bluuebunny/crossref_metadata_2025 huggingface dataset:
One and only SNARC? Spatial-Numerical Associations are not fully flexible and depend on both relative and absolute number magnitude
Authors: Roth Lilly , Caffier John , Reips Ulf-Dietrich , Nuerk Hans-Christoph , Overlander Annika Tave , Cipora Krzysztof
Published: January 2025

Numbers are associated with space, but it is unclear how flexible these associations are. We investigated whether the SNARC effect (Spatial-Numerical Association of Response Codes; Dehaene
et al
. 1993
J. Exp. Psychol
.
122
, 371–396. (doi:
10.1037/0096-3445.122.3.371
); i.e. faster responses to small/large number magnitude with the left/right hand, respectively) is fully flexible (depending only on relative magnitude within a stimulus set) or not (depending on absolute magnitude as well). Evidence for relative-magnitude dependency came from studies observing that numbers 4 and 5 were associated with the right in a 0–5 range but with the left in a 4–9 range (Dehaene
et al
. 1993; Fias
et al
. 1996
Math. Cogn
.
2
, 95–110 (doi:
10.1080/135467996387552
). Within this Registered Report, we conducted two online experiments running Bayesian analyses with optional recruitment stopping at moderate evidence (BF
10
above 3 or below 1/3). Experiment 1 (
n
= 200) replicated relative-magnitude dependency using the original stimuli. However, Experiment 2 (
n
= 300) additionally demonstrated absolute-magnitude dependency, while considering recent advances in SNARC research using 1–5 excluding 3 and 4–8 excluding 6. In contrast to the frequently perpetuated notion of fully flexible Spatial-Numerical Associations, some fixed relation to absolute magnitude prevails. These findings have important consequences for understanding how Spatial-Numerical Associations might support numerical processing.
Inconclusive evidence for associations between adverse experiences in adulthood and working memory performance
Authors: Vermeent Stefan , Schubert Anna-Lena , DeJoseph Meriah L. , Denissen Jaap J. A. , van Gelder Jean-Louis , Frankenhuis Willem E.
Published: January 2025

Decades of research have shown that adversity tends to be associated with lower working memory (WM) performance. This literature has mainly focused on impairments in the capacity to hold information available in WM for further processing. However, some recent adaptation-based studies suggest that certain types of adversity can leave intact, or even enhance, the ability to rapidly update information in WM. One key challenge is that WM capacity and updating tasks tend to covary, as both types of tasks require the creation and maintenance of bindings in WM; links between mental representations of information in WM. To estimate the associations between adversity and different processes in WM, we need to isolate variance in performance related to WM capacity from variance in performance related to updating ability. In this Registered Report, participants from the Dutch Longitudinal Internet studies for the Social Sciences (LISS) panel completed three WM tasks: two complex span tasks and a task measuring both binding and updating of information. In addition, we estimated participants’ exposure to neighbourhood threat, material deprivation and unpredictability. We estimated associations between the three types of adversity and latent estimates of WM capacity and updating using structural equation modelling. We did not find consistent associations between adversity and WM capacity or updating, nor did we find evidence that the associations were practically equivalent to zero. Our results show that adversity researchers should account for overlap in WM tasks when estimating specific WM abilities.
On the economic feasibility of tidal range power plants
Authors: Pappas Konstantinos , Quang Chien Nguyen , Zilakos Ilias , Beevers Lindsay , Angeloudis Athanasios
Published: January 2025

The potential energy associated with tides presents a sustainable energy resource that remains largely untapped. Uncertainties on the economic case of tidal range power plants are a known obstacle. Research on tidal range structures suggests energy yield may be maximized through operation strategy optimization, and that impacts can be mitigated through design optimization. While instructive, these perspectives alone are insufficient to support the feasibility of individual projects. We integrate operation optimization and hydrodynamic impact analyses within a cost evaluation framework for tidal range structures focusing on capital costs (CAPEX) and levelized cost of energy (LCOE). Once benchmarked against 11 historic proposal cost projections, we perform a redesign of 18 tidal power plants to deliver a comprehensive comparative basis across a diverse range of sites in the UK. Tidal power plant operation is simulated in regional shallow-water equation models, acknowledging tide variability. The cost evaluation framework demonstrates the impact of geospatial variations on key cost components. The redesign process indicates transformative implications in that equivalent and lower LCOE values can be achieved for designs at a substantially lower CAPEX. Given how the latter hinder development, we show how tidal range schemes could be far more economically feasible than commonly perceived.
Silent cells? Potential for context-dependent gene expression in mature sperm
Authors: Lymbery Rowan A. , Garcia-Gonzalez Francisco , Evans Jonathan P.
Published: January 2025

