bluuebunny/crossref_metadata_2025 huggingface dataset:
The ASPARAGINE-RICH PROTEIN–LYST-INTERACTING PROTEIN5 complex regulates noncanonical AUTOPHAGY8 degradation in Arabidopsis
Authors: Wu Yanying , Zhu Kaikai , Chen Si , Xing Enzhen , Li Jiajia , Tian Wenqi , Gao Ming , Kong Jiaxin , Zheng Danni , Wang Xue , Zhou Weihong , Men Shuzhen , Liu Xinqi
Published: January 2025

The endocytic and autophagic pathways play important roles in abiotic stress responses and maintaining cellular homeostasis in plants. Asparagine-rich proteins (NRPs) are plant-specific, stress-responsive proteins that are involved in many abiotic stress-related signaling pathways. We previously demonstrated that NRP promotes PIN FORMED 2 (PIN2) vacuolar degradation to maintain PIN2 homeostasis under abscisic acid treatment in Arabidopsis (Arabidopsis thaliana). However, the molecular function and mechanism of NRP in cellular vesicle trafficking remain unknown. In this study, we report that NRP directly interacts with LIP5 and ATG8, critical components of the endocytic and autophagic pathways, respectively. Genetic analyses show that NRP overexpression rescues canonical autophagy defects in a LIP5-dependent manner. Cellular and biochemical evidence indicates that NRP–LIP5 recruits ATG8 to multivesicular bodies for further vacuolar degradation, implying that a novel NRP-mediated endocytic pathway is utilized to compensate for the canonical autophagy defects that occur during plant stress responses. These findings provide insights into the crosstalk between the endocytic and autophagic pathways and uncover a function of ATG8 distinct from its canonical role in autophagy. The mechanism revealed here confers an evolutionary advantage to plants and provides a molecular basis for breeding crops with greater stress tolerance.
Decomposing changes in subnational income inequality in the United States, 1980–2019
Authors: Thiede Brian C , Brown David L , Jayasekera Deshamithra H W , Jensen Leif , Butler Jaclyn L W
Published: January 2025

The rapid growth of income inequality in the United States has unfolded unevenly across the country. Levels of, and changes in, income inequality within local economies have been spatially and temporally heterogeneous. While previous research has identified correlates of subnational inequality, it has given less attention to the contribution of compositional changes. Drawing on commuting zone (CZ)-level estimates produced from U.S. Census and American Community Survey data, we extend the literature on subnational income inequality by addressing four main objectives. First, we track changes in the prevalence of five sets of inequality risk factors. Second, we measure the associations between these factors and within-CZ income inequality in 1980 and 2019 and describe changes in these relationships over time. Third, we decompose changes in within-CZ income inequality (1980–2019) into components attributable to changes in composition and coefficients. Fourth, we compare the South to other regions to explore relevant patterns of socioeconomic change unique to the former. We find substantively large shifts in the prevalence of all five sets of risk factors and significant changes in the effects of many factors, especially the age and industrial structures of CZs. Coefficient effects explain the largest overall share of changing inequality between 1980 and 2019, but these overall effects mask considerable heterogeneity in the strength and direction of both composition and coefficient effects of individual blocks of variables. We also find significant regional variation in the size of coefficient effects and the relative contributions of composition and coefficient effects.
Heterogeneous effects of telework on job satisfaction across gender and employment precarity: evidence from postpandemic Japan
Authors: Araki Satoshi
Published: January 2025

Scholars have long investigated the impact of flexible work arrangements (FWA) on job satisfaction. However, in recent years, many workplaces have abruptly introduced telework as a form of FWA in response to the COVID-19 pandemic, only to later call workers back to offices as the pandemic subsides. This trend is particularly prevalent in societies with inflexible work cultures like Japan. Nevertheless, we know little about how telework affects job satisfaction unequally among workers during and after the pandemic. Using the nationwide survey dataset collected by the Government of Japan’s Cabinet Office from 2020 to 2023, this study examines heterogeneous associations between telework and job satisfaction. Propensity score matching analyses based on the counterfactual framework show that the average effect of telework is substantially positive in both 2020 and 2023, but its magnitude decreases by over two-thirds during this period. Nonetheless, female nonregular workers experienced a larger psychological return on telework in 2023 despite its null effect in 2020. Male nonregular workers also see a high telework effect on job satisfaction in 2020 and 2023, whereas the effect size among their regular counterparts declines to near zero. These findings suggest that, in postpandemic Japan, (1) regular workers, particularly men, do not gain psychological benefits from telework under the traditional work culture requiring them to be present in the office, but (2) telework underpins job satisfaction of relatively precarious workers with less job security and benefits; and thus (3) the expanded usage of telework may help mitigate labor stratification in worker well-being.
Exploring the protective role of Heracleum persicum L. extract in testicular toxicity induced by mercuric chloride: insights into hormonal modulation and cell survival pathways
Authors: Zhao Ronghui , Xu Shijuan , Jia Chao , Zhu Shufang , Ma Lianshun , Chen Yalan , Chen Dalei
Published: January 2025

