bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic cerebral autoregulation during step-wise increases in blood pressure during anaesthesia
Authors: van den Dool Rokus E.C. , Sperna Weiland Nicolaas H. , Schenk Jimmy , Kho Eline , Veelo Denise P. , van der Ster Björn J.P. , Immink Rogier V.
Published: January 2023

BACKGROUND

Classically, cerebral autoregulation (CA) entails cerebral blood flow (CBF) remaining constant by cerebrovascular tone adapting to fluctuations in mean arterial pressure (MAP) between ∼60 and ∼150 mmHg. However, this is not an on–off mechanism; previous work has suggested that vasomotor tone is proportionally related to CA function. During propofol-based anaesthesia, there is cerebrovascular vasoconstriction, and static CA remains intact. Sevoflurane-based anaesthesia induces cerebral vasodilation and attenuates CA dose-dependently. It is unclear how this translates to dynamic CA across a range of blood pressures in the autoregulatory range.

OBJECTIVE

The aim of this study was to quantify the effect of step-wise increases in MAP between 60 and 100 mmHg, using phenylephrine, on dynamic CA during propofol- and sevoflurane-based anaesthesia.

DESIGN

A nonrandomised interventional trial.

SETTING

Single centre enrolment started on 11 January 2019 and ended on 23 September 2019.

PATIENTS

We studied American Society of Anesthesiologists (ASA) I/II patients undergoing noncardiothoracic, nonneurosurgical and nonlaparoscopic surgery under general anaesthesia.

INTERVENTION

In this study, cerebrovascular tone was manipulated in the autoregulatory range by increasing MAP step-wise using phenylephrine in patients receiving either propofol- or sevoflurane-based anaesthesia. MAP and mean middle cerebral artery blood velocity (MCAV
mean) were measured in ASA I and II patients, anaesthetised with either propofol (n = 26) or sevoflurane (n = 28), during 10 mmHg step-wise increments of MAP between 60 and 100 mmHg. Static CA was determined by plotting 2-min averaged MCAV
mean versus MAP. Dynamic CA was determined using transfer function analysis and expressed as the phase lead (°) between MAP and MCAV
mean oscillations, created with positive pressure ventilation with a frequency of 6 min−1.

MAIN OUTCOMES

The primary outcome of this study was the response of dynamic CA during step-wise increases in MAP during propofol- and sevoflurane-based anaesthesia.

RESULTS

MAP levels achieved per step-wise increments were comparable between anaesthesia regiment (63 ± 3, 72 ± 2, 80 ± 2, 90 ± 2, 100 ± 3 mmHg, and 61 ± 4, 71 ± 2, 80 ± 2, 89 ± 2, 98 ± 4 mmHg for propofol and sevoflurane, respectively). MCAV
mean increased more during step-wise MAP increments for sevoflurane compared to propofol (P≤0.001). Dynamic CA improved during propofol (0.73° mmHg−1, 95% CI 0.51 to 0.95; P ≤ 0.001)) and less pronounced during sevoflurane-based anaesthesia (0.21° mmHg−1 (95% CI 0.01 to 0.42, P = 0.04).

CONCLUSIONS

During general anaesthesia, dynamic CA is dependent on MAP, also within the autoregulatory range. This phenomenon was more pronounced during propofol anaesthesia than during sevoflurane.

TRIAL REGISTRATION

NCT03816072 (https://clinicaltrials.gov/ct2/show/NCT03816072).
Opportunities to Advance Postpartum Pelvic Floor Care With a Health Equity-based Conceptual Framework
Authors: Mou Tsung , Nelson Latasha , Lewicky-Gaupp Christina , Brown Oluwateniola
Published: January 2023

An essential part of postpartum care includes the evaluation and treatment of pelvic floor disorders (PFDs). Postpartum PFDs are common and occur in over 40% of postpartum women. Despite significant advancements in urogynecology to understand postpartum PFDs and their treatments, there has been a lack of attention to addressing equity in postpartum pelvic floor care. In this article, we address the current scientific understanding of postpartum PFDs while adapting a health equity-based conceptual framework to highlight areas of opportunity in optimizing postpartum pelvic floor care.
Enrollment of Racial and Ethnic Minoritized Groups in Gynecologic Oncology Clinical Trials: A Review of the Scope of the Problem, Contributing Factors, and Strategies to Improve Inclusion
Authors: Barry Danika , Steinberg Jecca R. , Towner Mary , Barber Emma L. , Simon Melissa A. , Roque Dario R.
Published: January 2023

Racial inequities are well-documented across the gynecologic oncology care continuum, including the representation of racial and ethnic minoritized groups (REMGs) in gynecologic oncology clinical trials. We specifically reviewed the scope of REMG disparities, contributing factors, and strategies to improve inclusion. We found systematic and progressively worsening under-enrollment of REMGs, particularly of Black and Latinx populations. In addition, race/ethnicity data reporting is poor, yet a prerequisite for accountability to recruitment goals. Trial participation barriers are multifactorial, and successful remediation likely requires multi-level strategies. More rigorous, transparent data on trial participants and effectiveness studies on REMG recruitment strategies are needed to improve enrollment.
The Dobbs Double Bind: Lessons From Substance Use Disorder on the Conflict Between Privacy and Quality Care
Authors: Simon Melissa A. , O’Brian Catherine A. , Post Sharon L.
Published: January 2023