Sperm are traditionally viewed as transcriptionally and translationally silent cells. However, observations that components of the cellular machinery of gene expression are maintained in ejaculated sperm are increasingly cited as challenges to this fundamental assumption. Here, we critically evaluate these arguments and present three lines of evidence from both model and non-model systems that collectively raise the question of whether ejaculated sperm may be capable of active gene expression. First, and critical for arguments surrounding the possibility of differential gene expression, we review recent evidence that spermatozoa may retain the capacity to transcribe and translate their genomes. Second, we highlight how sperm cells can exhibit differential transcript quantities across different post-ejaculation environments. Third, we ask whether the accumulating evidence of remarkable phenotypic plasticity in post-ejaculatory sperm phenotypes could be mechanistically underpinned by changes in sperm gene expression. While these lines of evidence are indirect and do not definitively show transcription of sperm genomes, we highlight how emerging technologies may enable us to test this hypothesis explicitly. Our review advocates for progress in this field and highlights several important evolutionary, ecological and practical implications that will probably transcend disciplines to the clinical and applied reproductive sectors.
Calcium and strontium isotopes in extant diapsid reptiles reflect dietary tendencies—a reference frame for diet reconstructions in the fossil record
Authors: Weber Michael , Weber Katrin , Winkler Daniela E. , Tütken Thomas
Published: January 2025

Dietary preferences of extant reptiles can be directly observed, whereas diet reconstruction of extinct species typically relies on morphological or dental features. More specific information about the ingested diet is contained in the chemistry of hard tissues. Stable isotopes of calcium and strontium show systematic fractionations between diet and skeletal bioapatite, which is applied for diet and trophic-level reconstructions of extant and extinct vertebrate species. Here, we present the first comprehensive analysis of stable calcium and strontium isotopes of bones and teeth from 28 extant reptiles, including lepidosaurs and archosaurs (crocodilians) with distinct herbivorous to faunivorous feeding behaviour, establishing a dietary reference frame. Both calcium and strontium isotopes exhibit systematic offsets between dietary groups, with insectivores having the highest, herbivores intermediate and carnivores the lowest calcium and strontium isotope values. Although the isotopic trophic-level effect is similar to mammals, the absolute calcium isotope values in reptiles are more positive in each diet category. Combining isotopic data with dental microwear texture analysis enables a refined understanding of reptile feeding ecology and the identification of durophagous diets. This toolbox opens new possibilities for improved dietary reconstructions of extinct taxa, such as dinosaurs and other non-mammalian species in the fossil record.
Whole-genome sequencing of the Streptomyces coelicolor bldA39 mutant (J1700) of reveals hundreds of previously unknown mutations.
Authors: Stone Jack W. , Munnoch John T. , Hoskisson Paul A
Published: January 2025

We report the genome sequence of the bldA39 (J1700) mutant Streptomyces coelicolor, a historically important strain that is deficient in sporulation and antimicrobial production. The S. coelicolor J1700 strain was used extensively from the 1980s onwards to underpin important discoveries in development and antibiotic production in Streptomyces. The bldA gene encodes a leucyl transfer RNA (tRNA), required for the translation of the rare TTA codon found in ~2% of genes in Streptomyces. The whole genome of S. coelicolor J1700 was obtained via Illumina sequencing and mapped to the of S. coelicolor M145 reference genome. Analysis of the genome sequence compared to S. coelicolor M145 identified the known bldA39 mutation (T>C) and revealed more than 300 further mutations, likely associated with the S. coelicolor J1501 genetic background the strain was created in, including the nature of the hisA1 and uraA1 alleles used extensively in genetic mapping experiments and several mutations in natural product biosynthetic gene clusters. This work highlights the importance of whole genome sequencing of historically important strains.
Molecular and Microscopy Evaluation of Lymphatic filariasis in Ilorin Metropolis, Kwara State Nigeria
Authors: Omah Prosper , Nmorsi Onyebiguwa Patrick Goddey , Egwunyenga Andy Ogochukwu
Published: January 2025

Background

Lymphatic filariasis is widespread and a major public health problem in many developing countries with warm and humid climate and it is one of the most prevalent neglected tropical diseases. This study, evaluated the diagnostics performance of molecular and conventional microscopy method of Lymphatic filariasis in Ilorin Metropolis, Kwara State Nigeria.

Methods

Genomic DNA was collected from 45 human blood samples obtained from Ilorin, Kwara State. They were then amplified by PCR and detected through gel electrophoresis. The PCR products were purified with QIAquick PCR purification kit (Qiagen, Valencia, CA) and then DNA quantified for Sanger sequencing, Bio Edit Software were used for sequence alignment and editing. 37 sequences were selected for analysis by MEGA X software to access the evolutionary connection of W. bancrofti isolates.

Results

37 (82.2%) PCR products were positive for W. bancrofti and 16 (35.6%) were Positive for Microscopy. Hence, the sensitivity of PCR (82.2%) while the specificity was (64.4%).With the microscopy, the chances of a negative samples turning out positive by PCR, also known as the positive predictive value (PPV) was (69.8%) while the chances of being picked as truly negative predictive value was (78.4%). In assessing the level of agreement show that microscopy has a weak agreement, Kappa index statistics (0.46) with molecular techniques 95% CI,0.2-0.4).

Conclusion

Since Polymerase Chain Reaction showed higher sensitivity (82.2%) as positive predictive value, it is therefore recommended to include PCR as complementary routine diagnosis for lymphatic filariasis especially subclinical cases due to W. bancrofti despite its relatively higher cost.
Five-Year Survival Outcomes for Breast Cancer Patients Across Continental Africa: A Contemporary Review of Literature with Meta Analysis
Authors: Badu-Peprah Augustina , Kontor Ernest Kissi , Benjamin Adu-Gyamfi , Kumah Jessica , Essuman Akosua Aya , Selorm Bossoh , Nurudeen Issahak , Owusu Bismark Osei , Jain Nityanand
Published: January 2025

Background

Breast cancer associated mortality in Africa remains high due to poor survival rates, varying widely across countries. Despite medical advancements, barriers like limited access to early detection and treatment persist. This meta-analysis offers a crucial update on 5-year survival trends and influencing factors across continental Africa.