The study investigated the effects of Heracleum persicum L. extract (HPE) on oxidative damage caused by mercuric chloride (HgCl₂) in rat testes. Sixty male Wistar rats were divided into six groups: a sham group, a HgCl₂ group, three groups receiving HgCl₂ with HPE at doses of 250, 500, and 750 mg/kg, and a control group treated with 750 mg/kg HPE alone over 50 days. HgCl₂ was administered intraperitoneally for the first 10 days, followed by HPE gavage for 40 days. On day 51, hormone levels (testosterone, FSH, LH), nitric oxide levels, antioxidant enzyme activity, and pro-inflammatory cytokines were measured. Testicular tissue was analyzed for thiobarbituric acid reactive substances, ferric reducing capacity, thiol levels, and stereological indicators of seminiferous tubules. The study also examined the p53/Cas-3/Bax/Bcl-2 apoptotic pathway. LC-ESI/MS and SEM-EDS analysis detected 25 substances and 14 mineral elements. HgCl₂ exposure significantly reduced LH, T, and FSH levels, while HPE improved these hormones, especially at higher doses. Inflammatory cytokines were elevated due to HgCl₂, but HPE reduced (P < 0.05) these levels and enhanced (P < 0.05) antioxidant enzyme activity, indicating protective effects against oxidative stress. Testicular analysis showed significant (P < 0.05) damage from HgCl₂, but HPE preserved tissue integrity and improved parameters. Weight measurements indicated that HgCl₂ reduced (P < 0.05) body and reproductive weights, while HPE restored these weights. HPE also counteracted apoptotic changes, highlighting its potential as a therapeutic agent against HgCl₂-induced damage.
Wearing Hearing Protection Makes Me Worse at My Job: Impacts of Hearing Protection Use on Sensorimotor Tracking Performance
Authors: Wisniewski Matthew G. , Chuwonganant C. Shane
Published: January 2025

Objectives:

Occupational hearing loss is a significant problem worldwide despite the fact that it can be mitigated by the wearing of hearing protection devices (HPDs). When surveyed, workers frequently report that worsened work performance while wearing HPDs is one reason why they choose not to wear them. However, there have been few studies to supplement these subjective reports with objective measures. Where they do exist, assessed performance measures have mostly characterized auditory situational awareness in gross terms (e.g., average speech comprehension scores over an entire session). The temporal dynamics of performance and HPD impacts on nonauditory aspects of work performance are largely unknown. In the present study, we aimed to fill this gap in the literature by measuring how HPD usage impacted sensorimotor tracking performance in relation to ongoing auditory events.

Design:

In two experiments, listeners heard commands sourced from the coordinate response measure (CRM) corpus (i.e., sentences of the form “Ready  go to   now”). These commands informed listeners of which of nine moving on-screen objects to track with a computer mouse (e.g., “blue four” refers the listener to a blue square). The commands were presented in background street noise and were heard under either “No HPD” or “HPD” conditions. In experiment 1, HPD wearing was simulated with a digital filter designed to mimic the attenuation profile of a passive HPD. In experiment 2, actual HPDs were worn by listeners. Continuous recording of tracking error allowed us to simultaneously examine how HPD wearing impacted speech comprehension, the accuracy of tracking, and how tracking accuracy varied as a function of time on task and ongoing auditory events (e.g., the presentation of a critical CRM sentence).

Results:

In both experiments, listeners spent less time tracking the correct object in the HPD condition. After trimming data to those time points in which the target object was known, worse performance was exhibited by the HPD condition than the No HPD condition. In the examination of the temporal dynamics of tracking error, it was apparent that differences arose strongly during the presentation of CRM sentences.

Conclusions:

Workers’ complaints of poorer performance while wearing HPDs are justified and extend beyond just diminished auditory situational awareness. The negative impact on nonauditory aspects of work performance may be strongest around critical listening periods. Addressing these aspects of performance will be an important part of addressing HPD nonuse in occupational settings.
Recurrent uncomplicated lower urinary tract infections in women
Authors: Liu Jiaxin , Xu Kaiyun , Hu Jiajie , Wang Lei , Liu Zhiyong
Published: January 2025

Recurrent uncomplicated lower urinary tract infections (RULUTIs) are common among women without anatomical or physiological abnormalities and affect women of all age groups, races, and ethnicities. Herein, we summarized the sources of epidemiology, etiology, diagnosis, treatment, prophylaxis, and follow-up evaluations in cases of RULUTIs. Patients' medical histories, symptoms, and signs were recorded. The review showed that urinalysis, culture, and sensitivity should be tested before empiric treatment. A first-line therapeutic strategy should be applied based on the results of the urine culture and sensitivity tests. Therefore, estrogen should be used as an ancillary therapy. After the successful treatment of acute infections, intermittent or continuous prophylaxis can be administered. Patients may benefit from follow-up evaluations to avoid recurrent infections. We expect that clinicians will pay more attention to RULUTIs.
Effect of different doses of dexmedetomidine on atrial fibrillation in adults after cardiac surgery
Authors: Zhang Xinling , Liu Jian , Shi Yafei , Wang Huirong , Wang Fei , Wang Wenzhu
Published: January 2025

