. Between 2018 to 2023 at HFH, the PSA screening rate overall increased from 8.2% to 12.7%. Conclusion Although our outreach efforts were effective at increasing PSA screening, half the men with elevated PSA did not follow-up. Future efforts should further reduce barriers to PCa screening and follow-up. Citation Format: Shane A. Tinsley, Doreen Dankerlui, Camille Romain, Wilma Ruffin, Clarence Burnett, Donna Long, Karen Yacobucci, Jaye Clement, Abisola Fasakin, Biola Makinde-Odusola, Eric Williams, Tiffany Fields, Firas Abdollah, Daniel Moore, Clara Hwang, Eleanor M. Walker. Increasing prostate cancer education and screening for black men in southeastern Michigan: Your prostate, your health [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C130.

Exploring Factors Linked to Home-Reported Acute Pain Events and Pain Crises in Sickle Cell Disease (SCD) through Flare Tracking in the Ascend Study

Introduction: Pain is a prominent symptom in sickle cell disease (SCD) and often broadly categorized as persistent chronic pain or more intense acute pain episodes compared to regular chronic pain experiences. Many research studies focus solely on pain events requiring healthcare utilization, neglecting those experienced at home, which may cloud the understanding of an individual's daily experience in managing their symptoms. Capturing home-reported evidence is crucial for comprehending SCD's impact on patients and potential effects of medical interventions. Objective: The objective of the Ascend Study was to collect individuals' experiences with pain events in SCD, employing a flexible, home-reported outcomes data collection methodology in Folia Health's mobile and web-based platform. Methods: The Advarra IRB-approved study recruited individuals with any genotype of SCD in the U.S., aged 13 and above, and caregivers of children aged 4 to 12. E-consent and data collection occurred through the Folia platform, where participants selected and tracked relevant symptoms (including, but not limited, to pain-specific symptoms) and treatments, along with health-related quality of life, over the course of 3 months per participant. Baseline severity scores were collected on a 1 to 10 Likert scale for symptoms that were pre-selected by participants at the start of the study. Participants also directly reported potential acute pain events and pain crises experienced in monthly surveys. Detailed flare tracking was set up for four symptom types (chronic pain, acute pain, pain crises, pain and discomfort), enabling structured follow-up questions on select pain flare events. Flare tracking was activated if participants reported a 2-point increase in severity compared to self-identified baselines or opted to track a pain symptom outside of their pre-selected routine. Overall pain burden was collected by participants who routinely tracked all of these various pain experiences, comprising the Ascend Study's home-reported pain hierarchy (Figure A). Results: 89% (n=59) of tracking participants reported experiencing a potential pain crisis for at least 1 month through monthly surveys. Analysis using the flare threshold applied to all pain symptoms tracked (sensitivity 77.5%; specificity 44.9%) identified 2,660 potential pain flare events. Among participants, 86% (n=57) experienced at least one flare event based on the flare threshold. On average, each participant had 24.9 flare days. Flare events identified by the threshold included 9 pain types tracked on a 1-10 Likert scale and 26 pain types tracked as binary “yes/no.” A total of 812 potential pain flare events reported by 46 participants prompted flare tracking follow-up questions (Table 1). Increases in chronic pain were more common than new types. 74% of these participants (n=34) opted to provide additional information through flare tracking in 282 pain flare events. Real-time flare tracking was reported in 85% of flare tracking events. From follow-up responses, most common classifications of pain were stabbing(188, 30.3%), pulsing or throbbing(144, 23.2%), and dull or aching(143, 23.0%). The back (155, 15.7%) and leg (268, 27.2%) were the most prevalent pain locations, with weather (177) and seasonal change (92) identified as potential triggers. Top flare descriptors included ‘can't do normal activities’ (84, 24.4%) and ‘not getting better with home pain meds’ (78, 22.7%). Conclusion: The Ascend Study provides detailed insights into SCD acute pain experiences, showing a high percentage of real-time flare tracking. Chronic pain flares were frequently reported, back and leg pain being the most prevalent locations, and seasonal changes identified as potential triggers. While the flare threshold analysis identified many potential pain flare events, the method's sensitivity might lead to lower specificity for pain flare events and the inclusion of potentially non-flare events. Findings provide valuable insights into the acute pain experiences of individuals with SCD, emphasizing the significance of capturing home-reported evidence to improve patient care and SCD therapies.