Methods

A systematic search of four biomedical databases and citation searching identified 79 articles from 22 African countries, analyzing 27,559 patients (97% female). A random-effects model was used to estimate the 5-year survival rate with subgroup analyses. Publication bias was assessed using Egger’s test and funnel plots.

Results

Pooled overall 5-year breast cancer survival in Africa averaged 48% (95% CI: 43-53%) with high statistical heterogeneity (I² = 98%). Survival was highest in Northern Africa (64%; 95% CI: 59-69%) and lowest in Western Africa (32%; 95% CI: 23-42%). Males (51%; 95% CI: 36-65%) had marginally higher survival than females (48%; 95% CI: 42-54%). Socioeconomic indices were positively associated with better outcomes. Publication bias, adjusted by the trim-and-fill method, raised survival to 62% (95% CI: 55-67%). A country-wise comparison with 2018 estimates suggests a declining survival tendency, with WHO AFRO countries reporting the poorest estimates among other WHO regions. Despite regional differences, survival trends seem to have plateaued near 48-49% level continent-wide since the early 2010s.

Conclusions

Our findings reveal marked regional disparities in survival rates across Africa, underscoring the urgent need for targeted healthcare interventions. Strengthening healthcare systems, ensuring universal access, and driving socioeconomic progress are vital to improving survival outcomes.
Determination of the mechanisms of MCPA resistance inAmaranthus powellii
Authors: Aicklen Isabelle , Jugulam Mithila , Gaines Todd , Kramer William , Laforest Martin , Robinson Darren , Sikkema Peter , Tardif François
Published: January 2025

Resistance to 2-methyl-4-chloro-phenoxyacetic acid (MCPA) was recently confirmed in a population of green pigweed (Amaranthus powellii) from Dresden, Ontario, Canada, with a resistance factor of 4.4. Resistance to synthetic auxin herbicides inAmaranthusspecies has previously been linked to non-target site resistance mechanisms with low-level resistance factors (<10). Based on this information an investigation into the mechanism of resistance to MCPA was conducted in this population of green pigweed. No significant differences in absorption, translocation, and metabolism of14C-MCPA existed between the resistant and a susceptible population of green pigweed. An RNA-Sequencing experiment to identify differentially expressed genes also confirmed this result. Genes that were differentially expressed in the resistant population were linked to target site modifications. A single nucleotide polymorphism (SNP) conferring a leucine to phenylalanine substitution was identified in auxin response factor (ARF) 9. This mutation may be in the Phox and Bem1p (PB1) domain in ARF9 which facilitates the interaction between ARFs and Aux/IAA repressor proteins. The results demonstrate that the mechanism of resistance to MCPA is not a non-target site mechanism and may be linked to a target site modification. Specifically, a SNP in ARF9 could disrupt the interaction between ARF9 and other Aux/IAAs which could prevent ubiquitination of Aux/IAAs and subsequent lethal action of MCPA.
Strategic Conservation Prioritization Through Creating and Updating the Regional Species of Greatest Conservation Need (RSGCN) List in the Northeastern U.S.
Authors: Starking Melissa D. , Rice Tracy Monegan , Terwilliger Karen , Drummey Donovan , Frantz Mack , Haffner Catherine D. , Hess Brian , Holst Lisa , Marchand Michael , Burgio Kevin R.
Published: January 2025

Through the end of the century, biodiversity is expected to markedly decline around the world due to climate change, habitat loss, and other factors. Because of this, there is an increasing need for more efficient, effective, and collaborative conservation efforts worldwide. While many global and national threat assessment databases exist, they may only have limited utility at regional and local scales where on-the-ground conservation is best implemented. To better identify species risk at a more regional scale, the 14 state fish and wildlife agencies in the northeastern United States worked with taxonomic experts across the Northeast to create the most recent (2023) list of Regional Species of Greatest Conservation Need (RSGCN). We compared a preliminary list compiled from global and national datasets to the finalized list after the process documented here. We found that the global and national datasets only identified ∼55% of the 806 species statuses accurately for the region, demonstrating the importance of current local and regional expertise and data. The process of identifying RSGCN for the northeastern U.S. has resulted in specific actionable information leading to beneficial outcomes, such as dedicated funding for regional initiatives, data-sharing, and coordination among regional, state, and local conservation organizations - enabling beneficial conservation outcomes across the region for many of the species and habitats of the region. The methods described may serve as a framework for other regions to help identify conservation targets using the best available and more localized landscape- and watershed-scale information.
Developing a model system to sustain ex vivo chloroplast function
Authors: Mohagheghi Mariam , Navid Ali , Mossington Thomas , Ye Congwang , Coleman Matthew , Honag-Phou Steven
Published: January 2025

