bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing functionally defective old HSCs alleviates aging-related phenotypes in old recipient mice
Authors: Wang Yuting , Zhang Wenhao , Zhang Chao , Van Hoang Tran , Seino Takashi , Zhang Yi
Published: November 2024

Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process. Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit “younger” molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150lowHSCs from old mice can effectively differentiate into downstream lineage cells but not their CD150highcounterparts. Notably, transplantation of old CD150lowHSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150highHSCs. Importantly, reducing the dysfunctional CD150highHSCs can alleviate aging phenotypes in old recipient mice. Thus, our study demonstrates the presence of “younger” HSCs in old mice, and aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.
Sex-dependent additive effects of dorzagliatin and incretin on insulin secretion in a novel mouse model ofGCK-MODY
Authors: Salazar Shadai , Delgadillo-Silva Luis Fernando , Carapeto Priscila , Dakessian Karen , Melhem Rana , Provencher-Girard Audrey , Ostinelli Giada , Turgeon Julie , Kaci Imane , Migneault Francis , Huising Mark O. , Hébert Marie-Josée , Rutter Guy A.
Published: November 2024

Glucokinase (GK) catalyses the key regulatory step in glucose-stimulated insulin secretion. Correspondingly, hetero– and homozygous mutations in humanGCKcause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes (PNDM), respectively. To explore the possible utility of glucokinase activators (GKA) and of glucagon–like receptor-1 (GLP-1) agonists in these diseases, we have developed a novel hypomorphicGckallele in mice encoding an aberrantly spliced mRNA deleted for exons 2 and 3. In islets from homozygous knock-in (GckKI/KI) mice, GK immunoreactivity was reduced by >85%, and glucose-stimulated insulin secretion eliminated. Homozygous GckKI/KImice were smaller than wildtype littermates and displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c ∼12%), ketosis and nephropathy. Heterozygous GckKI/+mice were glucose intolerant (HbA1c ∼5.5%). Abnormal glucose-stimulated Ca2+dynamics and beta cell-beta cell connectivity in GckKI/+islets were completely reversed by the recently-developed GKA, dorzagliatin, which was largely inactive in homozygous GckKI/KImouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male GckKI/+mice, an action potentiated by dorzagliatin, in male but not female mice. Sex-dependent additive effects of these agents were also observed on insulin secretionin vitro. Combined treatment with GKA and incretin may thus be useful inGCK-MODY orGCK-PNDM.

Article Highlights

a.

Glucokinase deficiency can drive maturity-onset diabetes of the young (GCK-MODY;heterozygotes) and permanent neonatal diabetes (GCK-PNDM;homozygotes)

b.

We describe a hypomorphicGckallele where aberrant splicing in islets lowers GK activity to by ∼85%. We use these mice to explore the effects of the glucokinase activator, dorzagliatin, and incretin on insulin secretion

c.

Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of GLP-1 receptor activation sex-dependently in heterozygotes

d.

Combined use of these drugs may be useful in some forms ofGCKdiabetes
Florigen and antiflorigen gene expression correlates with reproductive state in a marine angiosperm,Zostera marina
Authors: Nolan Christine T. , Campbell Ian , Farrell-Sherman Anna , Briones Ortiz Bryan A. , Naish Kerry A. , Di Stilio Verónica , Kaldy James E. , Donoghue Cinde , Ruesink Jennifer L. , Imaizumi Takato
Published: November 2024

Florigen and antiflorigen genes within the phosphatidylethanolamine-binding protein (PEBP) family regulate flowering in angiosperms. In eelgrass (Zostera marina), a marine foundation species threatened by climate change, flowering and seed production are crucial for population resilience. Yet, the molecular mechanism underpinning flowering remains unknown.

Using phylogenetic analysis and functional assays inArabidopsis, we identified thirteenPEBPgenes inZ. marina(ZmaPEBP) and showed that four genes altered flowering phenotypes when overexpressed. We used quantitative RT-PCR onZ. marinashoots from perennial and annual populations in Willapa Bay, USA to assess expression of these four genes in different tissue and expression changes throughout the growth season.

We demonstrated thatZmaFT2andZmaFT4promote flowering, andZmaFT9andZmaTFL1arepress flowering inArabidopsis. Across five natural sites exhibiting different degrees of population genetic structure,ZmaFT2andZmaFT4were expressed in leaves of vegetative and reproductive shoots and in stems and rhizomes of reproductive shoots.ZmaFT9was distinctively expressed in leaves of vegetative and juvenile shoots, whileZmaTFL1alevels increased after flowering shoots emerged.

