Browse Articles

The master male sex determinant Gdf6Y of the turquoise killifish arose through allelic neofunctionalization

Abstract Although sex determination is a fundamental process in vertebrate development, it is very plastic. Diverse genes became major sex determinants in teleost fishes. Deciphering how individual sex-determining genes orchestrate sex determination can reveal new actors in sexual development. Here, we demonstrate that the Y-chromosomal copy of the TGF-β family member gdf6 ( gdf6Y ) in Nothobranchius furzeri , an emerging model organism in aging research, gained the function of the male sex determinant through allelic diversification while retaining the skeletal developmental function shared with the X-chromosomal gdf6 allele ( gdf6X ). Concerning sex determination, gdf6Y is expressed by somatic supporting cells of the developing testes. There it induces the male sex in a germ cell-independent manner in contrast to sex determination in zebrafish and the medaka. Looking for downstream effectors of Gdf6Y, we identified besides TGF-β signaling modulators, especially the inhibitor of DNA binding genes id1/2/3 , the mRNA decay activator zfp36l2 as a new GDF6 signaling target.

Exploring factors influencing university students’ entrepreneurial intentions: The role of attitudes, beliefs, and environmental support

Entrepreneurship is an increasingly popular career choice among students, driven by the transformative impact of emerging technologies and evolving professional landscapes. This study focuses on how higher education shapes students’ professional identities and entrepreneurial intentions, particularly among business school students. Utilizing the Theory of Planned Behavior (TPB) as the foundational framework, the study examines the factors influencing entrepreneurial intentions, with a specific emphasis on the moderating role of departmental identification. The primary aim of this research is to explore how students’ identification with their academic departments influences the relationship between entrepreneurial attitude, self-efficacy, and environmental support with entrepreneurial intentions. The study hypothesizes that the stronger the departmental identification, the more significant these relationships become. A survey is conducted among students from several public universities in the eastern provinces of Mainland China, yielding 1,632 valid responses. The results confirm a positive correlation between entrepreneurial attitude, self-efficacy, and environmental support with entrepreneurial intentions. Furthermore, departmental identification moderates these relationships, amplifying the effects when students identify strongly with their academic departments. These findings emphasize the critical role of departmental identity in shaping entrepreneurial aspirations. They highlight the need for higher education institutions to leverage departmental identity as a strategic tool to guide students’ career trajectories. By fostering a supportive academic environment that strengthens departmental identity, institutions can better prepare their students for entrepreneurial success in a rapidly evolving professional world.

Integrated healthy lifestyle even in late-life mitigates cognitive decline risk across varied genetic susceptibility

AbstractIt remains unclear whether the benefits of adhering to a healthy lifestyle outweigh the effects of high genetic risk on cognitive decline. We examined the association of combined lifestyle factors and genetic risk with changes in cognitive function and six specific dimensions of cognition among older adults from the Chinese Longitudinal Healthy Longevity Survey (1998–2018, n = 18,811, a subset of 6301 participants with genetic information). Compared to participants with an unfavorable lifestyle, those with a favorable lifestyle showed a 46.81% slower rate of cognitive decline, with similar results across most cognitive domains. High genetic risk was associated with a 12.5% faster rate of cognitive decline. Individuals with a high genetic risk and a favorable lifestyle have slower cognitive decline than those with a low genetic risk and an unfavorable lifestyle. These data suggest that the benefits of a favorable lifestyle outweigh genetic factors, and therefore that adhering to a favorable lifestyle may offset the genetic risk for accelerated cognitive decline.

Self- versus clinician-collected swabs in anal cancer screening: A clinical trial

Background Risk of anal cancer is high in certain populations and screening involves collection of anal swabs for HPV DNA and/or cytology testing. However, barriers exist, such as the need for an intimate examination, and stigma around HIV status, sexual orientation, and sexual practices. Self-collected anal swabs (SCA) are a proposed alternative to clinician-collected swabs (CCA) to overcome these barriers. Methods Participants were order-randomised to undergo SCA or CCA first, with a second swab taken immediately afterwards. Sample adequacy was assessed for HPV DNA and cytology testing. CCA was used as the gold standard to calculate sensitivity and specificity of SCA for cytology and HPV results. Acceptability of swab collection was assessed following the procedure. Results There was no significant difference in sample validity for HPV DNA testing between SCA and CCA (p = 0.564). Concordance was >90% for detection of any HR-HPV and HPV16. There was no significant difference in cellular adequacy for cytological testing between SCA and CCA, (p = 0.162). Concordance for cytologic prediction was 88.2% for any cytologic abnormality. Almost half (48.5%) of participants expressed no preference for SCA versus CCA; 15.2% preferred SCA and 35.4% CCA. Conclusions SCA may be an acceptable and feasible alternative to CCA for detecting HPV and cytological abnormalities in a clinic population.