The Dobbs decision overturned the right to abortion in the United States and allowed states to enact total abortion bans. In addition to restricting access to abortion, laws criminalizing pregnancy outcomes deter providers from offering timely, appropriate care for pregnancy complications. To avoid litigation or prosecution, providers are under pressure to strictly guard the privacy of patient health information related to pregnancy. Perinatal care is at risk of repeating the experience of similar enhanced privacy rules for substance use disorders, which have impeded information sharing and care coordination that improves outcomes.
Pathways From Recent Incarceration to Antiretroviral Therapy Adherence: Opportunities for Interventions to Support Women Living With HIV Post Release From Correctional Facilities
Authors: Erickson Margaret , Krüsi Andrea , Shannon Kate , Braschel Melissa , Norris Candice , Buxton Jane , Elwood Martin Ruth , Deering Kathleen ,   on behalf of the SHAWNA Project
Published: January 2023

Women living with HIV are increasingly incarcerated and experience suboptimal HIV health outcomes post release from incarceration. Drawing on cohort data with cisgender and trans women living with HIV (Sexual Health and HIV/AIDS: Women's Longitudinal Needs Assessment), we used path analysis to investigate pathways from recent incarceration to optimal antiretroviral therapy (ART) adherence. We tested direct effects between recent incarceration, mediating variables, and ART adherence, along with indirect effects between incarceration and ART adherence through each mediator. We assessed model fit using chi-square, root-mean-square error of approximation (RMSEA), and comparative fit index (CFI). Our hypothesized model fit well to the data (χ2(1)=1.100; p=.2943; CFI = 1.000; RMSEA = 0.007). Recent experiences of homelessness, criminalized substance use, and gender-based violence each fully mediated the pathway between recent incarceration and optimal ART adherence. Findings highlight the need for safe and supportive housing, supports for criminalized substance use, and trauma and violence–informed care and practice post release from incarceration.
Social Network Influence on Syphilis Testing for Black Sexual Minority Men in Baltimore, Maryland: A Cross-sectional Social Network Analysis
Authors: Heidari Omeid , Tobin Karin E. , Pollock Sarah , Li Fang-Ying , Webel Allison R. , Duncan Dustin T. , Latkin Carl
Published: January 2023

Black sexual minority men (BSMM), including those with HIV, have disproportionate rates of syphilis infection. This study examines the associations of social network characteristics on syphilis testing, given that social network approaches are well established as effective methods to establish health-promoting social norms. We analyzed baseline data from a sexual health behavioral intervention. Using multivariable logistic regression, we modeled individual and social network characteristics on syphilis testing. Of the 256 participants, 37% tested for syphilis in the past year. In the adjusted model controlling for individual factors, odds of syphilis testing increased 89% for each increase in network member participants being encouraged to get a syphilis test (95% confidence interval [1.19-3.00]). Feeling comfortable accompanying a friend for HIV/sexually transmitted infection testing was associated with 2.47 increased odds of syphilis testing. Encouraging and training individuals to discuss sexual health topics with their network members may lead to the establishment of testing in social networks of Black sexual minority men.
Label-free quantitative proteomics analyses of mouse astrocytes provides insight into the host response mechanism at different developmental stages ofToxoplasma gondii
Authors: Xie Huanhuan , Xu Chao , Zhao Guihua , Dong Hongjie , Dai Lisha , Xu Haozhi , Zhang Lixin , Sun Hang , Wang Qi , Zhang Junmei , Yin Kun
Published: January 2023

Toxoplasma gondii(T. gondii) is an opportunistic parasite that can infect the central nervous system (CNS), causing severe toxoplasmosis and behavioral cognitive impairment. Mortality is high in immunocompromised individuals with toxoplasmosis, most commonly due to reactivation of infection in the CNS. There are still no effective vaccines and drugs for the prevention and treatment of toxoplasmosis. There are five developmental stages forT. gondiito complete life cycle, of which the tachyzoite and bradyzoite stages are the key to the acute and chronic infection. In this study, to better understanding of howT. gondiiinteracts with the host CNS at different stages of infection, we constructed acute and chronic infection models ofT. gondiiin astrocytes, and used label-free proteomics to detect the proteome changes before and after infection, respectively. A total of 4676 proteins were identified, among which 163 differentially expressed proteins (DEPs) (fold change≥1.5 or ≤0.67 andp-value≤0.05) including 109 up-regulated proteins and 54 down-regulated proteins in C8-TA vs C8 group, and 719 DEPs including 495 up-regulated proteins and 224 down-regulated proteins in C8-BR vs C8-TA group. AfterT. gondiitachyzoites infected astrocytes, DEPs were enriched in immune-related biological processes to promote the formation of bradyzoites and maintain the balance ofT. gondii, CNS and brain. AfterT. gondiibradyzoites infected astrocytes, the DEPs up-regulated the host’s glucose metabolism, and some up-regulated DEPs were closely related to neurodegenerative diseases. These findings not only provide new insights into the psychiatric pathogenesis ofT. gondii, but also provide potential targets for the treatment of acute and chronic Toxoplasmosis.
Association of Abnormal Cytology and risk factors in Women of Assam, India
Authors: Barmon Debabrata , Sarma Anupam , Baruah Upasana , Kakoti Lopamudra , Barman Debanjana , Sarma Pallavi , Kalita Manoj , Rai Avdhesh Kumar
Published: January 2023

The study was conducted to perform cytological abnormality screening by PAP test among women of Assam, India. Two hundred thirty four women in the age group of 35-60 years were enrolled in screening camps for the study. Smear on the glass slide of the cervical scrap specimen were prepared for PAP test. Statistical analysis for PAP test outcome with risk factors was analyzed by applying Fisher’s exact test. Significance was considered for p<0.05.