Our results suggest thatZmaFT2andZmaFT4may promote flowering, whileZmaFT9may inhibit a floral transition in eelgrass. We speculate thatZmaTFL1amay be involved in flowering shoot architecture.
KaMLs for Predicting Protein pKaValues and Ionization States: Are Trees All You Need?
Authors: Shen Mingzhe , Kortzak Daniel , Ambrozak Simon , Bhatnagar Shubham , Buchanan Ian , Liu Ruibin , Shen Jana
Published: November 2024

Despite its importance in understanding biology and computer-aided drug discovery, the accurate prediction of protein ionization states remains a formidable challenge. Physics-based approaches struggle to capture the small, competing contributions in the complex protein environment, while machine learning (ML) is hampered by scarcity of experimental data. Here we report the development of pKaML (KaML) models based on decision trees and graph attention networks (GAT), exploiting physicochemical understanding and a new experiment pKadatabase (PKAD-3) enriched with highly shifted pKa’s. KaML-CBtree significantly outperforms the current state of the art in predicting pKavalues and ionization states across all six titratable amino acids, notably achieving accurate predictions for deprotonated cysteines and lysines – a blind spot in previous models. The superior performance of KaMLs is achieved in part through several innovations, including separate treatment of acid and base, data augmentation using AlphaFold structures, and model pretraining on a theoretical pKadatabase. We also introduce the classification of protonation states as a metric for evaluating pKaprediction models. A meta-feature analysis suggests a possible reason for the lightweight tree model to outperform the more complex deep learning GAT. We release an end-to-end pKapredictor based on KaML-CBtree and the new PKAD-3 database, which facilitates a variety of applications and provides the foundation for further advances in protein electrostatics research.

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Vascular Transcription Factor TMO5 Regulates PIN1 Polarity and Organogenesis Downstream of MONOPTEROS in the Shoot Meristem
Authors: Kareem Abdul , Ohno Carolyn , Heisler Marcus G.
Published: November 2024

Plants continuously produce lateral organs, such as leaves and flowers, from the shoot apical meristem (SAM). This process is guided by the accumulation of the plant hormone auxin and the polar localization of the efflux protein PIN-FORMED1 (PIN1). The transcription factor MONOPTEROS (MP) plays a crucial role in orienting PIN1 polarity, thereby facilitating auxin-driven organogenesis. In this study, we investigated how MP regulates PIN1 polarity and organogenesis, discovering that the downstream vascular transcription factor TMO5 regulates PIN1 polarity non-cell-autonomously and promotes organ initiation in the SAM. Furthermore, we find that exogenous auxin and cytokinin can partially rescue the organ defects associated with loss of MP and TMO5 activity. Collectively, these findings uncover a novel role for TMO5 in controlling PIN1 polarity and driving organogenesis by coordinating hormonal signalling.
Isolation of bacteria that catabolize abiotically synthesized tetroses via the formose reaction
Authors: Kawasaki Kosei , Igarashi Kensuke , Tabata Hiro , Nishijima Hiroaki , Nakanishi Shuji , Kato Souichiro
Published: November 2024

Sugars synthesized through abiotic processes, specifically the formose reaction, are promising candidates for next-generation feedstocks for biomanufacturing due to their significantly higher productivity compared to cultivated crops. One of the significant challenges associated with the utilization of abiotically synthesized sugars via the formose reaction is the presence of unusual sugars, which are not metabolized by typical microorganisms. This study aimed to identify microorganisms capable of catabolizing tetroses, which are among the unusual sugars present in the abiotically synthesized sugars. Four model bacteria commonly used in biomanufacturing, includingEscherichia coli, were unable to catabolize tetroses and their growth was completely inhibited by 2 to 4 g/L of D-erythrose or 0.5 to 1 g/L of L-erythrulose. We successfully isolated eight phylogenetically diverse bacterial strains from river sediments, capable of utilizing D-erythrose and L-erythrulose as the sole carbon sources. These isolates exhibited higher tolerances to tetroses compared to the model bacteria. The isolates exhibited the ability to grow in high concentrations of the abiotically synthesized sugars, which inhibit the growth of typical microorganisms, and to consume tetroses contained therein. Further investigation into the molecular mechanisms of tetrose metabolisms in the isolates will facilitate the development of biomanufacturing processes utilizing the abiotically synthesized sugars.
Deep Learning with Evolutionary Scale Modeling to discover Antibiotic-Resistance Drug against Klebsiella Pneumoniae
Authors: Jin Linxiao , Lei Zhihao , Lin Peng , Ma Cong , Zhang Wen , Zhou Jiali , Meng Sijun , Jiang Zhenghua , Bu Yemei , Xu Yingfan , Wei Nijun , Hsu Tsehao , Qin Glen , Qiu Hesong
Published: November 2024

The development of effective antibiotics is crucial in combating antibiotic-resistant pathogens such as Klebsiella pneumoniae (KP). This study utilizes deep learning, specifically Evolutionary Scale Modeling (ESM), to identify potential drug candidates. By analyzing molecular similarities between known drugs and KP strains, we aim to accelerate the discovery of new treatments and reduce the risks associated with clinical trials. This approach may shed new lights in the field of drug repositioning.
Root metaxylem area influences drought tolerance and transpiration in pearl millet in a soil texture dependent manner
Authors: Affortit Pablo , Faye Awa , Jones Dylan H. , Benson Ezenwoko , Sine Bassirou , Burridge James , Ndoye Mame Sokhatil , Barry Luke , Moukouanga Daniel , Barnard Stephanie , Bhosale Rahul , Pridmore Tony , Gantet Pascal , Vadez Vincent , Cubry Philippe , Kane Ndjido , Bennett Malcolm , Atkinson Jonathan A. , Laplaze Laurent , Wells Darren M. , Grondin Alexandre
Published: November 2024

Pearl millet is a key cereal for food security in drylands but its yield is strongly impacted by drought. We investigated how root anatomical traits contribute to mitigating the effects of vegetative drought stress in pearl millet.