Chloroplasts are critical organelles in plants and algae responsible for accumulating biomass through photosynthetic carbon fixation and cellular maintenance through metabolism in the cell. Chloroplasts are increasingly appreciated for their role in biomanufacturing, as they can produce many useful molecules, and a deeper understanding of chloroplast regulation and function would provide more insight for the biotechnological applications of these organelles. However, traditional genetic approaches to manipulate chloroplasts are slow, and generation of transgenic organisms to study their function can take weeks to months, significantly delaying the pace of research. To develop chloroplasts themselves as a quicker and more defined platform, we isolated chloroplasts from the green algae,Chlamydomonas reinhardtii, and examined their photosynthetic function after extraction. Combined with a metabolic modeling approach using flux-balance analysis, we identified key metabolic reactions essential to chloroplast function and leveraged this information into reagents that can be used in a “chloroplast media” capable of maintaining chloroplast photosynthetic function over timeex vivocompared to buffer alone. We envision this could serve as a model platform to enable more rapid design-build-test-learn cycles to study and improve chloroplast function and potentially as a foundation for the bottom-up design of a synthetic organelle-containing cell.
Highly divergent mesnidoviruses found in TSA database, especially in spiders
Authors: Xie Jiazheng , Zhang Yu
Published: January 2025

The mesnidoviruses are positive single-stranded viruses belonging to the orderNidovirales. They were mostly found in mosquitoes, and represent a link from small to large nidoviruses. In this study, we report 18 newly discovered nidoviruses in TSA database, most of them are from spiders (OrderArachnida). After reassembly, we got 9 nearly complete genomes with sizes ranged from ∼19,500 to 33,500 nt. Further phylogenetic analyses assigned these nidoviruses toMesnidovirineae. Among them, the spider viruses represent a new clade. Pairwise evolutionary distance (PED) analysis showed these mesnidoviruses are highly divergent, with PED values from 2.2 to 4.9 with existing ones. Even among themselves the PED values are notable: with most exceeding the threshold of 0.32 that defines a new virus genus, suggesting these viruses are new species or belong to new higher-ranking taxa. In summary, we reported 18 mesnidoviruses in spiders, insects, plant andAnthozoa, the highly divergence suggested that spiders may harbor diverse mesnidoviruses. As the first nidovirus reported inArachnidaandAnthozoa, this discovery will contribute to the evolution study ofNidovirales.
Next-Generation Mapping of the ACINUS-Mediated Alternative Splicing Machinery and Its Regulation by O-glycosylation inArabidopsis
Authors: Shrestha Ruben , Reyes Andres V , Carey Shane , Karunadasa Sumudu S , Zhai Wenxuan , Byun Danbi , Lin Wen-Dar , Li Jie , Alerte Kathrine , Cui Hongchang , Wang Zhi-Yong , Xu Shou-Ling
Published: January 2025

Alternative splicing (AS) is a key mechanism of gene regulation, but the full repertoire of proteins involved and the regulatory mechanisms governing this process remain poorly understood. Using TurboID-based proximity labeling coupled with mass spectrometry (PL-MS), we comprehensively mapped the Arabidopsis AS machinery, focusing on the evolutionarily conserved splicing factor ACINUS, its paralog PININ, and the stable interactor SR45. We identified 298 high-confidence components, including both established and novel interactors, providing strong evidence that alternative splicing is coupled to transcription and that multiple RNA processing steps occur simultaneously in plants. Selected interactors were validated through AS readouts and phenotypic analysis. Furthermore, a systematic evaluation of O-glycosylation double mutants revealed that SECRET AGENT (O-GlcNAc transferase) and SPINDLY (O-fucose transferase) modulate AS through both ACINUS-dependent and -independent pathways. Our results unravel the plant AS network and highlight the global role of sugar modification in RNA processing.
EFFECTS OF MODIFIED PROGRESSIVE MUSCLE RELAXATION COMBINED WITH SLOW STROKE BACK MASSAGE ON BLOOD PRESSURE REDUCTION, STRESS ALLEVIATION, AND ENHANCED SLEEP QUALITY IN OLDER ADULTS: A LITERATUR REVIEW
Authors: Asriadi  , Pandin Moses Glorino Rumambo , Nursalam
Published: January 2025

Background

Progressive muscle relaxation is a systematic technique used to achieve deep states of relaxation and has been proven to improve the quality of life related to both medical and non-medical conditions. The goal is to consciously experience the difference between tension and relaxation, just like applying pressure to the muscles, where all the muscles in the body from the tip of the head to the tip of the toes, which were initially tense, become relaxed after receiving progressive pressure. Therefore, an explanation is needed that discusses the influence of modified slow stroke back massage progressive muscle relaxation on reducing blood pressure, stress, and sleep quality in the elderly.

Objective

to identify the effects of progressive muscle relaxation and slow stroke back massage on the reduction of blood pressure, stress, and sleep quality in the elderly.

Method

a scope review of this research by searching for articles related to the effects of progressive muscle relaxation and slow stroke back massage on the reduction of blood pressure, stress, and sleep quality in the elderly. Using several databases such as Scopus, Proquest, PubMed, and Google Scholar. Then, the found articles were checked for duplication using Mendeley, resulting in 327 articles. After the title screening process, 129 articles remained. Then 25 articles were included and 15 articles were excluded because they did not meet the study quality.

Results

From the review of 10 journals, two main topics were identified, including the effect of progressive muscle relaxation on lowering blood pressure, reducing stress and anxiety, stabilizing vital signs, and improving sleep quality, and the effect of slow stroke back massage therapy on lowering blood pressure, reducing stress and anxiety, and improving sleep quality.