It was found that women using contraceptive piles have higher risk of abnormal cytology (p-0.0238). Women with irregular menstrual cycle frequency have also higher risk of abnormal cytology (p-0.0002). Women not using commercially available sanitary pads ahe also high risk of abnormal cytology( p-0.0052). Women having urinary tract infection have also high risk of abnormal cytology (p-0.0102). Our study finding suggest that use of contraceptive pills, urinary infection, irregular frequency of menstrual cycle, non-use of sanitary pads may increase the risk of abnormal cytology positivity in women of Assam, India. There are limitations of our studyfindings because of small sample size and univariate statistical analysis.
Caution Regarding the Specificities of Pan-Cancer Microbial Structure
Authors: Gihawi Abraham , Cooper Colin S. , Brewer Daniel S.
Published: January 2023

The results published in Poore and Kopylovaet al. 2020[1] revealed the possibility of being able to almost perfectly differentiate between types of tumour based on their microbial composition using machine learning models. Whilst we believe that there is the potential for microbial composition to be used in this manner, we have concerns with the manuscript that make us question the certainty of the conclusions drawn. We believe there are issues in the areas of the contribution of contamination, handling of batch effects, false positive classifications and limitations in the machine learning approaches used. This makes it difficult to identify whether the authors have identified true biological signal and how robust these models would be in use as clinical biomarkers. We commend Poore and Kopylovaet al. on their approach to open data and reproducibility that has enabled this analysis. We hope that this discourse assists the future development of machine learning models and hypothesis generation in microbiome research.
Unlocking the potential ofmiR-19bin the regulation of temozolomide response in glioblastoma patients via targeting PPP2R5E, a subunit of the protein phosphatase 2A complex
Authors: Kashani Elham , Hlavackova Kristyna , Haemmig Stefan , Sadowski Martin C , Phour Jaison , Baumgartner Ulrich , Mueller-Wirth Nicole , Trefny Carmen , Sharf Den Abu Fakher Bushra , Nydegger Coline , Maragkou Theoni , Schucht Philippe , Perren Aurel , Zinn Pascal , Lüdi Markus , Marti Thomas Michael , Krebs Philippe , Vassella Erik
Published: January 2023

Despite the standard of care, glioblastoma IDH wildtype (GBM) inevitably recurs, underscoring the need to develop new treatment strategies. To address the role of microRNAs in temozolomide (TMZ) response, we performed functional microRNA screens and consistently identifiedmiR-19b. Our study reveals a novel axis betweenmiR-19band PPP2R5E subunit of serine/threonine protein phosphatase PP2A and establishes a so far unappreciated contribution ofmiR-19bin TMZ resistance of GBM. Specifically, our results demonstrate that attenuation ofmiR-19bin GBM cell lines and glioblastoma stem cells (GSCs) induces DNA damage, which further enhances the cytotoxic effects of TMZ treatment. We confirmed TMZ resistance induced by knocking down PPP2R5E in orthotopic mouse xenografts of GSCs. Furthermore, our results indicate that treating cells with the PP2A-activating drug FTY720 or knocking down endogenous PP2A-inhibiting proteins potentiates the cytotoxic effects of TMZ.MiR-19battenuation or PPP2R5E activation could potentially be exploited in adjuvant therapy of GBM patients.
Hierarchical Bayesian modeling identifies key considerations in the development of quantitative loop-mediated isothermal amplification assays
Authors: Bradley Jacob R. , Borges Diego , Cavaleiro Mafalda , Mayhew Michael B.
Published: January 2023

Motivation

Loop-mediated isothermal amplification (LAMP) is a rapidly growing, fast, and cost-effective technique for detection of DNA/RNA in point-of-care biomedical applications. However, it remains unclear what factors affect LAMP’s quantitative resolution, and experimental optimization of primers presents a major bottleneck in assay design. A lack of model-based frameworks to characterize LAMP data and address these questions presents an unmet need for LAMP assay development.

Results

We present hierarchical Bayesian models of LAMP amplification based on Gompertz functions, and use these models to infer the effect of RNA variation and other factors on LAMP amplification curves derived from 80 blood samples of patients with suspected acute infection. Our analysis uncovers associations between LAMP assay resolution and characteristics such as primer sequence composition and thermodynamic properties. In addition to correlations between RNA input abundance and time shift of the the LAMP amplification curve, we also detect RNA-dependent assocations with amplification rate. We further investigate associations between primer/target properties and quantitative performance of the assay by generating a set of synthetic RNA samples with systematically varied primer sequences and applying our framework. We find evidence that the associations observed are driven by across-target rather than within-target variation, an important observation for study design. Our findings represent important first steps towards guided development of quantitative LAMP assays.