We examined associations between root anatomical traits and agronomical performance in a pearl millet diversity panel under irrigated and vegetative drought stress treatments in field trials. The impact of associated anatomical traits on transpiration was assessed using subpanels grown in different soil within a greenhouse.

In the field, total metaxylem area was positively correlated with grain weight and its maintenance under drought. In the greenhouse, genotypes with larger metaxylem area grown in sandy soil exhibited a consumerist water use strategy under irrigation, which shifted to a conservative strategy under drought. Water savings was mediated by transpiration restriction under high evaporative demand. This mechanism was dependent on soil hydraulics as it was not observed in peat soil with higher hydraulic conductivity upon soil drying.

We propose that water savings under drought, mediated by large metaxylem area and its interaction with soil hydraulics, help mitigate vegetative drought stress. Our findings highlight the role of soil hydraulic properties in shaping plant hydraulics and drought tolerance.
Using Convolutional Neural Networks for the Classification of Suboptimal Chest Radiographs
Authors: Liu Emily , Carrion D , Badawy MK
Published: November 2024

Background

Chest X-rays (CXR) rank among the most conducted X-ray examinations. They often require repeat imaging due to inadequate quality, leading to increased radiation exposure and delays in patient care and diagnosis. This research assesses the efficacy of DenseNet121 and YOLOv8 neural networks in detecting suboptimal CXRs, which may minimise delays and enhance patient outcomes.

Method

The study included 3,587 patients with a median age of 67 (0-102). It utilised an initial dataset comprising 10,000 CXRs randomly divided into a training subset (4,000 optimal and 4,000 suboptimal) and a validation subset (400 optimal and 400 suboptimal). The test subset (25 optimal and 25 suboptimal) was curated from the remaining images to provide adequate variation. DenseNet121 and YOLOv8 were chosen due to their capabilities in image classification. Their performance was assessed via the area under the receiver operating curve (AUROC) and compared to radiologist classification, utilising the chi-squared test.

Results

DenseNet121 attained an AUROC of 0.97, while YOLOv8 recorded a score of 0.95, indicating a strong capability in differentiating between optimal and suboptimal CXRs. The alignment between radiologists and models exhibited variability partly due to the lack of clinical indications. However, the performance was not statistically significant.

Conclusion

Both AI models effectively classified chest X-ray quality, demonstrating the potential for providing radiographers with feedback to improve image quality. Notably, this was the first study to include both PA and lateral CXRs, as well as pediatric cases, and the first to evaluate YOLOv8 for this application.
Association between biomarkers of environmental enteric dysfunction and growth and neurodevelopment in Guatemalan infants
Authors: Connery Amy K. , Calvimontes Diva M. , Bucardo Filemon , Olson Daniel , Colbert Alison M. , Bartelt Luther , Asturias Edwin J. , Lamb Molly M. , Becker-Dreps Sylvia
Published: November 2024

BACKGROUND

There is growing evidence that environmental enteric dysfunction (EED) is a driver of poor growth and neurodevelopment (ND) in early childhood. To further investigate this, we measured the associations between biomarkers reflecting various domains of EED and growth and ND in Guatemalan infants. METHODS. A subset of 114 cohort infants were randomly selected for inclusion from a 2017-2019 population-based cohort study of 499 young infants in rural southwest Guatemala. Growth and neurodevelopmental performance using the Mullen Scales of Early Learning (MSEL) were assessed at a household visit around 12 months of age. Serum samples collected at the visit were analyzed for concentrations of α-1 acid glycoprotein (AGP), glucagon-like peptide-2 (GLP-2), and anti-flagellin IgA (Anti-FliC IgA), Multivariable regression analyses adjusted for relevant confounders were conducted to define associations between these EED biomarkers and length-for-age z-score (LAZ) and neurodevelopmental performance. We planneda priorito conduct analyses with and without excluding infants who had acute infectious disease symptoms (fever, cough, vomiting, diarrhea) at the 12-month visit.

RESULTS

No significant association between biomarkers representing different domains of EED and LAZ or MSEL scores at 12-14 months of age was found. However, removing children with acute infectious symptoms uncovered an association between Anti-FliC IgA and MSEL. Specifically, an increase in 10ng/L in Anti-FliC IgA concentration was associated in a decrease in the MSEL Early Learning Composite (ELC) raw score of 3.2 points, which equates to approximately a 9-point decrease in the ELC standard score.

CONCLUSIONS

In this study, having increased levels of Anti-FliC IgA was associated with lower ND in the first year of life and may represent an important risk to long-term health and development.