In this study, we compared the effects of various doses of dexmedetomidine on the incidence of atrial fibrillation following cardiac surgery in adults. 224 adult patients who underwent elective cardiac surgery were randomly assigned to two groups. The DEX0.5 group received a continuous infusion of dexmedetomidine at a rate of 0.5 μg·kg⁻1·h⁻1, while the DEX1 group received it at a rate of 1 μg·kg⁻1·h⁻1 during the induction of anesthesia, which was maintained for 24 hours. The primary outcome was the incidence of atrial fibrillation, while the secondary outcomes included other tachyarrhythmias, bradycardia, hypotension, duration of mechanical ventilation, time spent in the cardiac care unit, and length of hospitalization. A total of 101 patients were included in the DEX0.5 group, while 104 patients were included in the DEX1 group. The incidence of atrial fibrillation was significantly lower in the DEX1 group compared to the DEX0.5 group (10.6% vs. 21.8%, P = 0.029). Additionally, the duration of mechanical ventilation was shorter in the DEX1 group than in the DEX0.5 group (8.9 vs. 15.2 hours, P = 0.018). Logistic regression analyses were conducted to investigate the factors influencing atrial fibrillation. The results indicated that the dose of dexmedetomidine was the only independent predictor (odds ratio = 0.394, 95% confidence interval 0.172 to 0.903, P = 0.028). Compared to a continuous infusion of 0.5 μg·kg⁻1·h⁻1, this study suggested that administering dexmedetomidine at a dose of 1 μg·kg⁻1·h⁻1 for 24 hours is effective in reducing the incidence of atrial fibrillation following cardiac surgery.
Identification of glycogen synthase kinase 3alpha/beta as a host factor required for HBV transcription using high-throughput screening
Authors: Nishitsuji Hironori , Naito Yui , Murakami Yuuna , Sugiyama Masaya , Mizokami Masashi , Shoji Ikuo , Murata Takayuki , Shimotohno Kunitada
Published: January 2025

Background and Aims:

HBV leads to severe liver diseases, such as cirrhosis and HCC. Identification of host factors that regulate HBV replication can provide new therapeutic targets. The discovery of sodium taurocholate cotransporting polypeptide (NTCP) as an HBV entry receptor has enabled the establishment of hepatic cell lines for analyzing HBV infection and propagation. Using this new system, studies aimed at identifying host factors that regulate HBV propagation have increased.

Approach and Results:

We established an HBV-based-reporter gene expression system that mimics HBV replication from transcription to virus egress. Using this approach, we screened 1827 Food and Drug Administration–approved compounds and identified glycogen synthase kinase 3 (GSK3)alpha/beta inhibitors, including AZD1080, CHIR-98014, CHIR-98021, BIO, and AZD2858, as anti-HBV compounds. These compounds suppressed HBeAg and HBsAg production in HBV-infected human primary hepatocytes. Proteome analysis revealed that GSK3alpha/beta phosphorylated forkhead box K1/2 (FOXK1/2)s. A double-knockout of FOXK1/2 in HBV-infected HepG2-NTCP cells reduced HBeAg and HBsAg production. The rescue of FOXK2 expression, but not FOXK1 expression, in FOXK1/2-double-knockout cells restored HBeAg and HBsAg production. Importantly, phosphorylation of FOXK2 at Ser 424 is required for GSK3alpha/beta-mediated HBeAg and HBsAg production. We observed the binding of FOXK2 to HBV DNA in HepG2-NTCP cells.

Conclusions:

Our recombinant HBV-based screening system enables the discovery of new targets. Using our approach, we identified GSK3 inhibitors as potential anti-HBV agents.
Therapeutic Advances in Drug-Resistant Epilepsy
Authors: Hodelin Maynard Edwin Humberto , Diana Ţînț  , González Judith González , Morales Chacón Lilia María
Published: January 2025

Background:

Drug-resistant epilepsy (DRE) is a condition that affects up to 40% of the total population of patients with epilepsy. Advancements in the pharmaceutical field over recent decades have facilitated a significant expansion in the range of available drug options. Nevertheless, the prevalence of DRE has remained unaltered in recent years.

Areas of Uncertainty:

It is not completely understood how the new antiseizure medications and therapeutic strategies will impact the current burden of patients with DRE.

Data Sources:

A bibliographic search was made in MEDLINE to make a content analysis of the identified studies on the management of DRE.

Therapeutic Advances:

The elucidation of different underlying mechanisms of DRE has helped to create therapeutic alternatives for DRE. Some current drugs under clinical studies are cenobamate (100% and ≥90% of sustained seizure reduction), padsevonil (50% of seizure reduction), radiprodil, and NRTX-1001 (good tolerability, safety, and pharmacokinetic profiles), and BL-001 (favorable safety profile and good tolerability). Preclinical studies have also shown promising results of LRP-661, a cannabidiol derivative with superior bioavailability compared with the actual formulation of cannabidiol available in the market. In addition, gene therapies such as CAMK2A-EKC have achieved good effects in the control of focal cortical dysplasia type II in animal models. However, the combination of epilepsy surgery with novel ways of antiseizure medications administration, such as intraventricular delivery of valproate, increases the possibility of therapeutic success for patients with DRE.