Availability and Implementation

Analysis and modeling code is available upon reasonable request.
Ccn2 deficiency causes smooth muscle cell de-differentiation and severe atherosclerosis in hyperlipidemic mice
Authors: Larsen JH , Stubbe J , Beck HC , Overgaard M , Lindegaard CA , Hansen DR , Goldschmeding R , Rodriguez-Díez RR , Ruiz-Ortega M , Pyke C , Wirka RC , Lindholt JS , Rasmussen LM , Steffensen LB
Published: January 2023

Cellular communication network factor 2 (CCN2/CTGF) is a matricellular protein with an established role in fibrotic diseases and cancers, and therapies targeting CCN2 is currently in Phase II and III clinical trials for idiopathic pulmonary fibrosis, pancreatic cancer and Duchenne Muscular Dystrophy. Recent studies have highlighed a protective role of CCN2 in aortic aneurysm disease, but its role in atherosclerosis remains to be investigated.

We identified arteries as having the highest relative expression ofCCN2across 54 human tissues. In aortas,CCN2was among the highest expressed genes, andin situhybridization of human internal thoracic arteries revealed vascular smooth muscle cells (SMCs) as its principal source.

Hypothesizing a role for CCN2 in SMC phenotype maintenance and athero-protection, we investigated inducible Ccn2 knockout (Ccn2Δ/Δ) mice in normo- and hyper-lipidemic settings. Induction of hyperlipidemia by single intravenous injection of 1·1011viral genomes of rAAV8-D377Y-mPcsk9 combined with 24 weeks of western type diet resulted in severe enlargement (3-5-fold increase of relative aorta mass compared to wildtype littermates,p< 0.0001) and whitening ofCcn2Δ/Δaortas. Oil Red O-staining ofen faceprepared thoracic aortas showed a marked increase in atherosclerosis inCcn2Δ/Δmice as compared to wildtype littermates (75% vs. 10% Oil Red O-positive aortic area,p< 0.0001). Transcriptomic profiling of cultivated SMCs derived from aortas of normolipidemic mice showed signatures of dedifferentiation (reduced expression ofe.g. Myocd, Acta2andMyh11) and modulation toward a synthetic, pro-inflammatory phenotype ofCcn2Δ/ΔSMCs. These effects were verifiedin vivoand inCCN2-silenced human aortic SMCs. Taken together, we find that CCN2 plays a critical athero-protective role in artery tissues, likely through maintaining SMCs in a differentiated, contractile phenotype.
Nitrogen niche partitioning between tropical legumes and grasses conditionally weakens under elevated CO2
Authors: Churchill Amber C. , Zhang Haiyang , Kim Gil Won , Catunda Karen L. M. , Anderson Ian C. , Isbell Forest , Moore Ben , Pendall Elise , Plett Jonathan M. , Powell Jeff R. , Power Sally A.
Published: January 2023

Plant community biodiversity can be maintained, at least partially, by shifts in species interactions between facilitation and competition for resources as environmental conditions change. These interactions also drive ecosystem functioning, including productivity, and can promote over-yielding-an ecosystem service prioritized in agro-ecosystems, such as pastures, that occurs when multiple species together are more productive than the component species alone. Importantly, species interactions that can result in over-yielding may shift in response to rising CO2concentrations and changes in resource availability, and the consequences these shifts have on production is uncertain especially in the context of tropical mixed-species grasslands.

We examined the relative performance of two species pairs of tropical pasture grasses and legumes growing in monoculture and mixtures in a glasshouse experiment manipulating CO2. We investigated how over-yielding can arise from nitrogen (N) niche partitioning and biotic facilitation using stable isotopes to differentiate soil N from biological N fixation (BNF) within N acquisition into aboveground biomass for these two-species mixtures.

We found that N niche partitioning in species-level use of soil N vs. BNF drove species interactions in mixtures. Importantly partitioning and overyielding were generally reduced under elevated CO2. However, this finding was mixture-dependent based on biomass of dominant species in mixtures and the strength of selection effects for the dominant species.

This study demonstrates that rising atmospheric CO2may alter niche partitioning between co-occurring species, with negative implications for the over-yielding benefits predicted for legume-grass mixtures in working landscapes with tropical species. Furthermore, these changes in inter-species interactions may have consequences for grassland composition that are not yet considered in larger-scale projections for impacts of climate change and species distributions.

Graphical abstract

(Image by H. Zhang): Among our tropical pasture species we found that grasses (dotted lines) grown in monoculture rely fully on soil nitrogen (N), while legumes (solid lines) grown in monoculture relied approximately equally on soil N and biological nitrogen fixation (BNF) to meet N requirements. When grown with tropical grasses, however, legumes shifted to rely more strongly on BNF, indicative of niche partitioning and decreased competition for soil nutrients with grasses. This separation of niche space was weakened under elevated CO2conditions, ultimately reducing legume production.
Dbx2, an aging-related homeobox gene, inhibits the proliferation of adult neural progenitors
Authors: Giuliani Andrea , Licursi Valerio , Nisi Paola S. , Fiore Mario , Biagioni Stefano , Negri Rodolfo , Rugg-Gunn Peter J. , Cacci Emanuele , Lupo Giuseppe
Published: January 2023