Systematically developing a registry of splice-site creating variants utilizing massive publicly available transcriptome sequence data

Abstract Genomic variants causing abnormal splicing play important roles in genetic disorders and cancer development. Among them, variants that cause the formation of novel splice-sites (splice-site creating variants, SSCVs) are particularly difficult to identify and often overlooked in genomic studies. Additionally, these SSCVs are frequently considered promising candidates for treatment with splice-switching antisense oligonucleotides (ASOs). To leverage massive transcriptome sequence data such as those available from the Sequence Read Archive, we develop a novel framework to screen for SSCVs solely using transcriptome data. We apply it to 322,072 publicly available transcriptomes and identify 30,130 SSCVs. Among them, 5121 SSCVs affect disease-causing variants. By utilizing this extensive collection of SSCVs, we reveal the characteristics of Alu exonization via SSCVs, especially the hotspots of SSCVs within Alu sequences and their evolutionary relationships. We discover novel gain-of-function SSCVs in the deep intronic region of the NOTCH1 gene and demonstrate that their activation can be suppressed using splice-switching ASOs. Collectively, we provide a systematic approach for automatically acquiring a registry of SSCVs, which facilitates the elucidation of novel biological mechanisms underlying splicing and serves as a valuable resource for drug discovery. The catalogs of SSCVs identified in this study are accessible on the SSCV DB ( https://sscvdb.io ).

Examining the risk of delirium in patients hospitalized with COVID-19: Insights from the homeless population

For patients hospitalized with COVID-19, delirium is a serious and under-recognized complication, and people experiencing homelessness (PEH) may be at greater risk. This retrospective cohort study compared delirium-associated risk factors and clinical outcomes between PEH and non-PEH. This study used patient records from 154 hospitals discharged from 2020–2021 from the Texas Inpatient Public Use Data file. Study subjects (n = 878) were patients, aged 18–69 years, who were hospitalized with COVID-19 and were identified as homeless. The baseline group included (n = 176,518) patients with COVID-19 aged 18–69 years who were not homeless. Logistic regression models were used to identify risk factors for delirium. Relevant risk factors included chronic comorbidities, substance use disorders, and traumatic brain injury (TBI). Seven of the delirium-associated risk factors were more prevalent among PEH compared to baseline. PEH had higher rates of TBI, alcohol, cannabis, and opioid use disorders. PEH had significantly higher rates of delirium (10.6% vs. 8.1%; P<0.01). However, PEH had fewer respiratory complications, including pneumonia (48.5% vs. 81.9%; P<0.001) and respiratory failure (28.7% vs. 61.9%; P<0.001), and lower in-hospital mortality (3.3% vs. 9.5%; P<0.001). The anti-viral Remdesivir had a protective effect against delirium (AOR = 0.63; CI: 0.60, 0.66). Mean hospital length of stay (LOS) was more than twice as long for delirious patients compared with non-delirious patients (18.4 days vs. 7.7 days; P<0.001). Delirium greatly increased the risk of in-hospital mortality (AOR = 3.8; CI: 3.6, 4.0). For PEH (n = 29) who died from COVID-19, delirium was present in more than half (52%) of cases. Hospitals should screen PEH for delirium and adopt nursing protocols to prevent delirium and reduce its severity.

High-impedance microwave resonators with two-photon nonlinear effects

AbstractNonlinear effects play a central role in photonics as they form the foundation for most of the device functionalities such as amplification and quantum state preparation and detection. Typically the nonlinear effects are weak and emerge only at high photon numbers with strong drive. Here we present an experimental study of a Josephson junction -based high-impedance resonator. We show that by taking the resonator to the limit of consisting effectively only of one junction, results in strong nonlinear effects already for the second photon while maintaining a high impedance of the resonance mode. Our experiment yields thus resonators with strong interactions both between individual resonator photons and from the resonator photons to other electric quantum systems. We also present an energy diagram technique which enables to measure, identify and analyse different multi-photon optics processes along their energy conservation lines.