Conclusions:

The promising therapeutic advances in the pharmacologic field have still not made great changes in the prevalence of DRE. Utilizing established and widely recognized antiseizure medications continues to be a viable treatment approach, particularly when complemented by additional therapeutic modalities such as physical exercise, ketogenic diet, interventional procedures, and epilepsy surgery.
The role of germline and somatic mutations in predicting cancer-associated thrombosis: a narrative review
Authors: Lanting Vincent , Oskam Merel , Wilmink Hanneke , Kamphuisen Pieter W. , van Es Nick
Published: January 2025

Purpose of review

Patients with cancer have an increased risk of venous thromboembolism (VTE). Guidelines suggest to use risk assessment tools to guide decisions about thromboprophylaxis, but current tools have modest discriminatory ability. Genetic information from the germline or tumor has the potential to improve VTE prediction. Here, we provide a clinical overview of the current role of genetics in cancer-associated VTE.

Recent findings

Germline mutations, such as factor V Leiden and prothrombin G20210A, are associated with a 2- to 2.5-fold increased VTE risk in patients with cancer. Tumor-specific somatic mutations also contribute to VTE risk, such as ALK rearrangements increasing the risk in nonsmall cell lung cancer and IDH1 mutations decreasing the risk in gliomas. Other somatic mutations associated with VTE independent of tumor type include KRAS, STK11, MET, KEAP1, CTNNB1, and CDKN2B. Incorporating data on germline or somatic mutations in risk scores improves discriminatory ability compared with the Khorana score.

Specific germline and somatic mutations are associated with an increased VTE risk in patients with cancer and potentially improve performance of clinical risk scores. The increasing and widespread use of genetic testing in cancer care provides an opportunity for further development of prediction models incorporating genetic predictors.
Safety and Tolerability of Interval Compressed Chemotherapy Schedule in Children Receiving Treatment for Ewing Sarcoma: A Real-world Experience From India
Authors: Pal Somdipa , Krishnan Yamini , Parameswaran Krishnan V. , Sainulabdin Gazel
Published: January 2025

Background and Aims:

Chemotherapy with alternating cycles of vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide, along with primary tumor treatment with surgery or radiotherapy or both, constitute the usual treatment of Ewing sarcoma. The AEWS0031 study demonstrated survival benefits after interval-compressed chemotherapy without significant toxicity. The aim of this study was to assess the tolerability of dose-intensified chemotherapy in developing countries like India.

Methods:

This was a retrospective analysis of children younger than 18 years of age with newly diagnosed Ewing sarcoma who came for treatment from December 2017 to December 2022. Children received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2), etoposide (500 mg/m2) for 17 cycles, with filgrastim (5 µg/kg; maximum 300 µg) between cycles. Primary tumor treatment was provided with surgery or radiotherapy or both. Local treatment was given between weeks 12 to 16. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Radiologic response assessment was carried out with restaging CT or MRI scans after 6 to 8 cycles of chemotherapy in nonmetastatic and metastatic settings, respectively.

Results:

Thirty-one children were enrolled. Twenty-three children received all 17 cycles of chemotherapy. The median cycle interval was 18 days and 41% of children received chemotherapy at the 2-week interval. Grade 4 febrile neutropenia was observed in 32% of cycles but no treatment-related mortality was reported. Anemia and thrombocytopenia requiring transfusion support were recorded in 28 (5.6%) and 69 cycles (13.9%) of chemotherapy, respectively. There were 2 events of grade 4 cardiac toxicities in the form of cardiomyopathy and arrhythmia requiring intensive care management. After surgery, good necrosis was achieved in 61% of cases. Three children had a relapse with an event-free survival (EFS) of 87%.

Conclusion:

Intensified chemotherapy administered every 2 weeks intervals in Ewing sarcoma, is tolerable with adequate supportive care in resource-constrained settings.
Factors influencing participation and engagement in post-stroke cardiac rehabilitation and exercise: an exploratory qualitative study
Authors: Martin Emma , Cameron Trudi , Radford Kate
Published: January 2025

The secondary prevention benefits of cardiac rehabilitation and similar exercise classes for stroke survivors are well established, however post-stroke exercise participation remains low. This research aimed to explore the factors affecting participation and engagement in UK-based post-stroke cardiac rehabilitation and exercise, from the perspective of the service user and service provider. An exploratory study, using semi-structured interviews, was conducted (n = 8, service user = 4), adopting a phenomenological approach. All interviews applied a topic guide informed by the Health Belief Model and the International Classification of Functioning, Disability and Health, and were analysed using inductive thematic analysis. Post-stroke cardiac rehabilitation and exercise participation was influenced by numerous factors, encompassed into three themes: Accessibility (describing the environmental pre-class limiting factors), Programme Structure (valuing in-class supervision, socialisation and adaptations) and Patient Characteristics (encompassing the influence of the service user’s personality and experiences). Effective secondary prevention of stroke through cardiac rehabilitation and other exercise-based rehabilitation requires policy development and commissioning to ensure appropriate delivery. Further research should determine the feasibility of novel exercise class formats, in addition to larger trials investigating their clinical benefit and cost effectiveness.
Role of [68Ga]FAPI PET/CT in Diagnosing Thymoma and Its Implications
Authors: Dahlke Paul Martin , Senger Carolin , Rückert Jens-Carsten , Neudecker Jens , Furth Christian
Published: January 2025