IntS6 and the Integrator phosphatase module tune the efficiency of select premature transcription termination events

The metazoan-specific Integrator complex catalyzes 3' end processing of small nuclear RNAs (snRNAs) and premature termination that attenuates the transcription of many protein-coding genes. Integrator has RNA endonuclease and protein phosphatase activities, but it remains unclear if both are required for complex function. Here, we show IntS6 (Integrator subunit 6) over-expression blocks Integrator function at a subset of Drosophila protein-coding genes, although having no effect on snRNAs or attenuation of other loci. Over-expressed IntS6 titrates protein phosphatase 2A (PP2A) subunits, thereby only affecting gene loci where phosphatase activity is necessary for Integrator function. IntS6 functions analogous to a PP2A regulatory B subunit as over-expression of canonical B subunits, which do not bind Integrator, is also sufficient toinhibit Integrator activity. These results show that the phosphatase module is critical at only a subset of Integrator-regulated genes and point to PP2A recruitment as a tunable step that modulates transcription termination efficiency.

Genome scans capture key adaptation and historical hybridization signatures in tetraploid wheat.

Tetraploid wheats (Triticum turgidum L.), including durum wheat (T. turgidum ssp. durum (Desf.) Husn.), are important crops with high nutritional and cultural values. However, their production is constrained by sensitivity to environmental conditions. In search of adaptive genetic signatures tracing historical selection and hybridization events, we performed genome scans on two datasets: (1) Durum Global Diversity Panel comprising a total of 442 tetraploid wheat and wild progenitor accessions including durum landraces (n=286), domesticated emmer (T. turgidum ssp. dicoccum (Schrank) Thell.; n=103) and wild emmer (T. turgidum ssp. dicoccoides (Korn. ex Asch. & Graebn.) Thell.; n=53) wheats genotyped using the 90K single nucleotide polymorphism (SNP) array, and (2) a second dataset comprising a total 121 accessions of nine T. turgidum subspecies including wild emmer genotyped with>100M SNPs from whole-genome resequencing. The genome scan on the first dataset detected six outlier loci on chromosomes 1A, 1B, 3A (n=2), 6A, and 7A. These loci harbored important genes for adaptation to abiotic stresses, phenological responses, such as seed dormancy, circadian clock, flowering time, and key yield-related traits, including pleiotropic genes, such as HAT1, KUODA1, CBL1, and ZFN1. The scan on the second dataset captured a highly differentiated region on chromosome 2B that shows significant differentiation between two groups: one group consists of Georgian (T. turgidum ssp.paleocolchicum A. Love & D. Love) and Persian (T. turgidum ssp. carthlicum (Nevski) A. Love & D. Love) wheat accessions, while the other group comprises all the remaining tetraploids including wild emmer. This is consistent with a previously reported introgression in this genomic region from T. timopheevii Zhuk. which naturally cohabit in the Georgian and neighboring areas. This region harbored several adaptive genes, including the thermomorphogenesis gene PIF4, which confers temperature-resilient disease resistance and regulates other biological processes. Genome scans can be used to fast-track germplasm housed in gene banks and in situ; which helps to identify environmentally resilient accessions for breeding and/or to prioritize them for conservation.