Retrospective study of incidence/prevalence of pigmentary maculopathy and retinopathy in patients receiving pentosan polysulfate sodium

Purpose To evaluate prevalence and incidence rates of pigmentary maculopathy and retinopathy (PM/PR), and visual acuity (VA) changes in patients exposed to pentosan polysulfate sodium (PPS) and in patients with interstitial cystitis (IC) not exposed to PPS. Methods This is a retrospective cohort study (January 2015–March 2021) which included adult de-identified patients from the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) and Komodo Health database. Three patient cohorts were identified: two PPS-exposed patient cohorts, and Non-PPS-exposed IC patient cohort. Key study outcomes included PM/PR/Any (defined based on prior literature regardless of PPS exposure) and PM/PR/PPS (further defined by an algorithm that was based on clinical notes and other protocol-prespecified criteria in PPS-exposed patients), and VA changes in each respective cohort. Results Prevalence of PM/PR/Any was relatively common in patients prior to PPS exposure (4.16%–8.43%). Incidence rate of PM/PR/PPS was uncommon in both PPS-exposed cohorts (0.13–0.15 per 100 person-years). Crude incidence rates of PM/PR/Any (based on ITT analysis) varied slightly across 3 study cohorts (2.13–2.81 and 2.38 per 100-person-years for PPS-exposed cohorts and Non-PPS-exposed IC cohort, respectively). Across all 3 study cohorts, patients with PM/PR/Any appeared to have approximately 2-fold higher proportion of 3 lines of VA worsening than those without PM/PR/Any. Conclusion Prevalence of PM/PR was common in patients prior to PPS exposure. Incidence of PM/PR/PPS that may be associated with PPS exposure was relatively uncommon. Crude incidence rates of PM/PR appeared similar across all patient cohorts regardless of PPS exposure.

Impact of population screening for Lynch syndrome insights from the All of Us data

Relative validity and reproducibility of a short semi-quantitative food frequency questionnaire for Chinese athletes

A convenient but efficient tool for evaluating dietary intakes in Chinese professional athletes has yet to be established. The aim of this study was to assess the validity of a short semi-quantitative food frequency questionnaire (FFQ) through comparison with 3-day weighed food records (3DWFRs) and corresponding serum biomarkers from a cohort of 102 professional athletes, while also evaluating its reproducibility. The relative validity was assessed using Spearman correlation coefficients, cross-quintiles classification, weighted kappa, and Bland–Altman analysis, while reproducibility was evaluated using the Spearman correlation coefficients and intraclass correlation coefficient (ICC) between two FFQs. The results showed the median (range) crude correlation coefficients (CCs) between the first FFQ and 3DWFRs for energy and nutrients, and the food groups were 0.331 (0.219 to 0.568) and 0.292 (-0.035 to 0.455), respectively. Omega-3 polyunsaturated fatty acid (EPA, DHA, and EPA+DHA) intake estimated from the FFQ significantly correlated with corresponding serum biomarkers, with CCs ranging from 0.389 to 0.520. Weighted kappa statistics, indicating acceptable consistency (> 0.2) for most items, varied from -0.076 to 0.581, except for vitamin C, vegetables, and oils. Misclassification of nutrients and food groups into extreme quartiles was rare, with a median misclassification rate of 2% (ranging from 1% to 12%) and 3% (ranging 0 to 10%), respectively. Bland–Altman analysis revealed good agreement between FFQ and 3DWFRs, with over 90% of data points falling within the limits of agreement (LOA) for all assessed nutrients and food groups. In the reproducibility analysis, the median (range) crude CC and ICC for energy and nutrients were 0.574 (0.423 to 0.643) and 0.668 (0.558 to 0.763), respectively, while for food groups, they were 0.681 (0.242 to 0.764) and 0.640 (0.371 to 0.787), respectively. In conclusion, the short FFQ demonstrated acceptable relative validity and reproducibility for most nutrients and food groups, suggesting its potential as a valuable tool for assessing dietary intake and nutrition status among young Chinese athletes.