We report the case of a 71-year-old woman with recurrence of type B3 thymoma in which the diagnostic accuracy has benefited considerably from the additional use of [68Ga]FAPI PET/CT when compared with the standard [18F]FDG PET. [68Ga]FAPI PET/CT confirmed the known lesions with higher lesion-to-background ratio and additionally identified a previously undetected lesion near the FDG-avid apex of the heart. This case demonstrates a potential superiority of [68Ga]FAPI PET/CT in patients suffering from thymoma as detection of local recurrence close to metabolically active organs (ie, liver, heart) is improved. An improved planning of subsequent treatments (ie, lesion delineation for radiotherapy) appears possible.
Walthard Cell Nests Leading to 18F-FDG Increased Uptake of Fallopian Tube
Authors: Xu Shufan , Ou Lei , Chen Xiaoliang
Published: January 2025

We present 18F-FDG PET/CT findings of fallopian tube with Walthard cell nests. The images revealed a thickening of the bilateral fallopian tubes with increased FDG uptake. Malignant tumor or tuberculosis of the fallopian tube was suspected. Histopathology suggested fallopian tube with Walthard cell nests.
Individual associations of self-reported sleep duration, sleep quality, chronotype and social jet lag with infectious disease risk
Authors: Martínez-Albert Estefanía , Bless Josef J. , Besedovsky Luciana
Published: January 2025

Sleep deficiency is associated with infectious disease risk. However, little is known about the individual roles of different aspects of sleep, including sleep duration, sleep quality, sleep timing (assessed by chronotype) and sleep regularity (in the form of social jet lag) in this context. Here, we examined associations of the probability of reporting a cold or other infections with self-reported sleep duration, sleep quality and chronotype in a sample of 642 adults, and with social jet lag in a subsample of 274 adults. We found that short (≤ 6 h) and long sleepers (≥ 9 h) were more likely to report a cold in the past 30 days than average sleepers (7–8 h). Also, individuals with a definite evening chronotype were more likely to report a cold in the past 30 days than those with an intermediate chronotype, even when controlling for sleep duration. Finally, social jet lag was dose-dependently associated with the risk of reporting a cold in the past 12 months, independently of sleep duration, sleep quality and chronotype. No associations were found with sleep quality or with infections other than colds. The findings show that different aspects of sleep are independently associated with incidence of reported colds.

This article is part of the Theo Murphy meeting issue ‘Circadian rhythms in infection and immunity’.
Circadian rhythms: pervasive, and often times evasive
Authors: Larrondo Luis F.
Published: January 2025

Most circadian texts begin by stating that clocks are pervasive throughout the tree of life. Indeed, clock mechanisms have been described from cyanobacteria to humans, representing a notable example of convergent evolution: yet, there are several phyla in animals, protists or within fungi and bacteria, in which homologs of some—or all—known clock components seem to be absent, posing inevitable questions about the evolution of circadian systems. Moreover, as we move away from model organisms, there are several taxa in which core clock elements can be identified at the genomic levels. However, the functional description of those putative clocks has been hard to achieve, as rhythmicity is not observed unless defined abiotic or nutritional cues are provided. The mechanisms ‘conditioning’ the functionality of clocks remain uncertain, emphasizing the need to delve further into non-model circadian systems. As the absence of evidence is not evidence of absence, the lack of known core-clock homologs or of observable rhythms in a given organism, cannot be an
a priori
criterion to discard the presence of a functional clock, as rhythmicity may be limited to yet untested experimental conditions or phenotypes. This article seeks to reflect on these topics, highlighting some of the pressing questions awaiting to be addressed.

This article is part of the Theo Murphy meeting issue ‘Circadian rhythms in infection and immunity’.
Flavobacterium aerium sp. nov., a bacterium isolated from the air of the Icelandic volcanic island Surtsey
Authors: Daussin Aurélien , Vannier Pauline , Ménager Marine , Mater Émilien , Marteinsson Viggó Þór
Published: January 2025

A novel bacterium, designated 19SA41, was isolated from the air of the Icelandic volcanic island Surtsey. Cells of strain 19SA41 are Gram-stain-negative, strictly aerobic, non-motile rods and form pale yellow-pigmented colonies. The strain grows at 4–30 °C (optimum, 22 °C), at pH 6–10 (optimum, pH 7.5) and with 0–4% NaCl (optimum, 0.5%). Phylogenetic analyses based on 16S rRNA gene sequences showed that 19SA41 belonged to the genus Flavobacterium and is most similar to Flavobacterium xinjiangense DSM 19743T, with a sequence similarity of 96.52%. The new strain contained iso-C15 : 0 (22%) and summed feature 3 (C16∶1ω6c/C16∶1ω7c) (20%) as the predominant fatty acids. The major respiratory quinone was menaquinone-6 (100%). The polar lipid profile consisted of phosphatidylethanolamine and several uncharacterized amino lipids, glycolipids and lipids. The genome of the new strain was 4.01 Mbp, and its G+C content was 33.2 mol%. Based on characterization and comparative results, using a polyphasic taxonomic approach, we propose that the new isolate represents a novel species of the genus Flavobacterium with the name Flavobacterium aerium sp. nov. The type strain is ISCaR-07695T (=DSM 116640T =UBOOC-M-3567T).
Shigella sonnei and Shigella flexneri infection in Caenorhabditis elegans led to species-specific regulatory responses in the host and pathogen
Authors: Wong Bao Chi , Tan Hock Siew
Published: January 2025