Impact of Patient Selection and Management over Different Time Periods on the Outcome of Patients with Large B-Cell Lymphoma Receiving Chimeric Antigen Receptor T-Cell Therapy

Introduction. Autologous chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is an effective treatment for relapsed or refractory large B-cell lymphoma (LBCL). Real-world studies have reported improved outcomes in terms of safety and efficacy in comparison with pivotal trials. These differences have been associated to a learning curve in patient selection and adverse event control, but this hypothesis has not been proven. The aim of this study was to analyze patient selection and CAR T-cell management across different time periods and assess its impact on treatment outcomes Methods. This retrospective analysis included all consecutive LBCL patients receiving CAR-T cell therapy (axicabtagene-ciloleucel [axi-cel] and tisagenlecleucel) in the third line setting from approval in 2019 to 2023 and reported in the Spanish Registry. Patients were categorized in 3 consecutive time periods of 18 months each according to infusion date. Baseline characteristics, manufacturing times and production failures as well as efficacy and safety outcomes were compared across periods. An additional safety and efficacy analysis was conducted in patients receiving axi-cel. Results. The study included 458 patients: 117 (26%), 194 (42%) and 147 (32%) in the early (EP) (January 2019-June 2020), intermediate (IP) (July 2020-December 2021) and recent period (RP) (January 2022-June 2023), respectively. In terms of patient profile, baseline characteristics evolved overtime as patients in the RP had received less number of prior therapies, had less primary refractory disease, less bulky disease and had lower LDH at lymphodepletion. On the contrary, the RP had more patients with ECOG performance status ³2 and higher comorbidity burden. Regarding the product, the use of axi-cel increased overtime, from 45% in the EP to 83% in the RP (Table). The time from apheresis to infusion improved overtime, moving from 48 days in the EP to 38 days in the RP. Manufacturing failures (5%) and use of bridging therapy (81%) remained stable overtime. Regarding efficacy, overall (complete) response rates improved overtime (from 66% [25%] in the EP to 78% [52%] in the RP [p<0.001], respectively). Median PFS and OS for the whole cohort were 3.9 months (95% CI 3.23-5.83) and 18.5 months (95% CI 13.53 - 27.67) without differences across periods. In terms of toxicity, patients in the RP had more grade > or = 3 CRS and ICANS, received more tocilizumab and corticosteroids and required more ICU admission compared with the EP. These results were driven by the higher use of axi-cel in the RP. When focusing exclusively on axi-cel patients (n=301), the CR rate also improved overtime (32% in the EP; 37% in the IP and 55% in the RP, p=0.016) (Figure) while median PFS (6.63 months, 95%CI 3.90 - 11.43) and OS (25.73 months, 95%CI 18.57 - NA) remained stable. In the multivariable analysis, ECOG PS > 1 (HR 2.68, 95% CI 1.35-5.09, p=0.005) and LDH ³ 500 UI/L (HR 1.54, 95% CI 1.02-2.31, p=0.04) but not treatment period were associated with a shorter PFS. In terms of toxicity, the time to CRS onset (median of 3 vs. 1 days, p=0.001) and ICANS (median of 8 vs. 6 days, p=0.06) was later in the EP compared with the RP. The incidence of grade > or = 3 CRS and ICANS (ranging from 10% to 7% and 36% to 41%, respectively), the use of tocilizumab, corticosteroids, and anakinra as well as ICU admission rate and 12-month non-relapse mortality (2% vs 5%) remained stable across periods. Conclusion. The criteria for selecting patients for CAR T-cell therapy have evolved overtime towards a less aggressive disease profile and allowing less fit patients for therapy in recent times. Patients treated in the RP were more likely to respond to these therapies but this did not translate into prolonged survival or an improved safety profile.

Tumor-Agnostic Treatment Heading to the Clinic?

The antibody-drug conjugate trastuzumab deruxtecan could soon be the first therapy of its kind to be approved as a tumor-agnostic treatment for HER2-mutant or -expressing tumors. However, appropriate patient selection and adverse event management will be key to maximizing its benefit.