Conclusion

Progressive muscle relaxation and slow stroke back massage therapy have a significant impact on lowering blood pressure, reducing stress, and improving the sleep quality of the elderly.
RNA-triggered CRISPR-Cas12a2 Preferentially and Cooperatively Cleaves Collateral DNA
Authors: Hallmark Thomson , Kunwar Sobita , Manna Sudeshna , Keiser Dylan , Naegle Bronson , Thomas Aaron , Beisel Chase L. , Jackson Ryan N.
Published: January 2025

CRISPR-Cas systems often rely on collateral cleavage activities against nucleic-acid substrates to combat recognized mobile genetic elements. Of the associated RNA-guided Cas effector nucleases, Cas12a2 stands out as the only known example exhibiting RNA-triggered collateral cleavage of three distinct substrates: single-stranded (ss)RNA, ssDNA, and double-stranded (ds)DNA. However, little is known about the underlying mechanisms of collateral cleavage, including which of these activities dominates during the Cas12a2-mediated immune response. Here, we show that Cas12a2 cleaves collateral DNA substrates over RNA substrates, even when RNA substrates are more abundant. This preference relies on a positive cooperativity mechanism that requires the four “aromatic clamp” residues that stabilize unwound and distorted dsDNA in the RuvC nuclease active site. Leveraging the cleavage preference for collateral DNA, we demonstrate that RNA-activated Cas12a2 can cleave a ssDNA probe in the presence of high concentrations of non-target RNA, while the RNA-targeting Cas13a cannot. This work thus reveals how Cas12a2 decides amongst different collateral cleavage substrates, with immediate implications for understanding Cas12a2-based immunity, improving molecular diagnostics, and laying a mechnastic foundation for future Cas12a2-based technologies.
Transcriptional stochasticity reveals multiple mechanisms of long non-coding RNA regulation at the Xist – Tsix locus
Authors: Kesler Benjamin K. , Adams John , Neuert Gregor
Published: January 2025

Long noncoding RNAs (LncRNAs) are increasingly recognized as being involved in human physiology and diseases, but there is a lack of mechanistic understanding for the majority of lncRNAs. We comparatively tested proposed mechanisms of antisense lncRNA regulation at the X-chromosome Inactivation (XCI) locus. We find that due to stochasticity in transcription, different mechanisms based on the act of transcription regulate Xist and Tsix at different levels of nascent transcription. At medium levels, RNA polymerases transcribe Xist and Tsix on each strand at the same transcription site and deposit significant amounts of the histone mark H3K36me3, which inhibits Xist. At high levels of nascent transcription, many RNA polymerases transcribe Xist or Tsix resulting in transcriptional interference. Therefore, lncRNA expression variability is not just a quirk of transcription but an important aspect of regulation that allows multiple mechanisms to be employed by the same gene locus within the same cell population.
Nutrient availability dictates cancer metabolism-based therapeutic responses of non-oncology drugs
Authors: Pyun Woo Yang , Park Jae Hyung , Roh Jae Won , Jeon Dongkyu , Kim Jongwan , Paik Ji Eun , Cho Seok Chan , Park So Yeon , Lim Hocheol , Kim Hyungwoo , Jang Young Jin , Lee Jaehoon , Kim Soo-Youl , Guan Kun-Liang , Gee Heon Yung , Lee Han-Woong , No Kyoung Tai , Jeong Han-Sol , Namkung Wan , Nam Joo Hyun , Park Hyun Woo
Published: January 2025

Metabolic deregulation is a major hallmark of cancer, therefore, interventions that modify tumor nutrient availability are considered attractive adjuvants for improving clinical outcomes for cancer patients. Much work remains, however, in clarifying how the nutritional status of each patient can affect the metabolic vulnerability of drugs and inform individual medication guidelines. Working toward the goal of oncometabolic precision medicine, we introduce CM-SLP (cancer metabolism-based synthetic lethality platform), a high-throughput screening platform that explores the metabolic vulnerability of non-oncology drugs induced by altered nutrient availability and predicts the potential synthetic lethal interactions with either hyper- or hypo-nutrient conditions. We present promising CM-SLP candidates, such as propafenone and biguanides, as representative non-oncology drugs that cooperatively enhance cytotoxicity via dysregulated metabolic pathways. Furthermore, identifying mTOR and Hippo pathways as mediators of combined propafenone/hypoglycemia or biguanides/hypoglycemia treatments, respectively, we were able to circumvent the need for dietary interventions by administering the mTOR or TEAD inhibitors to induce energy stress and cancer cell death. Together, CM-SLP represents a critical step toward integrating metabolic profiling into precision oncology, offering novel therapeutic avenues tailored to individual patient needs.
Combining seasonal malaria chemoprevention with novel therapeutics for malaria prevention: a mathematical modelling study
Authors: Braunack-Mayer Lydia , Malinga Josephine , Nekkab Narimane , Kelly Sherrie L , Möhrle Jörg J , Penny Melissa A
Published: January 2025

Background

Vaccines, monoclonal antibodies, and long-acting injectables are being developed to preventPlasmodium falciparummalaria. These therapeutics may target multiple stages of the parasite life cycle, and evidence is needed to articulate their benefits with chemoprevention and prioritise candidates for clinical development.