AUTHOR SUMMARY

There is growing evidence that a key driver of stunting and poor neurodevelopment in low-resource settings is environmental enteric dysfunction. Environmental enteric dysfunction is a subclinical condition of the small intestine that may include chronic mucosal inflammation and/or increased intestinal permeability; it is common in children experiencing repeated infections with fecal-oral pathogens. In this preliminary study, we examined the link between biomarkers of environmental enteric dysfunction and neurodevelopment in 114 infants. After excluding children with acute infectious symptoms (which could transiently modify biomarker levels), we found a strong link between one marker of EED and poor neurodevelopment, independent of child growth. Further research is warranted to explore the associations between EED and ND to guide future interventions to reduce these risks.
An implementation-effectiveness trial investigating feasibility, safety and efficacy of Best pRacticE guideline cAre physioTHErapy with addition of protocolised ventilator hyperinflation on patient-important outcomes for critically ill adults intUbated and ventilated with Pneumonia. (BREATHE UP)
Authors: van der Lee Lisa , Regli Adrian , Allen Christopher , Anstey Matthew , Blakeman Robert , Denehy Linda , Dennis Diane , Elliott Mercedes , Hill Anne-Marie , Ho Kwok-Ming , Jacob Wendy , Jacques M Angela , Marsh Lisa , Palermo Mark , Wibrow Bradley , Ntoumenopoulos George
Published: November 2024

Pneumonia is a common cause for intensive care unit (ICU) admission for breathing support from a mechanical ventilator, resulting in high morbidity, mortality, and healthcare costs. Physiotherapists working in ICU treat patients with critical pneumonia using a range of respiratory treatments to improve breathing, hasten weaning from the ventilator, and restore functional independence. Evidence supports the short-term benefits of these treatments, however currently no standard of physiotherapy practice exists for these ICU patients. Despite a plethora of studies which have shown that physiotherapy treatments, such as ventilator lung hyperinflation (VHI), aid the lungs to work better short-term, there are no studies to date which investigate the effect of these important treatments on meaningful patient-important outcomes, such as earlier weaning from the ventilator, earlier hospital discharge, less breathlessness and lung secretions, short- and longer-term disability, health- related quality of life and survival. Through previous multiphase mixed-methods research, a clinical practice guideline was developed outlining best physiotherapy practice for this ICU patient cohort. This proposed research involves conducting a multicentre hybrid implementation-effectiveness randomised, controlled trial which aims to: evaluate implementation of physiotherapy guideline care for management of pneumonia in ICU regarding feasibility, safety and acceptability; and to determine the safety and effectiveness of a standardised dosage of daily ventilator hyperinflation in addition to standard guideline care on patient-important outcomes, health system outcomes; and cost effectiveness. This study will address critical knowledge gaps in the ICU physiotherapy evidence base regarding the impact of a course of standardised, best practice respiratory physiotherapy intervention during the ICU stay for patients with critical pneumonia requiring invasive mechanical ventilation, provide valuable information for clinicians to inform clinical practice regarding treatable traits and streamlining care to promote clinical efficiency, and determine the impact of respiratory physiotherapy care on patient-important and health service outcomes.

Trial registration

ANZ Clinical trials Registry number ACTRN12624001130550.
REMINDer randomized controlled study: Feasibility and impact of an online multimodal mind-body intervention in older adults
Authors: Wirth Miranka , Stamer Selina , Podolski Odile , Maßalsky Annemarie , Koch Sabine C. , Klimecki Olga
Published: November 2024

Background

The increase in life expectancy and age-related diseases, such as Alzheimer’s disease, is a global challenge. Given the drawbacks of pharmacological treatments, it is important to pursue non-pharmacological strategies for dementia risk reduction. To effectively promote health and well-being in later life, multimodal, low-threshold, and cost-effective lifestyle interventions are needed.

Methods

REMINDeris a monocentric, outcome assessor-blinded, randomized controlled pilot study to assess the feasibility and impact of an online (home-based and live-streamed) multimodal intervention. The 6-week (two one-hour sessions/week) mind-body group intervention will be compared to a 6-week passive control (waitlist with delayed intervention) using a cross-over (AB-BA) design. The intervention was designed for older adults and includes music, dance-based movement, and mindfulness. A total ofN=50 cognitively unimpaired older adults will be enrolled and randomized into the two intervention arms using a block randomization with a 1:1 allocation ratio.

Results

Outcomes will be assessed at pre-intervention, post-intervention, and follow-up using digital assessments of online questionnaires. Primary outcomes include feasibility, operationalized by adherence rates, and preliminary effectiveness of the intervention. The latter will be assessed by changes in self-reported mental and physical well-being, operationalized by the Short-Form Health Survey (SF-12). Secondary outcomes will include changes in cognitive, motor, sensory, emotional/affective, social, and lifestyle health behaviors.

Discussion

The study will provide evidence of the feasibility and preliminary effectiveness of an online multimodal mind-body intervention based on “Arts for Health” activities. If successful, the study may inform accessible lifestyle strategies to improve mental health and well-being and other risk factors for dementia in older adults.

Trail Registration

ClinicalTrials.gov,NCT06530277

Protocol

SR-EK-477112023
ComFB, a new widespread family of c-di-NMP receptor proteins
Authors: Samir Sherihan , Elshereef Abdalla A. , Alva Vikram , Hahn Jeanette , Dubnau David , Galperin Michael Y. , Selim Khaled A.
Published: November 2024