Integrating operant behavior and fiber photometry with the open-source python library Pyfiber

Despite the popularity of fiber photometry (FP), its integration with operant behavior paradigms is progressing slowly. This can be attributed to the complex protocols in operant behavior – resulting in a combination of diverse non-predictable behavioral responses and scheduled events, thereby complicating data analysis. To overcome this, we developed Pyfiber, an open-source python library which facilitates the merge of FP with operant behavior by relating changes in fluorescent signals within a neuronal population to behavioral responses and events. Pyfiber helps to 1. Extract events and responses that occur in operant behavior, 2. Extract and process the FP signals, 3. Select events of interest and align them to the corresponding FP signals, 4. Apply appropriate signal normalization and analysis according to the type of events, 5. Run analysis on multiple individuals and sessions, 6. Collect results in an easily readable format. Pyfiber is suitable for use with many different fluorescent sensors and operant behavior protocols. It was developed using Doric lenses FP systems and Imetronic behavioral systems, but it possesses the capability to process data from alternative systems. This work sets a solid foundation for analyzing the relationship between different dimensions of complex behavioral paradigms with fluorescent signals from brain regions of interest.

Human genetic adaptation related to cellular zinc homeostasis.

SLC30A9 encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show is found in homozygosis in the Denisovan genome and displays accompanying signatures suggestive of archaic introgression. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. Notably, the ZnT9 50Val variant was found associated with differences in zinc handling by the mitochondria and endoplasmic reticulum, with an impact on mitochondrial metabolism. Given the essential role of the mitochondria in skeletal muscle and since the derived allele at rs1047626 is known to be associated with greater susceptibility to several neuropsychiatric traits, we propose that adaptation to cold may have driven this selection event, while also impacting predisposition to neuropsychiatric disorders in modern humans.

Carbon-Bonding Metal Catalysis (CBMC): A Supramolecular Complex Directs Structural-Isomer Selection in Gold-Catalyzed Reactions.

Carbon is a primary element to constitute organic molecules, while metal catalysis is a basic tool in organic synthesis. The establishment of a link between the ubiquitous carbon bonding and metal catalysis is thus a fundamentally important problem. However, there is yet no experimental example to introduce the role of carbon bonding in a metal catalysis process. Herein, we merged the topics of carbon bonding and metal catalysis together and demonstrated that a supramolecular carbon-bonding metal complex can not only give rise to catalytic activity but, more remarkably, direct structural-isomer selection events in gold-catalyzed reactions. The experimental results unveil the fact that the imposing of weak carbon-bonding interactions on a gold complex can alter the carbene as well as the Lewis acid property of these catalysts. These results illustrate a non-negligible role of weak carbon-bonding interactions in the modulation of metal catalysis. As such, carbon-bonding metal catalysis is suggested to be used as a routine tool not only in the development of reactions but more frequently in analyzing reaction processes in metal catalysis.

Genomic characterization of respiratory syncytial virus genotypes circulating in the paediatric population of Sydney, NSW, Australia.

Respiratory syncytial virus (RSV), or human orthopneumovirus, is a major cause of acute lower respiratory infection (ALRI), particularly in young children, causing significant morbidity and mortality. We used pathogen genomics to characterize the population structure and genetic signatures of RSV isolates circulating in children in New South Wales between 2016 and 2018 and to understand the evolutionary dynamics of these strains in the context of publicly available RSV genomes from the region and globally. Whole-genome phylogenetic analysis demonstrated the co-circulation of a few major RSV clades in the paediatric population from Sydney. The whole-genome-based genotypes A23 (RSV-A ON1-like genotype) and B6 (RSV-B BA9-like genotype) were the predominant RSV-A and RSV-B genotypes circulating during the study period, respectively. These genotypes were characterized with high levels of diversity of predicted N- and O-linked glycosylation patterns in both the G and F glycoproteins. Interestingly, a novel 72-nucleotide triplication in the sequence that corresponds to the C-terminal region of the G gene was identified in four of the A23 genotype sequenced in this study. Consistently, the population dynamics analysis demonstrated a continuous increase in the effective population size of A23 and B6 genotypes globally. Further investigations including functional mapping of mutations and identifying the impact of sequence changes on virus fitness are highly required. This study highlights the potential impact of an integrated approach that uses WG-based phylogeny and studying selective pressure events in understanding the emergence and dissemination of RSV genotypes.