Methods

We used an individual-based malaria transmission model to estimate the health impact of combining new therapeutics with seasonal malaria chemoprevention (SMC). Our modelling framework used emulator-based methods with models of pre-liver and blood stage therapeutic dynamics. We evaluated the benefit of combining therapeutics with SMC in children under five by estimating reductions in the cumulative incidence of uncomplicated and severe malaria, relative to SMC or the new therapeutic alone, during and five years after deployment.

Results

New therapeutics may require extended pre-liver stage duration or multi-stage activity to combine with SMC. For three SMC cycles in a high transmission setting, a pre-liver stage therapeutic with partial initial efficacy (>50%) required a protection half-life >230 days to reduce cumulative severe cases by >5% five years after deployment stopped (>23% during interventions). Longer protection was needed when combined with four or five SMC cycles. Combining SMC with a multi-stage therapeutic increased public health impact both during and after deployment.

Conclusions

Combining SMC with malaria therapeutics active against multiple stages of the parasite life cycle can improve the effectiveness of SMC, highlighting the need to prioritise the clinical development of these therapeutics for combination with malaria chemoprevention.
Race and ethnic disparities in rehabilitation services and functional recovery post-stroke
Authors: Bishop Lauri , Gardener Hannah , Brown Scott C. , Veledar Emir , Johnson Karlon H. , Marulanda-Londono Erika T , Gutierrez Carolina M. , Kirk-Sanchez Neva , Romano Jose , Rundek Tatjana
Published: January 2025

Abstract

Objective

To identify race/ethnic disparities in rehabilitation services after stroke and characterize the independent associations of each of race/ethnicity and rehabilitation to functional recovery post-stroke.

Methods

The Transitions of Care Stroke Disparities Study (TCSD-S) is a prospective cohort study designed to reduce disparities and to optimize the transitions of care for stroke survivors throughout the state of Florida. Participant characteristics were extracted from the American Heart Association’s Get-With-The-Guidelines-Stroke dataset. Rehabilitation services, and modified Rankin Scale were recorded via follow up phone calls at 30- and 90-days after hospital discharge. Logistic regression models adjusted for potential confounders were used to determine: 1) race/ethnic differences in rehabilitation services received; 2) race/ethnic differences in functional change from discharge to 30- and 90-days, respectively; and 3) the influence of rehabilitation on functional change from discharge to 30- and 90-days.

Results

Of 1,083 individuals, 43% were female, 52% were Non-Hispanic White (NHW), 22% were Non-Hispanic Black (NHB), and were 22% Hispanic. Individuals who engaged in rehabilitation were more likely to show improvements [aOR=1.820, 95%CI (1.301,2.545)] at 90-days from hospital discharge. Irrespective of rehabilitation services, there were no differences in functional change between NHW and NHB individuals, yet Hispanic individuals were less likely to improve [aOR=0.647, 95%CI (0.425,0.983)] compared to NHW. Additionally, Hispanic individuals were significantly less likely to receive any rehabilitation services [aOR=0.626, 95%CI (0.442,0.886)] and were half as likely to receive outpatient services [aOR=0.543, 95%CI (0.368,0.800)] as compared to NHW.

Conclusions

Rehabilitation is key to functional improvement after stroke. We are making strides in health equity between NHW and NHB individuals, yet there remain disparities in functional outcomes and in rehabilitation services particularly for Hispanic individuals after stroke.
Aging-related Changes in Bimanual Coordination As a Screening Tool for Healthy Aging
Authors: Shizuka Yusuke , Murata Shin , Goda Akio , Sawai Shun , Fujikawa Shoya , Yamamoto Ryosuke , Maru Takayuki , Nakagawa Kotaro , Nakano Hideki
Published: January 2025

The steady increase in the global older adult population highlights critical challenges, including the development of preventive strategies to extend healthy life expectancy and support independence in activities of daily living. Although there is an aging-related reduction in manual dexterity, the difference in bimanual coordination performance between young and older adults remains unclear. We aimed to elucidate the characteristics of bimanual coordination among young, young-old, and old-old adults participants. The participants performed in-phase (tapping the thumb and index finger together as fast as possible) and anti-phase (alternating movement between the left and right fingers) bimanual coordination tasks, and intergroup comparison of the task parameters as performed. The number and frequency of taps significantly decreased sequentially in young, young-old, and old-old adults, whereas the average tap interval significantly increased in this order (p< 0.05). There was no significant difference between the young-old and old-old groups in the average local maximum distance (p> 0.05). These findings indicate that bimanual coordination task performance varies depending on specific parameters. Thus, the number, average interval, and frequency of taps are potential indicators of aging-related changes in bimanual coordination.
Engineering 3D Skeletal Muscle Tissue with Complex Multipennate Myofiber Architectures
Authors: Stang Maria A. , Lee Andrew , Bliley Jacqueline M. , Coffin Brian D. , Yerneni Saigopalakrishna S. , Campbell Phil G. , Feinberg Adam W.
Published: January 2025