In recent decades, Shigella sonnei has surpassed Shigella flexneri as the leading cause of shigellosis, possibly due to species-specific differences in their transcriptomic responses. This study used dual RNA sequencing to analyse the transcriptomic responses of Caenorhabditis elegans and the two Shigella species at early (10 minutes) and late (24 hours) stages of infection. While the nematode defence response was downregulated during both Shigella infections, only infection by S. sonnei led to downregulation of sphingolipid metabolism, cadmium ion response and xenobiotic response in C. elegans. Furthermore, S. sonnei upregulates biofilm formation and energy generation/conservation during infection, acid resistance-related genes and biofilm regulators compared to S. flexneri. These findings highlight species-specific responses during C. elegans infection.
Automatically Defining Protein Words for Diverse Functional Predictions Based on Attention Analysis of a Protein Language Model
Authors: Chen Hedi , Zhong Jingrui , Zhang Xiaochun , Chen Jingke , Guo Lin , Xiong Xiaoliang , Zhang Xiaonan , Liu Xiangyu , Xiao Bailong , Tian Boxue
Published: January 2025

Understanding the relationship between protein sequence and function remains a longstanding challenge in bioinformatics, and to date the lion’s share of related tools parse proteins at the domain or motif levels. Here, we define “protein words” as an alternative to “motif” for studying proteins and functional prediction applications. We first developed an unsupervised tool we term Protein Wordwise, which parses analyte protein sequences into protein words by analyzing attention matrices from a protein language model (PLM) through a community detection algorithm. We then developed a supervised sequence-function prediction model called Word2Function, for mapping protein words to GO terms through feature importance analysis. We compared the prediction performance of our protein word-based toolkit with a motif-based method (PROSITE) for multiple protein function datasets. We also assembled a functionally diverse data resource we term PWNet to support evaluation of protein words for predicting functional residues across 10 tasks (e.g., diverse biomolecular binding, catalysis, and ion-channel activity). Our toolkit outperforms PROSITE in all the examined datasets and tasks. By abandoning domains and instead using attention matrices from a PLM for automatic, systematic, and annotation-agnostic parsing of proteins, our toolkit both outperforms currently available tools for functional annotations at the residue and whole-protein levels and suggests innovative forms of protein analysis well-suited to the post-AlphaFold era of biochemistry.
Ak-mer-based maximum likelihood method for estimating distances of reads to genomes enables genome-wide phylogenetic placement
Authors: Şapcı Ali Osman Berk , Mirarab Siavash
Published: January 2025

Consider comparing a sequencing read of unknown origin to a set of reference genomes. This problem underlines many applications, including metagenomic analyses. The exact genome generating the read is not in the reference set, but may be evolutionarily related to some references. Ideally, we need not just the identity of the closest references to the read but also their distance to the read. The distances can help us identify the read at the right taxonomic level and, more ambitiously, place it on a reference phylogeny. Aligning reads to reference genomes, the only available approach for computing such distances, becomes impractical for very large reference sets. It is also not effective at higher distances when used with efficient indexes (e.g., Bowtie2). Whilek-mers can create scalable indexes, existingk-mer-based methods are incapable of distance calculation. Thus, estimating distances between short reads and large, diverse reference sets remains challenging and seldom used. We introduce a method called krepp that combines four ideas to solve this challenge and to further enable placing reads on a reference phylogeny. We usei) locality-sensitive hashing to find inexactk-mer matches,ii) a phylogeny-guided coloredk-mer index to map eachk-mer to all references containing it,iii) a maximum likelihood framework to estimate read-genome distances usingk-mer matches, andiv) an extension of distances to clades of the reference tree, which enables placement using a likelihood ratio test. We show that krepp matches true distances using a fraction of time compared to alignment, extends to higher distances, and accurately places short reads coming from any part of the genome (not just marker genes) on the reference phylogeny. We demonstrate that krepp easily extends to databases with tens of thousands of reference genomes and performs well in characterizing real microbial samples.

Availability

The tool is available atgithub.com/bo1929/krepp. All results, auxiliary data, and scripts used in the analyses can be found atgithub.com/bo1929/shared.krepp.
Combined expression of FOXO and Tribbles proteins predicts survival of glioma patients
Authors: Santos Bruno F. , Maia Ana-Teresa , Ferreira Bibiana I. , Link Wolfgang
Published: January 2025

1.