Author Correction: Pervasive fire danger continued under a negative emission scenario

CAMSAP2 is required for bridging fiber assembly to ensure mitotic spindle assembly and chromosome segregation in human epithelial Caco-2 cells

In mammalian epithelial cells, cytoplasmic microtubules are mainly non-centrosomal, through the functions of the minus-end binding proteins CAMSAP2 and CAMSAP3. When cells enter mitosis, cytoplasmic microtubules are reorganized into the spindle composed of both centrosomal and non-centrosomal microtubules. The function of the CAMSAP proteins upon spindle assembly remains unknown, as these do not exhibit evident localization to spindle microtubules. Here, we demonstrate that CAMSAP2, but not CAMSAP3, is required for spindle assembly upon mitotic entry. CAMSAP2 knockout (KO) Caco-2 cells showed a delay in mitotic progression, whereas CAMSAP3 KO cells did not. The spindle in CAMSAP2 KO cells was short and displayed a reduced microtubule density, particularly around chromosomes. This indicated a loss of bridging fibers, which are known to assist alignment of sister kinetochores through interaction with kinetochore fibers. Consistent with this, live-cell imaging of CAMSAP2 KO cells captured slow elongation of the anaphase spindle and errors in chromosome segregation. Therefore, we propose that CAMSAP2 ensures efficient reorganization of cytoplasmic microtubules into the mitotic spindle through constructing bridging fibers that assist faithful segregation of sister chromatids.

Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation

AbstractMutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear. Here, we present structures of KRAS, RRAS2, and MRAS bound to the catalytic subunit (p110α) of PI3Kα, elucidating the interaction interfaces and local conformational changes upon complex formation. Structural and mutational analyses highlighted key residues in RAS and PI3Kα impacting binding affinity and revealed isoform-specific differences at the interaction interface in RAS and PI3K isoforms, providing a rationale for their differential affinities. Notably, in the RAS-p110α complex structures, RAS interaction with p110α is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kα interaction in PI3Kα activation and provides a blueprint for designing PI3Kα isoform-specific inhibitors to disrupt this interaction.

Linguistically informed ChatGPT prompts to enhance Japanese-Chinese machine translation: A case study on attributive clauses

In the field of Japanese-Chinese translation linguistics, the issue of correctly translating attributive clauses has persistently proven to be challenging. Present-day machine translation tools often fail to accurately translate attributive clauses from Japanese to Chinese. In light of this, this paper investigates the linguistic problem underlying such difficulties, namely how does the semantic role of the modified noun affect the selection of translation patterns for attributive clauses, from a linguistic perspective. Through the analysis of numerous examples, the study develops a novel three-step prompt chaining strategy, which was tested using ChatGPT. The experimental results demonstrate that this approach significantly improves translation quality, with an average score increase of over 43%. These findings highlight the effectiveness and potential of linguistically informed prompt design in enhancing the translation accuracy of complex sentence structures. This study not only offers a new perspective on the integration of linguistics theory and machine translation technologies, but also provides valuable insights for optimizing large language models prompt and improving language education tools.

Coverage bias in small molecule machine learning

Abstract Small molecule machine learning aims to predict chemical, biochemical, or biological properties from molecular structures, with applications such as toxicity prediction, ligand binding, and pharmacokinetics. A recent trend is developing end-to-end models that avoid explicit domain knowledge. These models assume no coverage bias in training and evaluation data, meaning the data are representative of the true distribution. However, the domain of applicability is rarely considered in such models. Here, we investigate how well large-scale datasets cover the space of known biomolecular structures. For doing so, we propose a distance measure based on solving the Maximum Common Edge Subgraph (MCES) problem, which aligns well with chemical similarity. Although this method is computationally hard, we introduce an efficient approach combining Integer Linear Programming and heuristic bounds. Our findings reveal that many widely-used datasets lack uniform coverage of biomolecular structures, limiting the predictive power of models trained on them. We propose two additional methods to assess whether training datasets diverge from known molecular distributions, potentially guiding future dataset creation to improve model performance.