Cyclic dimeric GMP (c-di-GMP) is a widespread bacterial second messenger that controls a variety of cellular functions, including protein and polysaccharide secretion, motility, cell division, cell development, and biofilm formation, and contributes to the virulence of some important bacterial pathogens. While the genes for diguanylate cyclases and c-di-GMP hydrolases (active or mutated) can be easily identified in microbial genomes, the list of c-di-GMP receptor domains is quite limited, and only two of them, PliZ and MshEN, are found across multiple bacterial phyla. Recently, a new c-di-GMP receptor protein, named CdgR or ComFB, has been identified in cyanobacteria and shown to regulate their cell size and, more recently, natural competence. Sequence and structural analysis indicated that CdgR is part of a widespread ComFB protein family, named after the “late competence development protein ComFB” fromBacillus subtilis. This prompted the suggestion that ComFB and ComFB-like proteins could also be c-di-GMP receptors. Indeed, we revealed that ComFB proteins from Gram-positiveB. subtilisandThermoanaerobacter brockiiwere able to bind c-di-GMP with high-affinity. The ability to bind c-di-GMP was also demonstrated for the ComFB proteins from clinically relevant Gram-negative bacteriaVibrio choleraeandTreponema denticola. These observations indicate that the ComFB family serves as yet another widespread family of bacterial c-di-GMP receptors. Incidentally, some ComFB proteins were also capable of c-di-AMP binding, identifying them as a unique family of c-di-NMP receptor proteins. The overexpression ofcomFBinB. subtilis,combined with an elevated concentration of c-di-GMP, suppressed motility, attesting to the biological relevance of ComFB as a c-di-GMP binding protein.

IMPORTANCE

The cellular content of the bacterial second messenger c-di-GMP is controlled by c-di-GMP synthases (GGDEF domains) and hydrolases (EAL or HD-GYP domains), whose activities, in turn, respond to the signals perceived by their upstream sensory domains. Cyclic-di-GMP transmits the signals to a variety of its targets, which may contain inactivated GGDEF, EAL, or HD-GYP domains, widespread PilZ or MshEN domains, or various lineage-specific c-di-GMP receptors. Many organisms encode multiple GGDEF domains but few c-di-GMP-binding proteins, suggesting the existence of still unidentified c-di-GMP receptors. Here, we demonstrate that the ComFB family proteins, which include the recently characterized cyanobacterial CdgR/ComFB, constitute yet another widespread family of bacterial c-di-NMP receptors. We additionally show that ComFB controls bacillar motility in a c-di-GMP-dependent manner.
Evolutionary history of the grape sex-determining region in angiosperms and emergence of dioecy in Vitaceae
Authors: Massonnet Melanie , Cochetel Noe , Ricciardi Valentina , Minio Andrea , Figueroa-Balderas Rosa , Londo Jason , Cantu Dario
Published: November 2024

Dioecy, defined by the presence of either female or male flowers on separate individual plants, is rare in angiosperms. However, it has independently evolved multiple times from hermaphroditic ancestors. In Vitis spp., flower sex is determined by a ~200-kbp region with five genes involved in flower development and sexual identity. This study traces the evolutionary history of the Vitis sex-determining region (SDR) to assess whether it evolved in a conserved flowering-related locus. We analyzed the conservation of the Vitis SDR across 42 plant genomes and found collinearity in all 39 angiosperms, but not in non-flowering plants. The number of collinear genes and their rank-normalized gene conservation score were higher in the Vitis SDR compared to the rest of the genome, indicating its importance for flowering. We further explored SDR conservation within the Vitaceae family by long-read sequencing and haplotype phasing of eight species, including the outgroup Leea coccinea. Similarly, the Vitis SDR was highly conserved across the Vitaceae genomes, although variations in region size, primarily attributed to differences in repetitive elements, were observed. Interestingly, no recombination suppression was found in the dioecious Tetrastigma, suggesting a different sex determination mechanism. In Muscadinia rotundifolia, linkage disequilibrium analysis, haplotype comparison, and gene expression profiling showed that muscadine grapes have similar SDR boundaries and candidate sex-determining genes as Vitis. These results suggest that dioecy emerged in a common ancestor of the two grape genera at a locus associated with flower morphology and fertility, highly conserved in flowering plants.
Mass flowering and flowering asynchrony characterise a seasonal herbaceous community in the Western Ghats
Authors: Shrotri Saket , Kaur Sukhraj , Dhargalkar Rahul , Najla PV , Gowda Vinita
Published: November 2024

Seasonally flowering communities often exhibit higher flowering synchrony than what can be attributed to environmental factors alone. Flowering synchrony can either increase competition for pollinators or improve pollination through facilitation. Consequently, analysing a community’s flowering patterns can help identify its ecological constraints. In this study, we characterised the flowering phenology of a seasonal, herbaceous community (Kaas plateau) in Western Ghats, India, known for its endemic flora and mass flowering displays. Over three years, we addressed the following questions: (a) Is flowering seasonality shaped by environmental factors? (b) Is there evidence for flowering synchrony within the community? (c) Are plant-pollinator interactions specialised?

Our results show that flowering seasonality was shaped by long dry seasons and subsequent rainfall patterns. Based on the floral abundance, we categorised the flora into mass flowering and non-mass flowering species. To incorporate flowering abundance in defining flowering synchrony, we introduced two novel synchrony indices, which identified community-wide flowering asynchrony, despite having mass flowering species. Finally, the plant-pollinator networks identified native bees as dominant pollinators and the prominence of generalised interactions. We also noted sub-seasonal temporal shifts in pollination networks that matched flowering abundances within the community.