The subventricular zone (SVZ) of the adult mouse brain contains quiescent neural stem cells, which can be activated (aNSCs) to generate transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. Neurogenesis declines during aging, as the aged SVZ niche causes transcriptomic changes that promote NSC quiescence and decrease proliferating neural/stem progenitor cells (NSPCs). The transcription factors mediating these changes, however, remain unclear. We previously found that the homeobox geneDbx2is upregulated in aged SVZ NSPCs and inhibits NSPC culture growth. Here, we report thatDbx2is repressed by Epidermal Growth Factor Receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. We show thatDbx2inhibits NSPC proliferation by hindering the G2/M transition and elucidate the transcriptomic networks modulated byDbx2, highlighting its role in the downregulation of the cell cycle molecular pathways. Accordingly,Dbx2function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point toDbx2as a molecular node relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome.
Astrocyte and neuronal Panx1 support long-term reference memory in mice
Authors: Obot Price , Subah Galadu , Schonwald Antonia , Pan Jian , Velíšek Libor , Velíšková Jana , Stanton Patric K. , Scemes Eliana
Published: January 2023

Pannexin 1 (Panx1) are ubiquitously expressed proteins that form plasma membrane channels permeable to anions and moderate sized signaling molecules (e.g., ATP, glutamate). In the nervous system, activation of Panx1 channels have been extensively shown to contribute to distinct neurological disorders (epilepsy, chronic pain, migraine, neuroAIDS, etc.) but knowledge of extent to which these channels have a physiological role remains restricted to three studies supporting their involvement in hippocampus dependent learning. Given that Panx1 channels may provide an important mechanism for activity-dependent neuron-glia interaction, we used Panx1 transgenic mice with global and cell-type specific deletions of Panx1 to interrogate their participation in working and reference memory. Using the 8-arm radial maze, we show that long-term spatial reference memory, but not spatial working memory, is deficient in Panx1-null mice and that both astrocyte and neuronal Panx1 contribute to the consolidation of long-term spatial memory. Field potential recordings in hippocampal slices of Panx1-null mice revealed an attenuation of both long-term potentiation (LTP) of synaptic strength and long-term depression (LTD) at Schaffer collateral – CA1 synapses without alterations basal synaptic transmission or pre-synaptic paired-pulse facilitation. Our results implicate both neuronal and astrocyte Panx1 channels as critical players for the development and maintenance of long-term spatial reference memory in mice.
Ankh ☥: Optimized Protein Language Model Unlocks General-Purpose Modelling
Authors: Elnaggar Ahmed , Essam Hazem , Salah-Eldin Wafaa , Moustafa Walid , Elkerdawy Mohamed , Rochereau Charlotte , Rost Burkhard
Published: January 2023

As opposed to scaling-up protein language models (PLMs), we seek improving performance via protein-specific optimization. Although the proportionality between the language model size and the richness of its learned representations is validated, we prioritize accessibility and pursue a path of data-efficient, cost-reduced, and knowledge-guided optimization. Through over twenty experiments ranging from masking, architecture, and pre-training data, we derive insights from protein-specific experimentation into building a model that interprets the language of life, optimally. We present Ankh, the first general-purpose PLM trained on Google’s TPU-v4 surpassing the state-of-the-art performance with fewer parameters (<10% for pre-training, <7% for inference, and <30% for the embedding dimension). We provide a representative range of structure and function benchmarks where Ankh excels. We further provide a protein variant generation analysis on High-N and One-N input data scales where Ankh succeeds in learning protein evolutionary conservation-mutation trends and introducing functional diversity while retaining key structural-functional characteristics. We dedicate our work to promoting accessibility to research innovation via attainable resources.
Colonization of a novel host plant reduces phenotypic variation
Authors: Nilsson Kalle J , Tsuboi Masahito , Opedal Øystein , Runemark Anna
Published: January 2023

Understanding the evolutionary potential of populations –evolvability– is key to predicting their ability to cope with novel environments. Despite growing evidence that evolvability determines the tempo and mode of adaptation, it remains unclear how adaptations to novel environments influence evolvability in turn. Here we address the interplay between adaptation and evolvability in the peacock flyTephritis conura, which recently underwent an adaptive change in the length of female ovipositor following a host shift. By comparing evolvability in various morphological traits including female ovipositor length between ancestral and derived host races, we found that evolvability is decreased in females of the derived host race compared to the ancestral host race. We found a correlation between evolvability and divergence between populations in both sexes, indicating that the overall pattern of evolvability has not been disrupted by the host shift despite the reduction in females of the derived host race. Exploration of the pattern of phenotypic integration further revealed that the ovipositor length constitutes a module that is separated from other measured traits. These results suggest that adaptation to novel environments can affect evolvability, and that modularity helps minimizing detrimental effects that adaptations may cause to other correlated traits.
nf-root: a best-practice pipeline for deep learning-based analysis of apoplastic pH in microscopy images of developmental zones in plant root tissue
Authors: Wanner Julian , Cuellar Luis Kuhn , Rausch Luiselotte , Berendzen Kenneth W. , Wanke Friederike , Gabernet Gisela , Harter Klaus , Nahnsen Sven
Published: January 2023