Characterization and cross-comparison of digital stethoscopes for telehealth remote patient auscultation

— Stethoscopes are commonly used to diagnose cardiac and respiratory diseases. The advent of digital stethoscopes added the capability to remotely monitor the cardiorespiratory well-being of patients and facilitate digital remote auscultations for physicians to examine their patients outside of the clinic. To increase the adoption of a hybrid diagnosis between in-person and remote auscultations, it is important to characterize the frequency response of different configurations of digital stethoscopes. A standard testing platform was adopted from the literature and re-validated by seven physicians. Two wearable and two non-wearable digital stethoscopes were investigated. A similarity factor score was used to analyze select time-synchronized acoustic events that achieved high fidelity between stethoscopes. The frequency responses between devices were compared using the correlation coefficient. Two devices reported the highest correlation coefficient of 0.72 and 0.75 in the wearable and non-wearable categories, respectively. The correlation coefficient of the frequency responses between the same pair of devices on the human chest was 0.91. With such a high agreement in the frequency response between the wearable and non-wearable digital stethoscope, it can be concluded that the configuration of digital stethoscope is not a limiting factor of performance, and both are acceptable and desirable for physicians to adopt either configuration in remote delivery of healthcare.

Marine heatwaves threaten cryptic coral diversity and erode associations among coevolving partner.

Climate change-amplified marine heatwaves can drive extensive mortality in foundation species. However, a paucity of longitudinal genomic datasets has impeded understanding of how these rapid selection events alter cryptic genetic structure. Heatwave impacts may be exacerbated in species that engage in obligate symbioses, where the genetics of multiple coevolving taxa may be affected. Here, we tracked the symbiotic associations of reef-building corals for 6 years through a prolonged heatwave, including known survivorship for 79 of 315 colonies. Coral genetics strongly predicted survival of the ubiquitous coral, Porites (massive growth form), with variable survival (15 to 61%) across three morphologically indistinguishable-but genetically distinct-lineages. The heatwave also disrupted strong associations between these coral lineages and their algal symbionts (family Symbiodiniaceae), with symbiotic turnover in some colonies, resulting in reduced specificity across lineages. These results highlight how heatwaves can threaten cryptic genotypes and decouple otherwise tightly coevolved relationships between hosts and symbionts.

Y-Chromosome Haplotype Report among Eight Italian Horse Breeds.

Horse domestication and breed selection processes have profoundly influenced the development and transformation of human society and civilization over time. Therefore, their origin and history have always attracted much attention. In Italy, several local breeds have won prestigious awards thanks to their unique traits and socio-cultural peculiarities. Here, for the first time, we report the genetic variation of three loci of the male-specific region of the Y chromosome (MSY) of four local breeds and another one (Lipizzan, UNESCO) well-represented in the Italian Peninsula. The analysis also includes data from three Sardinian breeds and another forty-eight Eurasian and Mediterranean horse breeds retrieved from GenBank for comparison. Three haplotypes (HT1, HT2, and HT3) were found in Italian stallions, with different spatial distributions between breeds. HT1 (the ancestral haplotype) was frequent, especially in Bardigiano and Monterufolino, HT2 (Neapolitan/Oriental wave) was found in almost all local breeds, and HT3 (Thoroughbred wave) was detected in Maremmano and two Sardinian breeds (Sardinian Anglo-Arab and Sarcidano). This differential distribution is due to three paternal introgressions of imported stallions from foreign countries to improve local herds; however, further genetic analyses are essential to reconstruct the genetic history of native horse breeds, evaluate the impact of selection events, and enable conservation strategies.