This is the first study to exhaustively characterise the flowering phenology of plants from a laterite plateau in the Western Ghats. We show that despite seasonality, both mass flowering and flowering asynchrony emerged as the defining characteristics of this habitat. Our results suggest that competition for pollinators probably drives flowering asynchrony within these seasonal herbaceous communities, rather than pollination facilitation.
A Watershed Algorithm GUI for Personalized fMRI-guided rTMS Target
Authors: Feng Zi-Jian , Wei Ziyu , Hong Liquan , Fang Hongli , Han Yu , Yang Peifeng , Dongsheng Lv , Zang Yu-Feng
Published: November 2024

The FDA approved personalized resting-state functional connectivity for precise target localization in rTMS. However, objective methods for pinpointing optimal connectivity clusters have remained limited. This study proposed a watershed-based approach with a graphical user interface, offering threshold-independent segmentation that outperformed traditional threshold-based methods. Demonstrated in the context of Alzheimer’s disease, this approach enabled precise targeting within the default mode network, specifically the posterior cingulate cortex and inferior parietal lobule. By facilitating more accurate and individualized localization, this method holds promise for refining the precision of personalized rTMS treatment.
Assessing Conformation Validity and Rationality of Deep Learning-Generated 3D Molecules
Authors: Fan Fan , Xi Bin , Meng Xianghu , Wang Han , Zhang Bowen , Xu Qingbo , Feng Wei , Wang Xiaoman , Zhang Hongbo , Zhou Feng , Liu Zhenming , Zhou Wenbiao , Huang Bo
Published: November 2024

Recent advancements in artificial intelligence (AI) have revolutionized the field of 3D molecule generation. However, the lack of effective evaluation methods for 3D conformations limits further improvements. Current techniques, in order to achieve the necessary speed for evaluating large numbers of AI-generated molecules, often rely on empirical geometric metrics that do not adequately capture various conformational anomalies, or on molecular mechanics (MM) energy metrics that exhibit low accuracy and lack atomic or torsional details. To address this gap, we propose a two-stage approach that achieves both high speed and quantum mechanical (QM) level accuracy. The first stage, termed the validity test, employs an AI-derived force field to identify atoms with elevated energy resulting from implausible neighboring environments. The second stage, known as the rationality test, utilizes a deep learning network trained on data with density functional theory (DFT) accuracy to detect rotatable bonds with high torsional energies. To demonstrate the functionality of our evaluation system, we applied our approach to five recently reported 3D molecule generation AI models across 102 targets in Directory of Useful Decoys-Enhanced (DUD-E) dataset. To facilitate accessibility for the academic community, our method is available as an open-source package.
Large-scale remote sensing reveals that tree mortality in Germany appears to be greater than previously expected
Authors: Schiefer Felix , Schmidtlein Sebastian , Hartmann Henrik , Schnabel Florian , Kattenborn Teja
Published: November 2024

Global warming poses a major threat to forests, and increased tree mortality events are observed globally. Studying tree mortality often relies on local-level observations of dieback, while large-scale analyses are lacking. Satellite remote sensing provides the spatial coverage and sufficiently high temporal and spatial resolution needed to investigate tree mortality at the landscape scale. However, adequate reference data for training satellite-based models are scarce. In this study, we employed the first maps of standing deadwood in Germany for the years 2018-2022 with 10 m spatial resolution, created using tree mortality observations from hundreds of drone images as the reference. These maps were used to study spatial and temporal patterns of tree mortality in Germany and analyze their biotic and abiotic environmental drivers using random forest regression. In 2019, the second consecutive hotter drought year, standing deadwood increased steeply to 334 +- 189 kilohectares (kha), which corresponds to 2.5 +- 1.4% of the total forested area in Germany. Picea abies, Pinus sylvestris, and Fagus sylvatica showed the highest shares of standing deadwood. During 2018-2021, 978 +- 529 kha (7.9 +- 4.4%) of standing dead trees accumulated. The higher mortality estimates reported here, compared to other surveys (such as ground-based forest condition surveys), can be partially attributed to the remote sensing perspective, which captures mortality from above and includes scattered occurrences of tree mortality due to the high spatial detail (10 m). Atmospheric drought (i.e., climatic water balance and vapor pressure deficit) and temperature extremes (i.e., number of hot days and frosts after vegetation onset) were the most important predictors of tree mortality. Increased mortality was observed for smaller and younger stands and in less productive sites. Monospecific stands were generally not more affected by mortality, except when interactions with damaging insects (e.g., bark beetles) occurred. Excess tree mortality rates threaten many forests globally, making similar analyses of tree mortality both warranted and technically feasible on a global scale. We encourage the international scientific community to share and compile local data on deadwood occurrences (see example: www.deadtrees.earth) to facilitate a collaborative effort in understanding mortality events on a global scale.
ROSIE: AI generation of multiplex immunofluorescence staining from histopathology images
Authors: Wu Eric , Bieniosek Matthew , Wu Zhenqin , Thakkar Nitya , Charville Gregory W. , Makky Ahmad , Schürch Christian , Huyghe Jeroen R , Peters Ulrike , Li Christopher I , Li Li , Giba Hannah , Behera Vivek , Raman Arjun , Trevino Alexandro E. , Mayer Aaron T. , Zou James
Published: November 2024