Determinants of agricultural employment during the COVID-19 pandemic: A spatial analysis of Brazilian municipalities

The impact of COVID-19 has extended beyond the health toll it has taken on populations. The global economy has experienced significant downturns, with unemployment rates reaching unprecedented highs for this century. Nonetheless, the agricultural sector has been uniquely affected by the pandemic, particularly given its crucial role in food supply. This study sought to examine the effects of the COVID-19 pandemic on agricultural employment in Brazilian municipalities. To achieve this, we employed a dataset spanning the period before and during the pandemic (2018–2021). Spatial econometrics was utilized to identify potential spatial factors linked to this occurrence. Notably, the findings reveal that the transfer policies implemented by the Brazilian Federal Government have had a positive impact on agricultural employment in Brazilian municipalities, challenging the common assumption that such measures might discourage job-seeking efforts. Moreover, the results suggest that the agricultural sector has managed to absorb individuals displaced from other sectors of the economy, demonstrating remarkable resilience in the face of economic challenges.

Vertex model with internal dissipation enables sustained flows

AbstractComplex tissue flows in epithelia are driven by intra- and inter-cellular processes that generate, maintain, and coordinate mechanical forces. There has been growing evidence that cell shape anisotropy, manifested as nematic order, plays an important role in this process. Here we extend an active nematic vertex model by replacing substrate friction with internal viscous dissipation, dominant in epithelia not supported by a substrate or the extracellular matrix, which are found in many early-stage embryos. When coupled to cell shape anisotropy, the internal viscous dissipation allows for long-range velocity correlations and thus enables the spontaneous emergence of flows with a large degree of spatiotemporal organisation. We demonstrate sustained flow in epithelial sheets confined to a channel, providing a link between the cell-level vertex model of tissue dynamics and continuum active nematics, whose behaviour in a channel is theoretically understood and experimentally realisable. Our findings also show a simple mechanism that could account for collective cell migration correlated over distances large compared to the cell size, as observed during morphogenesis.

How traditional cultural load affects tourists’ purchasing intention of tourist souvenirs

Based on the previous studies on the impact of traditional culture on tourists’ purchasing intentions, this study aims to further explore the mechanism and boundary conditions regarding the traditional cultural load in tourist souvenir packaging. Through seven simulated experiments (N = 3203), the impact of different degrees of traditional cultural load on tourists’ purchasing intentions has been examined, with value perception, cultural identity, and purchase purpose, advancing the research in the field of traditional culture and tourism marketing. The findings provide insights for managers in the industry of tourism and souvenir marketing for their package design.

Inequitable distribution of risks associated with occupational heat exposure driven by trade

Clinical, histopathological and parasitological follow-up of dogs naturally infected by Leishmania infantum before and after miltefosine treatment and associated therapies

In Brazil, Visceral Leishmaniases is caused by Leishmania infantum, and domestic dogs are the main reservoirs in its urban transmission cycle. As an alternative to euthanizing dogs, miltefosine has been used to treat canine visceral leishmaniasis since 2016. In this study, we have assessed the efficacy of miltefosine for treating canine visceral leishmaniasis in a new endemic area through follow-up of naturally infected dogs was evaluated. The clinical, parasitological, and histopathological characteristics of 21 dogs naturally infected with L. infantum were assessed at three time points: on the day before initiating miltefosine treatment (T0), immediately after treatment completion (T1), and 6 months after treatment completion (T2). Three dogs were treated exclusively with miltefosine, while eighteen received combination therapy with miltefosine with other treatments such as allopurinol, domperidone and immunotherapy. Skin biopsies were obtained from the abdomen to assess inflammatory responses and to quantify parasite loads using qPCR. The parasites were isolated using aspirates acquired from popliteal lymph nodes. Molecular and parasitological analyses confirmed the presence of L. infantum in all dogs, validating the effectiveness of skin and lymph node samples for diagnosis. The clinical conditions of the infected animals were improved and the skin parasite load decreased after treatment, even when distinct combination therapies were performed. The histopathological assessment revealed a miltefosine-induced reduction in the inflammatory response and a decrease in amastigotes number. Furthermore, a positive correlation was established between the reduction in parasite load and the enhancement of clinical scoring, as well as a reduction in the skin inflammatory response. Our findings suggest that miltefosine-based combination therapies reduce skin parasite load and improve clinical outcomes, while the dogs treated with miltefosine alone showed increased parasitic load and worsened clinical staging at T2. Considering this data belonging to a recent transmission area, treatment strategy suggests effective in controlling canine visceral leishmaniasis.