Here we reportnextflow-root(nf-root), a novel best-practice pipeline for deep learning-based analysis of fluorescence microscopy images of plant root tissue, aimed at studying hormonal mechanisms associated with cell elongation, given the vital role that plant hormones play in the development and growth of plants. This bioinformatics pipeline performs automatic identification of developmental zones in root tissue images, and analysis of apoplastic pH measurements of tissue zones, which is useful for modeling plant hormone signaling and cell physiological responses. Mathematical models of physiological responses of plant hormones, such as brassinolide, have been successfully established for certain root tissue types, by evaluating apoplastic pH via fluorescence imaging. However, the generation of data for this modeling is time-consuming, as it requires the manual segmentation of tissue zones and evaluation of large amounts of microscopy data. We introduce a high-throughput, highly reproducibleNextflowpipeline based onnf-corestandards that automates tissue zone segmentation by implementing a deep-learning module, which deploys deterministically trained (i.e. bit-exact reproducible) convolutional neural network models, and augments the segmentation predictions with measures of predictionuncertaintyand modelinterpretability, aiming to facilitate result interpretation and verification by experienced plant biologists. To train our segmentation prediction models, we created a publicly available dataset composed of confocal microscopy images ofA. thalianaroot tissue using the pH-sensitive fluorescence indicator, and manually annotated segmentation masks that identify relevant tissue zones. We applied this pipeline to analyze exemplary data, and observed a high statistical similarity between the manually generated results and the output ofnf-root. Our results indicate that this approach achieves near human-level performance, and significantly reduces the time required to analyze large volumes of data, from several days to hours.
A field theoretic approach to non-equilibrium population genetics in the strong selection regime
Authors: Balick Daniel J.
Published: January 2023

Natural populations are virtually never observed in equilibrium, yet equilibrium approximations comprise the majority of our understanding of population genetics. Using standard tools from statistical physics, a formalism is presented that re-expresses the stochastic equations describing allelic evolution as a partition functional over all possible allelic trajectories (‘paths’) governed by selection, mutation, and drift. A perturbative field theory is developed for strong additive selection, relevant to disease variation, that facilitates the straightforward computation of closed-form approximations for time-dependent moments of the allele frequency distribution across a wide range of non-equilibrium scenarios; examples are presented for constant population size, exponential growth, bottlenecks, and oscillatory size, all of which align well to simulations and break down just above the drift barrier. Equilibration times are computed and, even for static population size, generically extend beyond the order 1/stimescale associated with exponential frequency decay. Though the mutation load is largely robust to variable population size, perturbative drift-based corrections to the deterministic trajectory are readily computed. Under strong selection, the variance of a new mutation’s frequency (related to homozygosity) is dominated by drift-driven dynamics and a transient increase in variance often occurs prior to equilibrating. The excess kurtosis over skew squared is roughly constant (i.e., independent of selection, provided 2Ns≳ 5) for static population size, and thus potentially sensitive to deviation from equilibrium. These insights highlight the value of such closed-form approximations, naturally generated from Feynman diagrams in a perturbative field theory, which can simply and accurately capture the parameter dependences describing a variety of non-equilibrium population genetic phenomena of interest.
Breast Milk Oligosaccharides Contain Immunomodulatory Glucuronic Acid and LacdiNAc
Authors: Jin Chunsheng , Lundstrøm Jon , Korhonen Emma , Luis Ana S. , Bojar Daniel
Published: January 2023

Breast milk is abundant with functionalized milk oligosaccharides (MOs), to nourish and protect the neonate. Yet we lack a comprehensive understanding of the repertoire and evolution of MOs across Mammalia. We report ∼400 MO-species associations (>100 novel structures) from milk glycomics of nine mostly understudied species: alpaca, beluga whale, black rhinoceros, bottlenose dolphin, impala, L’Hoest’s monkey, pygmy hippopotamus, domestic sheep, and striped dolphin. This revealed the hitherto unknown existence of the LacdiNAc motif (GalNAcβ1-4GlcNAc) in MOs of all species except alpaca, sheep, and striped dolphin, indicating widespread occurrence of this potentially antimicrobial motif in MOs. We also characterize glucuronic acid-containing MOs in the milk of impala, dolphins, sheep, and rhinoceros, previously only reported in cows. We demonstrate that these GlcA-MOs exhibit potent immunomodulatory effects. Our study extends the number of known MOs by >15%. Combined with >1,900 curated MO-species associations, we characterize MO motif distributions, presenting an exhaustive overview of MO biodiversity.
IDENTIFYING ASSOCIATIONS BETWEEN GENETIC CONDITIONS IN OFFSPRING AND PREGNANCY HEALTH COMPLICATIONS
Authors: Gibson Rebecca A. , Abar Bijan , Elman Lily , Walsh Kyle M. , Hurst Jillian H. , Cohen Jennifer L.
Published: January 2023

Background

Prior research has identified associations between pregnancy complications and specific fetal genetic diagnoses in the offspring.

Objective

The purpose of this study is to provide a large-scale investigation of associations between infant genetic diagnoses and pregnancy complications.

Methods

Retrospective chart review of maternal-infant dyads born at Duke University (2013-2021) identified 236 mothers who had infants with genetic diseases (exposed group) and 472 matched dyads without concern for newborn genetic disease (unexposed group). Logistic regression examined associations between gestational factors and infant genetic diseases.