Hematoxylin and eosin (H&E) is a common and inexpensive histopathology assay. Though widely used and information-rich, it cannot directly inform about specific molecular markers, which require additional experiments to assess. To address this gap, we presentROSIE,a deep-learning framework that computationally imputes the expression and localization of dozens of proteins from H&E images. Our model is trained on a dataset of over 1000 paired and aligned H&E and multiplex immunofluorescence (mIF) samples from 20 tissues and disease conditions, spanning over 16 million cells. Validation of ourin silico mIFstaining method on held-out H&E samples demonstrates that the predicted biomarkers are effective in identifying cell phenotypes, particularly distinguishing lymphocytes such as B cells and T cells, which are not readily discernible with H&E staining alone. Additionally,ROSIEfacilitates the robust identification of stromal and epithelial microenvironments and immune cell subtypes like tumor-infiltrating lymphocytes (TILs), which are important for understanding tumor-immune interactions and can help inform treatment strategies in cancer research.
Ligand binding characteristics of an NAD+ riboswitch revealed by FRET and biolayer interferometry
Authors: Conoan Nieves Nico E. , Widom Julia R.
Published: November 2024

The Class II NAD+riboswitch is a bacterial RNA that binds ligands containing nicotinamide. Herein, we report a fluorescence and biolayer interferometry study of riboswitch interactions with β-NMN. The results reveal a shift in the prevalence of a pseudoknot structure in the presence of ligand and Mg2+.
Contrast-Enhanced Micro-CT Imaging of a Foetal Female Pelvic Floor Reveals Anatomical Details
Authors: Aaldijk Dea , Halm Sebastian , Liashchenko Diana N. , Haberthür David
Published: November 2024

Background

The pelvic floor is a highly important structure for the stability of the pelvis, providing support for the organs that lie within it. Until today, the detailed anatomy of the female perineal centre and the exact course of surrounding muscles remain controversial. This paper demonstrated a method to non-destructively obtain high-resolution contrast-enhanced x-ray microtomography images from a long-fixed sample and thereby aimed to contribute to the detailed anatomical knowledge about the female pelvic floor.

Materials and Methods

A human foetal pelvis of 20-21 weeks gestational age, formalin-fixed for 4 years, was immersed in Lugol solution and tomographically scanned periodically to document the staining process. The influence of the former fixation time was addressed by comparison with a short time fixed mouse pelvis. High-resolution imaging was performed by µCT, and the detailed analysis of the anatomy was supported by segmentation and 3D reconstruction.

Results

Lugol staining of long-fixed tissue worked well and showed no disadvantages compared to short-fixed tissue. Lugol staining and high-resolution µCT images provided a nicely stained image- stack with clearly identifiable tissue types. The anatomy of the foetal pelvis and its structures were resolved in detail. Interconnections between the external anal sphincter, the bulbospongiosus muscle and the superficial transverse perineal muscle could be shown within the perineal centre. There was no evidence for a skeletal muscle that corresponded to the formerly described deep transverse perineal muscle, instead there was cloudy-looking tissue, most likely smooth muscle fibres dispersed in connective tissue in a 3-D arrangement.

Conclusions

X-ray microtomography of Lugol-stained tissue is an excellent method to gain anatomical details in high resolution, in a non-invasive and non-destructive way, independently of the fixation time. Using this method, the topographical relationships of the pelvic floor muscles could be illustrated, showing their linkage within the perineal centre.
Temporal and Geographic Variability of International Urinary Phthalates in Humans: A Systematic Review and Meta-Analysis of Biomonitoring Data
Authors: Acevedo Jonathan M. , Kahn Linda G. , Pierce Kristyn A. , Albergamo Vittorio , Carrasco Anna , Manuel Robbie S.J. , Singer Rosenberg Marissa , Trasande Leonardo
Published: November 2024

Phthalates are endocrine-disrupting chemicals (EDCs) that alter hormone functions throughout the lifespan. Growing awareness of the adverse health effects of phthalate exposure has led to regulating certain phthalates in the United States, Canada, and Europe. However, international comparisons of urinary phthalate metabolite concentrations as biomarkers of exposure are sparse, and few studies have controlled for cohort-specific variables like pregnancy.

We aimed to examine trends in urinary phthalate monoester metabolite concentrations in non-occupationally exposed populations globally, excluding locations where representative data are already available at the country level.

We systematically reviewed studies published between 2000 and 2023 that reported urinary phthalate monoester concentrations. We examined changes in metabolite concentrations across time, controlling for region, age, and pregnancy status, using mixed-effects meta-regression models with and without a quadratic term for time. We identified heterogeneity using Cochran’s Q-statistic and I2index, adjusting for it with the trim-and-fill method.

The final analytic sample consisted of 216 studies. Significant differences in phthalate metabolite concentrations were observed across regions, age groups, and between pregnant and non-pregnant cohorts. Our meta-regression identified a significant non-linear trend with time for Mono-n-butyl phthalate and Mono-isononyl phthalate concentration internationally and in Eastern and Pacific Asia (EPA). We also observed significant non-linear associations between time and Mono(2-ethyl-5-hydroxyhexyl) phthalate, Mono(2-carboxymethylhexyl) phthalate, and Mono(3-carboxypropyl) phthalate concentration internationally and/or in EPA, along with Mono(2-ethylhexyl) phthalate, Mono-carboxy-isononyl phthalate, and Mono-ethyl phthalate. Additionally, Mono-ethyl phthalate concentration showed a significant negative linear association with time in Latin America and Africa. Heterogeneity was high, indicating potential bias in our results.