Glioma, a primary tumor of the central nervous system originating from glial cells, continues to pose significant therapeutic challenges, particularly in its high-grade variants. Genetic analyses have revealed that the majority of gliomas exhibit significant alterations in the RTK/RAS/PI3K/AKT signaling cascade. Forkhead box protein O (FOXO) transcription factors and their upstream regulator protein family Tribbles have been characterized as important components of the downstream effector network of this pathway. Here, we investigated the role of the FOXO and Tribbles family members mRNA levels in the clinical outcomes of patients with gliomas. We show that while high expression of FOXO1 and low expression of FOXO3 and FOXO4 is associated with worse survival of glioma patients, low expression of TRIB1, TRIB2, and TRIB3 improves prognosis. We also found that FOXO3 and FOXO4 levels are downregulated in patients with grade 4 gliomas, compared to those with lower tumor grades, while FOXO1 and all three Tribbles isoforms are overexpressed in the same patients. We also show that transcriptional profiles of FOXO and Tribbles can predict the clinical outcome of glioma patients better than MGMT status, one of the most important biomarkers currently used in glioblastoma treatment. These findings highlight the potential of FOXO and Tribbles mRNA as predictive biomarkers and their proteins as therapeutic targets, paving the way for more personalized and effective glioma treatments.
ProtRAP-LM: Fast and accurate protein relative accessibility prediction and membrane protein screening through protein language model embeddings
Authors: Wang Lei , Kang Kai , Song Chen
Published: January 2025

Membrane proteins play pivotal roles in cellular signaling and transport, making them prime targets for therapeutic intervention. Therefore, expeditious screening and accurate property prediction of these proteins is crucial. Recently, we proposed a new metric, the membrane contact probability (MCP), to characterize the membrane-contacting features of membrane proteins and further refine the prediction of the relative accessibility of proteins (ProtRAP). However, these models relied on evolutionary information in the form of multiple sequence alignments (MSAs), which hindered rapid predictions. In this study, we present a novel transformer-based model, ProtRAP-LM, utilizing language model (LM) embeddings as input features, to quickly and accurately predict MCP and relative accessibility for each residue of a given protein sequence. ProtRAP-LM can achieve accurate predictions for entire proteomes within hours, demonstrating superior performance compared to previous MSA-based models, with a speedup of over 300 times. This empowers us to furnish more thorough annotations of membrane protein sequences on a proteome-wide scale, particularly for single-pass transmembrane proteins, membrane-anchored proteins, and β-sheet-containing membrane proteins, which have long been a challenge in the field. In the end, we provide a comprehensive list of membrane proteins for 48 living organisms, offering a rich resource for investigating the structure and function of these essential biomolecules in the future.
Benchmarking and optimizing Perturb-seq in differentiating human pluripotent stem cells
Authors: Sivakumar Sushama , Wang Yihan , Goetsch Sean C , Pandit Vrushali , Wang Lei , Zhao Huan , Sundarrajan Anjana , Armendariz Daniel , Takeuchi Chikara , Nzima Mpathi , Chen Wei-Chen , Dederich Ashley E , El Hayek Lauretta , Gao Taosha , Ghazawi Renad , Gogate Ashlesha , Kaur Kiran , Kim Hyung Bum , McCoy Melissa K , Niederstrasser Hanspeter , Oura Seiya , Pinzon-Arteaga Carolos A , Sanghvi Menaka , Schmitz Daniel A , Yu Leqian , Zhang Yanfeng , Zhou Qinbo , Kraus W. Lee , Xu Lin , Wu Jun , Posner Bruce A , Chahrour Maria H , Hon Gary C , Munshi Nikhil V
Published: January 2025

Perturb-seq is a powerful approach to systematically assess how genes and enhancers impact the molecular and cellular pathways of development and disease. However, technical challenges have limited its application in stem cell-based systems. Here, we benchmarked Perturb-seq across multiple CRISPRi modalities, on diverse genomic targets, in multiple human pluripotent stem cells, during directed differentiation to multiple lineages, and across multiple sgRNA delivery systems. To ensure cost-effective production of large-scale Perturb-seq datasets as part of the Impact of Genomic Variants on Function (IGVF) consortium, our optimized protocol dynamically assesses experiment quality across the weeks-long procedure. Our analysis of 1,996,260 sequenced cells across benchmarking datasets reveals shared regulatory networks linking disease-associated enhancers and genes with downstream targets during cardiomyocyte differentiation. This study establishes open tools and resources for interrogating genome function during stem cell differentiation.
Optimization of crossing strategy based on the usefulness criterion in inter-population crosses considering different genetic effects among populations
Authors: Kinoshita Sei , Sakurai Kengo , Hamazaki Kosuke , Tsusaka Takahiro , Sakurai Miki , Shirasawa Kenta , Isobe Sachiko , Iwata Hiroyoshi
Published: January 2025

In the breeding programs of self-pollinated plants, achieving genetic improvement in multiple traits can be challenging when relying solely on a single biparental population. Interpopulation crosses are employed to integrate favorable alleles from multiple biparental populations to overcome this limitation. In this context, it is crucial to consider the distinct genetic effects in different populations. In this study, we utilized a selection method based on the usefulness criterion (UC) to identify cross pairs suitable for interpopulation crosses. We expanded this approach to enhance breeding programs accounting for varying genetic backgrounds within the genomic selection framework. Using the medicinal plant red perilla as the study material, we conducted simulations to compare the efficacy of selection based on estimated genomic breeding values with that based on UC. Our findings demonstrate that the proposed method is effective in facilitating the simultaneous improvement of multiple traits, particularly by considerably increasing genetic gains among the top-performing individuals in the population. Furthermore, we provide guidelines for implementing interpopulation crosses, including recommendations for the optimal generation for crossing and the appropriate reference generation for calculating the UC. The results obtained in this study offer valuable insights for small-scale breeding programs aimed at simultaneously enhancing multiple traits through inter-population crosses and are applicable to a wide range of crops, including neglected and underutilized species.