Results

The risk of gestational diabetes was elevated among mothers of infants with aneuploidy (RR=1.65; 95% CI 1.05,2.61). The risk of preeclampsia was elevated among mothers of infants with imprinting conditions (RR=5.08; 95% CI 2.41,10.73). The presence of any infant genetic disease was associated with an increase in placental disorders (RR=1.98; 95% CI 1.61,2.43), including a 2.25-fold increase in placental infarction (RR=2.25; 95% CI 1.72,2.93).

Conclusions

These findings provide insight into relationships between fetal genetic diseases and gestational complications and may guide identification of pregnancies that would benefit from expanded prenatal and antenatal genetic screening for earlier identification and treatment of genetic conditions.

SYNPOSIS

Study question

Are there associations between genetic conditions in offspring and pregnancy health complications?

What’s already known

Prior research has identified associations between pregnancy complications and specific fetal genetic diseases, including pregnancy-related hypertension/preeclampsia in association withEP300-related Rubinstein-Taybi syndrome.

What this study adds

This retrospective cohort study provides the first comprehensive investigation into potential links between offspring genetic diagnoses and pregnancy complications, identifying associations between aneuploidy and gestational diabetes, imprinting disorders and preeclampsia, and fetal genetic conditions and specific placental abnormalities. These findings can inform future medical management of pregnancies affected by a fetal genetic condition and help guide the future development of algorithms to prospectively identify parent/infant dyads who may benefit from expanded prenatal and neonatal genetic testing.
Phenotypic convergence: a novel phenomenon in the diagnostic process of Mendelian genetic disorders
Authors: Tinker Rory J , Peterson Josh , Bastarache Lisa
Published: January 2023

Introduction

The study of Mendelian disease has yielded a large body of knowledge about the phenotypic presentation of disease. Less is known about the way the diseases are reflected in the electronic health record (EHR).

Aim

To develop an EHR-based model of the diagnostic trajectory and investigate data availability and the longitudinal distribution of signs and symptoms of a Mendelian disorder within EHRs.

Methods

We created a conceptual model to specify key time points of the diagnostic trajectory and applied it to individuals with genetically confirmed hereditary connective tissue diseases (HCTD). Using the model, we assessed EHR data availability within each time interval. We tested the performance of phenotype risk scores (PheRS), an algorithm that detects Mendelian disease patterns and assessed the phenotypic expression of HCTD over the diagnostic trajectory.

Results

We identified 251 individuals with HCTD; 79 (35%) of these patients had a fully ascertained diagnostic trajectory. There were few documented signs and symptoms prior to clinical suspicion that evoked an HCTD disorder (median PheRS 0.14); once suspicion was documented, median PheRS increased to 1.87 (SD). The majority (72%) of phenotypic features were identified post clinical suspicion.

Discussion

Using a novel conceptual model for the diagnostic trajectory of Mendelian disease, we demonstrated that phenotype ascertainment is, in part, driven by the diagnostic process and that many findings are only documented following clinical suspicion and diagnosis, a process we term phenotypic convergence. Therefore, algorithms that aim to detect undiagnosed Mendelian disease should censor EHR data to avoid data leakage.
ANTsX neuroimaging-derived structural phenotypes of UK Biobank
Authors: Tustison Nicholas J. , Yassa Michael A. , Rizvi Batool , Cook Philip A. , Holbrook Andrew J. , Sathishkumar Mithra T. , Tustison Mia G. , Gee James C. , Stone James R. , Avants Brian B.
Published: January 2023

UK Biobank is a large-scale epidemiological resource for investigating prospective correlations between various lifestyle, environmental, and genetic factors with health and disease progression. In addition to individual subject information obtained through surveys and physical examinations, a comprehensive neuroimaging battery consisting of multiple modalities provides imaging-derived phenotypes (IDPs) that can serve as biomarkers in neuroscience research. In this study, we augment the existing set of UK Biobank neuroimaging structural IDPs, obtained from well-established software libraries such as FSL and FreeSurfer, with related measurements acquired through the Advanced Normalization Tools Ecosystem. This includes previously established cortical and subcortical measurements defined, in part, based on the Desikan-Killiany-Tourville atlas. Also included are morphological measurements from two recent developments: medial temporal lobe parcellation of hippocampal and extra-hippocampal regions in addition to cerebellum parcellation and thickness based on the Shanneman anatomical labeling. Through predictive modeling, we assess the clinical utility of these IDP measurements, individually and in combination, using commonly studied phenotypic correlates including age, fluid intelligence, numeric memory, and several other sociodemographic variables. The predictive accuracy of these IDP-based models, in terms of root-mean-squared-error or area-under-the-curve for continuous and categorical variables, respectively, provides comparative insights between software libraries as well as potential clinical interpretability. Results demonstrate varied performance between package-based IDP sets and their combination, emphasizing the need for careful consideration in their selection and utilization.
Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1viaa comprehensive screening funnel
Authors: Zhang Si Min , Paulin Cynthia B.J. , Michel Maurice , Marttila Petra , Yagüe-Capilla Miriam , Bwanika Henri Colyn , Shu Huazhang , Vekatram Rajagopal Papagudi , Wiita Elisée , Jemth Ann-Sofie , Almlöf Ingrid , Loseva Olga , Ortis Florian , Dirks Christopher , Koolmeister Tobias , Linde Erika , Lee Sun , Llona-Minguez Sabin , Haraldsson Martin , Strömberg Kia , Homan Evert J. , Scobie Martin , Lundbäck Thomas , Helleday Thomas , Rudd Sean G.
Published: January 2023