Professiograms and psychograms as a tool for staff selection

Introduction. The relevance of the research topic is due to the increasing role of personnel in the organization, which, in turn, entails an increase in the requirements for the selection of personnel, the need to improve the personnel selection mechanism. Each organization, when selecting personnel, seeks to determine whether a person applying for a vacant position (future subject of labor) really meets the objective requirements put forward by professional activity. A successful selection of personnel will help to avoid further layoffs, which will inevitably follow in the event of an unsuccessful selection. On the contrary, successful selection of personnel helps to reduce the financial and organizational costs of the enterprise (firm). These issues can be solved by the development and use of professiograms and psychograms, which contribute to an objective assessment of the professional level of a potential employee, to identify his personal characteristics, thereby predicting the future success or failure of the candidate in the performance of job duties.Purpose of this study is to reveal and substantiate the specifics and important role of the professiogram and psychogram, which act as effective staff selection tools. The objectives of the study are defined as follows: disclosure of the essence and specifics of professiograms and psychograms; identification of the main types of professiograms and psychograms; determination of the structure of professiograms and psychograms; determination of their role in solving the problems of personnel selection.Materials and Methods. The methodological basis of the article was made up of studies conducted in the field of professiography - a technology aimed at studying the requirements that a profession makes for a complex of personal qualities, psychological abilities, psychological and physical capabilities of a candidate for a certain position.Results. The article presents different points of view on the concepts of "professiogram" and "psychogram", which do not have an unambiguous approach. The author's interpretation of the concepts under consideration is proposed.Conclusion. The results of the study (they are theoretical substantiation of the specifics of the professiogram and psychogram as a tool and means of personnel selection; the author's definition of the concepts "professiogram" and "psychogram"; their analysis and classification; identification of the optimal structure of the professiogram and psychogram in the context of their use for personnel selection) can be used in the process of further study of the problems under consideration, in the development by specialists of professiograms and psychograms in the organization, as well as applied by practical psychologists and sociologists.

Discretization-Based Feature Selection as a Bilevel Optimization Problem

Discretization-based feature selection approaches have shown interesting results when using several metaheuristic algorithms such as Particle Swarm Optimization (PSO), Genetic Algorithm (GA), Ant Colony Optimization (ACO), etc. However, these methods share the same shortcoming which consists in encoding the problem solution as a sequence of cut-points. From this cut-points vector, the decision of deleting or selecting any feature is induced. Indeed, the number of generated cut-points varies from one feature to another. Thus, the higher the number of cut-points, the higher the probability of selecting the considered feature and vice versa. This fact leads to the deletion of possibly important features having a single or a low number of cut-points, such as the infection rate, the glycemia level, and the blood pressure. In order to solve the issue of the dependency relation between the feature selection (or removal) event and the number of its generated potential cut-points, we propose to model the discretization-based feature selection task as a bi-level optimization problem and then solve it using an improved version of an existing co-evolutionary algorithm, named I-CEMBA. The latter ensures the variation of the number of features during the migration process in order to deal with the multimodality aspect. The resulting algorithm, termed Bi-DFS (Bi-level Discretization-based Feature Selection), performs selection at the upper level while discretization is done at the lower level. The experimental results on several high-dimensional datasets show that Bi-DFS outperforms relevant state-of-the-art methods in terms of classification accuracy, generalization ability, and feature selection bias.

Uncovering genes underlying coat color variation in indigenous cattle breeds through genome-wide positive selection

The identification of candidate genes related to pigmentation and under selective sweep provides insights into the genetic basis of pigmentation and the evolutionary forces that have shaped this variation. The selective sweep events in the genes responsible for normal coat color in Indian cattle groups are still unknown. To find coat color genes displaying signs of selective sweeps in the indigenous cattle, we compiled a list of candidate genes previously investigated for their association with coat color and pigmentation. After that, we performed a genome-wide scan of positive selection signatures using the BovineSNP50K Bead Chip in 187 individuals of seven indigenous breeds. We applied a wide range of methods to find evidence of selection, such as Tajima’s D, CLR, iHS, varLD, ROH, and FST. We found a total of sixteen genes under selective sweep, that were involved in coat color and pigmentation physiology. These genes are CRIM1 in Gir, MC1R in Sahiwal, MYO5A, PMEL and POMC in Tharparkar, TYRP1, ERBB2, and ASIP in Red Sindhi, MITF, LOC789175, PAX3 and TYR in Ongole, and IRF2, SDR165 and, KIT in Nelore, ADAMTS19 in Hariana. These genes are related to melanin synthesis, the biology of melanocytes and melanosomes, and the migration and survival of melanocytes during development.