Key Message

Herein, a method has been proposed for selecting optimal cross pairs based on the genetic potential of progeny in inter-population crosses, considering different genetic effects among populations.
Sex Hormone Binding Globulin Controls Gender Specific Lipolytic Activity in Human Abdominal Subcutaneous Adipocytes
Authors: Abildgaard Julie , Palani Nagendra , Henriksen Tora Ida , Aleliunaite Aiste , Horváth-Rudigier Carla , Svenstrup Victor , Frederiksen Hanne , Juul Anders , Scheele Camilla Charlotte , Pedersen Bente Klarlund , Nielsen Søren
Published: January 2025

Regulation of lipid metabolism is fundamental for metabolic health, and adipose tissue is a central component in this process. Adipose tissue differs dramatically between women and men with a higher subcutaneous capacity for storage and healthy metabolism in women. Sex hormone-binding globulin (SHBG) contributes to the regulation of circulating sex hormone bioavailability and has been shown to predict risk of metabolic dysfunction. We here investigate the sex-specific relationship of SHBG with metabolic status and adipocyte-dependent lipolysis. We measured serum concentrations of sex hormones, SHBG, fasting glucose and insulin in a cohort of 63 women and 27 men from which adipose biopsies were collected and mature adipocytes were isolated. We found that, in women, high serum SHBG concentrations were strongly associated with low HOMA-IR in vivo, and lower baseline lipolysis but higher responsiveness to isopropanol-induced lipolysis ex vivo. In contrast, no effect of SHBG on the above-mentioned parameters were observed in men. In vitro, cultured adipocytes also increased lipolytic capacity in response to SHBG, but only in the absence of testosterone, suggesting that testosterone inhibits the catecholmine-induced lipolysis of SHBG in adipose tissue. In conclusion, we here define a novel role for SHBG in adipocyte lipolysis. At the same time, our data emphasize sex-dependent differences in adipocyte lipid metabolism, and we propose testosterone binding to SHBG as a driving factor mediating these differences.
Enhancing tree seed germination prediction with image-driven machine learning models.
Authors: Barreiro Pablo Gomez , Richard-Bollans Adam , Mattana Efisio , Seal Charlotte E. , Chapman Ted , Dayrell Roberta
Published: January 2025

1. Tree planting is crucial for reversing deforestation and meeting net zero targets, requiring a reliable supply of high-quality seeds. Efficient use of limited native seeds can be promoted by sorting methods, but traditional techniques commonly used for agricultural species are often unsuitable for tree seeds due to their high trait variability. 2. Here, we explored the potential of combining image analysis with machine learning models to improve tree seed sorting outcomes. We selected five UK native tree species of interest for tree production and afforestation projects and applied machine learning XGBoost and Convolutional Neural Networks algorithms to predict seed germination using colour and X-ray images as well as features extracted from these images. 3. The machine learning models achieved good accuracy and F1-scores, but their specificity was limited, particularly when relying solely on colour images or related features. This poses a problem, as wild seeds are often scarce, and falsely classifying seeds that germinate as non-germinable would result in a waste of valuable resources. X-ray images and features were highly effective in identifying empty seeds but did not perform well when differentiating filled seeds into germinable and non-viable. Consequently, the models performed best for species with a high proportion of empty seeds. 4. For three of the five species, model performance varied significantly by mother tree, with some trees showing markedly poorer results. This aspect had not been previously investigated and raises concerns that biased seed sorting will disadvantage certain mother trees, leading to the loss of valuable genetic diversity and woodland resilience. Synthesis and applications: The performance of image-based machine learning models in predicting seed germination ultimately depended on whether most non-germinated seeds were empty, non-viable, or dormant. X-ray models showed strong performance in detecting empty seeds, but colour image models exhibited poor results due to the high variability in seed external features, the subtle differences between germinated and non-germinated seeds, and the variability among individual mother trees. Developing open, accessible training databases and more adaptable models is crucial for addressing these limitations and enable technologies to further support large-scale tree production.
Metrics Matter: Why We Need to Stop Using Silhouette in Single-Cell Benchmarking
Authors: Rautenstrauch Pia , Ohler Uwe
Published: January 2025

Current-day single-cell studies comprise complex data sets affected by nested batch effects caused by technical and biological factors, relying on advanced integration methods. Silhouette is an established metric for assessing clustering results, comparing within-cluster cohesion to between-cluster separation, and adaptations of it have emerged as the dominant choice to evaluate the success of these integration methods. However, silhouette’s assumptions are often violated in single-cell data integration scenarios. We demonstrate that silhouette-based metrics can neither reliably assess batch effect removal nor biological signal conservation and are thus inherently unsuitable for data with (nested) batch effects. We propose alternative, robust evaluation strategies that enable accurate integration method assessment and call to update benchmarking practices.