Sterile alpha motif and histidine-aspartic acid domain containing protein-1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase central to cellular nucleotide pool homeostasis. Recent literature has also demonstrated how SAMHD1 can detoxify chemotherapy metabolites thereby controlling their clinical responses. To further understand SAMHD1 biology and to investigate the potential of targeting this enzyme as a neoadjuvant to existing chemotherapies we set out to discover selective small molecule-based inhibitors of SAMHD1. Here we report a discovery pipeline encompassing a biochemical screening campaign and a set of complementary biochemical, biophysical, and cell-based readouts for further characterisation of the screen output. The identified hit compound TH6342 and its analogues, accompanied by their inactive negative control analogue TH7126, demonstrated specific, low μM potency in inhibiting the hydrolysis of both natural substrates and nucleotide analogue therapeutics, shown using complementary enzyme-coupled and direct enzymatic activity assays. Their mode of inhibition was subsequently detailed by coupling kinetic studies with thermal shift assays, where TH6342 and analogues were shown to engage with pre-tetrameric SAMHD1 and deter the oligomerisation and allosteric activation of SAMHD1 without occupying nucleotide binding pockets. We further outline the development and application of multiple cellular assays for assessing cellular target engagement and associated functional effects, including CETSA and an in-cell dNTP hydrolase activity assay, which highlighted future optimisation strategies of this chemotype. In summary, with a novel mode of inhibition, TH6342 and analogues broaden the set of tool compounds available in deciphering SAMHD1 enzymology and functions, and furthermore, the discovery pipeline reported herein represents a thorough framework for future SAMHD1 inhibitor development.

Abstract Figure
Natural variation inPrdm9affecting hybrid sterility phenotypes
Authors: AbuAlia Khawla FN , Damm Elena , Ullrich Kristian K , Mukaj Amisa , Parvanov Emil , Forejt Jiri , Odenthal-Hesse Linda
Published: January 2023

PRDM9-mediated reproductive isolation was first described in offspring ofMus musculus musculusstrain PWD/Ph andMus musculus domesticusstrain C57BL/6J. Male F1-hybrids do not complete chromosome synapsis and arrest meiosis at Prophase I. Currently, all data supports an oligogenic control of hybrid sterility based on incompatibilities between PRDM9 and hybrid-sterility locusHstx2inMus musculushybrids. Erosion of PRDM9 binding sites was proposed to result in asymmetric binding on diverged homologs of intersubspecific F1hybrids. Numerous alleles ofPrdm9have been characterized for different subspecies ofMus musculus, but only a few were analyzed for their impact on hybrid sterility. We analyzedPrdm9diversity in natural wild mouse populations from Europe, Asia, and the Middle East and identified several novelPrdm9alleles. We established that a singlePrdm9allele is associated witht-haplotype Chromosome 17 in all three subspecies ofMus musculusand characterized the phylogenetic relationships of novelPrdm9alleles with established sterility alleles. Novel wildPrdm9alleles produced F1-hybrid male offspring that were either fertile or showedPrdm9-dependent reduction of fertility and high levels of asynapsis. Fertility or sterility phenotypes segregated purely with thePrdm9genotype, although theMus musculus musculusbackground varied. Our data substantiate that hybrid sterility is under oligogenic control withPrdm9as the leading player but is consistent with a nonbinary regulation of hybrid sterility and gradual fertility decline when homologs diverge.
Metagenomic analysis of ecological niche overlap and community collapse in microbiome dynamics
Authors: Fujita Hiroaki , Ushio Masayuki , Suzuki Kenta , Abe Masato S. , Yamamichi Masato , Okazaki Yusuke , Canarini Alberto , Hayashi Ibuki , Fukushima Keitaro , Fukuda Shinji , Kiers E. Toby , Toju Hirokazu
Published: January 2023

Species utilizing the same resources often fail to coexist for extended periods of time. Such competitive exclusion mechanisms potentially underly microbiome dynamics, causing breakdowns of communities composed of species with similar genetic backgrounds of resource utilization. Although genes responsible for competitive exclusion among a small number of species have been investigated in pioneering studies, it remains a major challenge to integrate genomics and ecology for understanding stable coexistence in species-rich communities. Here, we show that community-scale analyses of functional gene redundancy can provide a useful platform for interpreting and predicting collapse of bacterial communities. Through 110-day time-series of experimental microbiome dynamics, we analyzed the metagenome-assembled genomes of co-occurring bacterial species. We then inferred ecological niche space based on the multivariate analysis of the genome compositions. The analysis allowed us to evaluate potential shifts in the level of niche overlap between species through time. We hypothesized that community-scale pressure of competitive exclusion could be evaluated by quantifying overlap of genetically determined resource-use profiles (metabolic pathway profiles) among coexisting species. We found that the degree of community compositional changes observed in the experimental microbiome was explained by the magnitude of gene-repertoire overlaps among bacterial species. The metagenome-based analysis of genetic potential for competitive exclusion will help us forecast major events in microbiome dynamics such as sudden community collapse (i.e., dysbiosis).