Our findings indicate the need for increased awareness of phthalate exposure. Further analysis of the attributable disease burden and cost at regional and international levels, especially in low- and middle-income countries, is essential to understanding these and other EDCs impact on population health and the economy.

Highlights

Some phthalate levels significantly differed by region, age, and pregnancy status.

Many phthalates had non-linear associations internationally from 2000 to 2023.

MnBP and MiNP levels increased, driven by Eastern and Pacific Asia results.

Most phthalate metabolites’ levels declined overall and region-specific over time.

There was insufficient data on phthalate metabolite levels for many regions.
Wearable Focal Muscle Vibration Improves Upper Limb Function in People with Sub-acute Stroke
Authors: Niazi Imran Khan , Amjad Imran , Farooq Irum , Shafi Hina , Rashid Usman , Kumari Nitika , Shaikh Nusratnaaz , Jochumsen Mads , Holt Kelly , Haavik Heidi , Farmer Simon F. , Pujari Amit N.
Published: November 2024

The objective of the study was to compare the effects of two focal muscle vibration (FMV) stimulation frequencies (60 Hz and 120 Hz), combined with conventional physical therapy (PT), on upper limb impairment and function in people with sub-acute stroke when FMV is delivered through a wearable FMV device.

The study was a parallel group, randomized controlled trial conducted at the Rehabilitation Centre of Railway General Hospital, Rawalpindi, Pakistan. A total of 98 individuals with sub-acute stroke were randomly allocated to control group (eight weeks of conventional physical therapy, (PT)) or experimental groups (eight weeks of conventional physical therapy combined with focal muscle vibration (FMV) at 60 Hz (PT + FMV60 Hz) or 120 Hz (PT + FMV120 Hz)). Outcome measures included Fugl Meyer Scale for upper extremity (FMUE), Motor Assessment Scale (MAS), and Modified Ashworth Scale (MASh). They were collected at baseline and after eight weeks of treatment. Data were analysed using linear regression model. The study was registered on the National Institutes of HealthClinicalTrials.govclinical trial registry (IdentifierNCT04289766).

At post-intervention time-point, FMUE scores varied across groups (F (2, 81) = 7.2, p = 0.001), MAS scores did not vary across groups (F (2, 81) = 0.2, p = 0.8) and MASh rank changes varied across groups (F (2, 81) = 3.3, p = 0.04). There were no differences between the PT + FMV60 Hz and the PT + FMV120 Hz groups.

This study provides the evidence that wearable Focal Muscle Vibration (at 60 and 120 Hz) improves the motor outcome of sub-acute stroke patients. Thus, it can be used along with conventional physiotherapy as a valid intervention to promote upper limb function and reduce spasticity in sub-acute post-stroke patients.
MosCoverY: a new method to estimate mosaic Loss of Y chromosome from NGS sequencing coverage data
Authors: Timonina V. , Marchal A. , Abel L. , Cobat A. , Fellay J.
Published: November 2024

Mosaic loss of the Y chromosome (mLOY) is the most common somatic event in men, strongly associated with aging and various health conditions. Current methods for detecting mLOY primarily rely on DNA genotyping arrays. Here, we present MosCoverY, a novel method for estimating mLOY from NGS sequencing data that can be applied to both exome and genome sequencing. MosCoverY addresses the challenges posed by the structure of the Y chromosome by focusing on single-copy genes and normalizing their coverage against autosomal exons matched by length and GC content. We validated MosCoverY using data from 212,062 male participants in the UK Biobank, comparing its results to those obtained using genotyping- or whole genome sequencing-based methods. MosCoverY identified mLOY in 5.6% of men, demonstrating performance that was comparable to the other methods. MosCoverY also replicated known associations between mLOY, age, smoking, all-cause mortality, and germline genetic loci, showing the strongest associations in many cases. MosCoverY offers a valuable tool for detecting mLOY from exome data in population-scale studies.
A regulator controls both DNA damage response and anti-phage defense networks inMoraxellaceae
Authors: Song Shuang , Zhong Shitong , Shi Qiucheng , Zheng Xiangkuan , Yao Yue , Wang Wenxiu , Chen Shanhou , Huang Zijun , An Dongyue , Xu Hong , Tian Bing , Zhao Ye , Wang Liangyan , Zhang Wei , Hua Xiaoting , Yu Yunsong , Lu Huizhi , Fan Lu , Hua Yuejin
Published: November 2024

DNA damage chemicals, including many antibiotics, often induce prophage induction and phage outbreaks in microbial communities, a major threat to bacterial survival.Moraxellaceaecontains clinically highly relevant strains with outstanding antibiotic and radio resistance, yet their cellular-level regulation in DNA damage response and anti-phage defense is largely unknown. Here, we identified a WYL family protein that had replaced the ubiquitous SOS system in evolution and directly regulated a transcriptional network of both DNA repair genes and anti-phage defense genes under DNA damage stress. This study depicts a mechanism that how bacteria maintain immunity to phages without compromising on antibiotic resistance, and sheds light on controlling the resistance ofMoraxellaceaestrains in clinical practice.