The hierarchical architecture of skeletal muscle spans from microscale sarcomeres to macroscale myofibers and is integral to its contractile functionality. Pathologies such as volumetric muscle loss (VML) compromise this structure and destroy the native extracellular matrix (ECM), exceeding the regenerative capacity of endogenous repair mechanisms. Here, we present a novel method for tissue engineering biomimetic three-dimensional (3D) skeletal muscle with complex architectures by leveraging freeform reversible embedding of suspended hydrogels (FRESH) 3D bioprinting of the ECM. Collagen type I scaffolds mimicking diverse muscle architectures— including parallel, unipennate, bipennate, multipennate, and convergent—were designed, FRESH printed, and seeded with C2C12 myoblasts to guide myogenesis. Engineered muscle tissues demonstrated scaffold-mediated alignment and fusion into functional myotubes, exhibiting contractile responses to electrical stimulation with architecture-dependent specific force of ∼1 kN/m2and a positive force-frequency relationship.In vivoimplantation further revealed scaffold-directed cellular and vascular organization, underscoring the translational potential of this approach. In summary, this study demonstrates the capability to use FRESH 3D bioprinting to engineer physiologically relevant muscle architectures, significantly advancing the design of functional muscle tissues for regenerative medicine and in vitro modeling applications.
Light and chloroplast redox state modulate the progression of tobacco leaf infection byPseudomonas syringaepvtabaci
Authors: Arce Rocío C. , Demarchi Mariana , Figueroa Nicolás , Delprato María L. , Hajirezaei Mohammad-Reza , Mayta Martín L. , Lodeyro Anabella F. , Krapp Adriana R. , Carrillo Néstor
Published: January 2025

Light significantly influences plant stress responses, with chloroplasts playing a pivotal role as both energy providers and light sensors. They communicate with the nucleus through retrograde signals, including secondary metabolites and reactive oxygen species (ROS). To investigate the contribution of chloroplast redox biochemistry to biotic responses, we studied the interactions of tobacco leaves expressing the alternative electron shuttle flavodoxin with virulent and nonhostPseudomonas syringaepathovars under light and dark conditions. Flavodoxin is reported to limit light-dependent ROS propagation and over-reduction of the photosynthetic electron transport system under stress. Light intensified the hypersensitive response against the nonhost pathovartomato (Pto), but slowed disease progression caused by the virulent pathovartabaci (Pta). Flavodoxin mitigated light responses during both interactions, including decreased ROS levels, reduced stromule occurrence, and lower phytoalexin production, with different signatures depending on the pathovar. Similar leaf metabolic profiles were observed in the dark for both strains, with a general up-regulation of sugars, metabolic intermediates, and amino acids. In the light, instead,Ptaincreased sugars and intermediates, whilePtodecreased them. Our results suggest that HR-like responses are elicited in the light even during virulent interactions, and that light effects are related to signals originating at the photosynthetic machinery.

Highlights

- Light inhibits disease progression during a tobacco-Pseudomonasvirulent interaction.

- Light exacerbates the hypersensitive response (HR) during a nonhost interaction.

- HR-like responses are elicited in the light even during virulent interactions.

- Plastid-targeted flavodoxin decreases plant damage only in photoperiod.

- The chloroplast redox state modulates plant biotic response.
protPheMut: An Interpretable Machine Learning Tool for Classification of Cancer and Neurodevelopmental Disorders in Human Missense Variants
Authors: Wang Jingran , Yang Miao , Zong Chang , Verkhivker Gennady , Fei Xiao , Hu Guang
Published: January 2025

Motivation

Recent advances in human genomics have revealed that missense mutations in a single protein can lead to distinctly different phenotypes. In particular, some mutations in oncoproteins like Ras, MEK, PI3K, PTEN, and SHP2 are linked various cancers and Neurodevelopmental Disorders (NDDs). While numerous tools exist for predicting the pathogenicity of missense mutations, linking these variants to certain phenotypes remains a major challenge, particularly in the context of personalized medicine.

Results

To fill this gap, we developed protPheMut (Protein Phenotypic Mutations Analyzer), leveraging multiple interpretable machine learning methods and integrate diverse biophysics and network dynamics-based signatures, for the prediction of mutations of the same protein can promote cancer, or NDDs. We illustrate the utility of protPheMut in phenotypes (cancer/NDDs) prediction by the mutation analysis of two protein cases, that are PI3Kα and PTEN. Compared to seven other predictive tools, protPheMut demonstrated exceptional accuracy in forecasting phenotypic effects, achieving an AUROC of 0.8501 for PI3Kα mutations related to cancer and Cowden syndrome. For multi-phenotypes prediction of PTEN mutations related to cancer, PHTS, and HCPS, protPheMut achieved an AUC of 0.9349 through micro-averaging. Using SHAP model explanations, we gained insights into the mechanisms driving phenotype formation. A userfriendly website deployment is also provided.

Availability

Source code and data are available athttps://github.com/Spencer-JRWang/protPheMut. We also provide a user-friendly website athttp://netprotlab.com/protPheMut.

Supplementary information

Supplementary data are available atBioinformaticsonline.

Graphical Abstract
Viral Simulation Reveals Overestimation Bias in Within-Host Phylodynamic Migration Rate Estimates Under Selection
Authors: Ochsner Nicolas , Bouman Judith , Vaughan Timothy , Stadler Tanja , Bonhoeffer Sebastian , Regoes Roland
Published: January 2025

Phylodynamic methods are widely used to infer the population dynamics of viruses between and within hosts. For HIV-1, these methods have been used to estimate migration rates between different anatomical compartments within a host. The methods typically assume that there is no selective pressure acting on the virus, even though it is known that viruses often experience strong selection pressures. In this study, we investigate how selection affects phylodynamic migration rate estimates. To this end, we developed a novel agent-based simulation tool, virolution, to simulate the evolution of virus within two anatomical compartments of a host. Using this tool, we generated viral sequences and genealogies assuming both, neutral evolution and purifying selection that is concordant in both compartments. We found that, under the selection regime, migration rates are significantly overestimated with a stochastic mixture model and a structured coalescent model in the Bayesian inference framework BEAST2. Our results reveal that commonly used phylogeographic methods, which assume neutral evolution, can significantly bias migration rate estimates in selective regimes. This study underscores the need for assessing the robustness of phylodynamic analysis with respect to more realistic selection regimes.
Signatures of genomic adaptation to Cuckoo brood parasitism in Reed Warbler hosts across Europe
Authors: Smith William J , Ronka Katja , Bensch Staffan , Bergman Nora , Dudaniec Rachael Y , Eroukhmanoff Fabrice , Fossoy Frode , Hansson Bengt , Jezierski Michal T , Kluen Edward , Prochazka Petr , Lo Cascio Saetre Camilla , Stokke Bard G , Thorogood Rose
Published: January 2025

Predicting coevolutionary outcomes is critical for understanding the consequences of climate change and biodiversity loss. The geographic mosaic theory of coevolution posits that coevolutionary interactions vary among populations, facilitating the persistence of such interactions over evolutionary timescales. Characterisation of geographic mosaics of coevolution is difficult, with mobile organisms and behavioural adaptations posing temporal and spatial challenges. The Reed Warbler (Acrocephalus scirpaceus) and its brood parasite, the Cuckoo (Cuculus canorus), have been used to study coevolution for decades. By leveraging RAD-sequencing and brood parasitism data for 188 Reed Warblers across 22 European sites, we first demonstrate that the magnitude of gene flow varies across the species' distribution, allowing for variable selection which is a fundamental component of the geographic mosaic theory. We then use genotype-environment association analysis to reveal genes that are putatively involved in the Reed Warbler's response to brood parasitism, providing the first evidence for a genetic basis to this geographic mosaic of coevolution. Together, these results help to characterise this important model of host-parasite coevolution. Further work is needed to confirm a causal relationship between parasitism and genomic variation, and to identify the exact selection mechanisms underpinning this relationship.
Quantifying Metagenomic Strain Associations from Microbiomes with Anpan
Authors: Ghazi Andrew R. , Thompson Kelsey N. , Bhosle Amrisha , Mei Zhendong , Yan Yan , Wang Fenglei , Wang Kai , Franzosa Eric A. , Huttenhower Curtis
Published: January 2025

Genetic and genomic variation among microbial strains can dramatically influence their phenotypes and environmental impact, including on human health. However, inferential methods for quantifying these differences have been lacking. Strain-level metagenomic profiling data has several features that make traditional statistical methods challenging to use, including high dimensionality, extreme variation among samples, and complex phylogenetic relatedness. We present Anpan, a set of quantitative methods addressing three key challenges in microbiome strain epidemiology. First, adaptive filtering designed to interrogate microbial strain gene carriage is combined with linear models to identify strain-specific genetic elements associated with host health outcomes and other phenotypes. Second, phylogenetic generalized linear mixed models are used to characterize the association of sub-species lineages with such phenotypes. Finally, random effects models are used to identify pathways more likely to be retained or lost by outcome-associated strains. We validated our methods by simulation, showing that we achieve more accurate effect size estimation and a lower false positive rate compared to alternative methodologies. We then applied our methods to a dataset of 1,262 colorectal cancer patients, identifying functionally adaptive genes and strong phylogenetic effects associated with CRC status, sometimes complementing and sometimes extending known species-level microbiome CRC biomarkers. Anpan’s methods have been implemented as a publicly available R library to support microbial community strain and genetic epidemiology in a variety of contexts, environments, and phenotypes.
Simple controls exceed best deep learning algorithms and reveal foundation model effectiveness for predicting genetic perturbations
Authors: Wong Daniel R. , Hill Abby S. , Moccia Robert
Published: January 2025

Modeling genetic perturbations and their effect on the transcriptome is a key area of pharmaceutical research. Due to the complexity of the transcriptome, there has been much excitement and development in deep learning (DL) because of its ability to model complex relationships. In particular, the transformer-based foundation model paradigm emerged as the gold-standard of predicting post-perturbation responses. However, understanding these increasingly complex models and evaluating their practical utility is lacking, along with simple but appropriate benchmarks to compare predictive methods. Here, we present a simple baseline method that outperforms both state of the art (SOTA) in DL and other proposed simpler neural architectures, setting a necessary benchmark to evaluate in the field of post-perturbation prediction. We also elucidate the utility of foundation models for the task of post-perturbation prediction via generalizable fine-tuning experiments that can be translated to different applications of transformer-based foundation models to tasks of interest. Furthermore, we provide a corrected version of a popular dataset used for benchmarking perturbation prediction models. Our hope is that this work will properly contextualize further development of DL models in the perturbation space with necessary control procedures.