bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolutionary Insights Into Felidae Iris Color Through Ancestral State Reconstruction
Authors: Tabin Julius A. , Chiasson Katherine A.
Published: March 2023

There have been almost no studies with an evolutionary perspective on eye (iris) color, outside of humans and domesticated animals. Extant members of the family Felidae have a great interspecific and intraspecific diversity of eye colors, in stark contrast to their closest relatives, all of which have only brown eyes. This makes the felids a great model to investigate the evolution of eye color in natural populations. Through machine learning cluster image analysis of publicly available photographs of all felid species, as well as a number of subspecies, five felid eye colors were identified: brown, green, yellow, gray, and blue. Using phylogenetic comparative methods, the presence or absence of these colors was reconstructed on a phylogeny. Additionally, through a new color analysis method, the specific shades of the ancestors’ eyes were quantitatively reconstructed. The ancestral felid population was predicted to have brown-eyed individuals, as well as a novel evolution of gray-eyed individuals, the latter being a key innovation that allowed the rapid diversification of eye color seen in modern felids, including numerous gains and losses of different eye colors. It was also found that the gain of yellow eyes is highly associated with, and may be necessary for, the evolution of round pupils in felids, which may influence the shades present in the eyes in turn. Along with these important insights, the methods presented in this work are widely applicable and will facilitate future research into phylogenetic reconstruction of color beyond irises.
Loss of endothelial glucocorticoid receptor accelerates organ fibrosis indb/dbmice
Authors: Srivastava Swayam Prakash , Goodwin Julie E.
Published: March 2023

Endothelial cells play a key role in maintaining homeostasis and are deranged in many disease processes, including fibrotic conditions. Absence of the endothelial glucocorticoid receptor (GR) has been shown to accelerate diabetic kidney fibrosis in part through up regulation of Wnt signaling. The db/db mouse model is a model of spontaneous type 2 diabetes that has been noted to develop fibrosis in multiple organs over time, including the kidneys. This study aimed to determine the effect of loss of endothelial GR on organ fibrosis in thedb/dbmodel. Db/Db mice lacking endothelial GR showed more severe fibrosis in multiple organs compared to endothelial GR-replete db/db mice. Organ fibrosis could be substantially improved either through administration of a Wnt inhibitor or metformin. IL-6 is a key cytokine driving the fibrosis phenotype and is mechanistically linked to Wnt signaling. The db/db model is an important tool to study mechanisms of fibrosis and its phenotype in the absence of endothelial GR highlights the synergistic effects of Wnt signaling and inflammation in the pathogenesis or organ fibrosis.
Harnessing the power of regional baselines for broad-scale genetic stock identification: A multistage, integrated, and cost-effective approach
Authors: Hsu Bobby , Habicht Christopher
Published: March 2023

Genetic stock identification (GSI) estimates the contribution of each population to a mixture and these analyses are usually conducted regionally using genetic baselines specific to the stocks expected in that region. Often these regional baselines cannot be combined to produce broader geographical baselines. In cases where the mixture contains stocks spanning across a wide area a broad-scale baseline is created, but these baselines often are unable to resolve among regional stocks. Here, we introduce a new GSI method to harness the resolution capabilities of baselines developed for regional applications in the analyses of mixtures containing fish from a broad geographic range. This multistage process allows for disparate baselines to be used in a single integrated process that estimates the propagated errors from each stage. The baselines used by this model do not require any overlap in markers or in populations representing the broad-scale or regional baselines. The integrated multistage framework allows GSI of a wide geographic area without first developing a large scale, high resolution genetic baseline, or dividing a mixture sample into smaller regions beforehand. This approach is more cost-effective than updating range-wide baselines with all critical regionally important markers.
A facile green synthesis approach to silver nanoparticles using calyx fromAbelmoschus esculentusand its anthelmintic activity
Authors: Majumdar Rima , Kar Pradip Kumar
Published: March 2023

In recent years, technology pertaining to nanobiomaterials has taken rapid strides, with the development of novel materials having unique properties. Silver nanoparticles (AgNPs) have gained attention among these materials due to their high chemical stability, surface-to-volume ratio, and strong antimicrobial activity. The traditional method for synthesizing AgNPs involves toxic chemicals, which can have negative environmental impacts and pose health risks. Hence, there is a growing need for green synthesis methods for AgNPs that are environmentally friendly and safe for animal and human health. In this study, we explore the green synthesis of AgNPs using calyx fromAbelmoschus esculentus, also known as okra, as an anthelmintic.Raillietinaspp. is a common poultry parasite causing significant economic losses to the livestock industry. It is a major cause of ailment and mortality in livestock, deterring the host health. While chemical-based anthelmintic drugs are available, the increasing prevalence of drug-resistant parasite strains has made searching for new and effective treatments imperative. Although ethnomedicine has been promising for treating various diseases, including parasitic infections, nanoparticles have emerged as a viable alternative to traditional anthelmintic curative development. Our study aims at investigating the recent advances in nanomedicine, particularly AgNPs, as anthelmintic agents, which has shown remarkable alterations in the levels of tegumental enzymes, eventually leading to their paralysis and death. We discuss the mechanisms of action of AgNPs againstRaillietinaspp. and highlight the potential benefits of using biosynthesized curatives that interfere with the host-parasite interface to treat parasite-related disorders.
Biosynthesis, Characterization and Anthelmintic Activity of Silver Nanoparticles ofClerodendrum infortunatumIsolate
Authors: Majumdar Rima , Kar Pradip Kumar
Published: March 2023

Over the past few decades, the green synthesis of nanoparticles has gained importance for their therapeutic efficacy and eco-friendly nature. Integrating green chemistry principles into multidisciplinary nanoscience research has paved the way for developing environmentally benign and sustainable methods for synthesizing gold and silver nanoparticles. In the present study, the flowers obtained fromClerodendrum infortunatum(L.), belonging to the family Verbenaceae, have been used for biosynthesizing silver nanoparticles (AgNPs) to evaluate the anthelmintic potential. UV-Vis spectroscopy, XRD, FTIR and TEM analyses were performed to ascertain the formation of AgNPs. Clerodendrum-derived AgNP (CLE-AgNP) has significantly affected the normal physiological functions of the poultry parasiteRaillietinaspp, a menace to the livestock industry. Our study manifests that CLE-AgNPs cause considerable distortion of the surface tegument of this cestode parasite leading to changes in the host-parasite interface. The histochemical localization studies of the tegument-associated enzymes viz. AcPase, AlkPase, ATPase and 5’-Nu, exposed to the drug, showed a substantial activity decline, thus establishing the anthelmintic potential of the CLE-AgNPs.
Association between postoperative fine particulate matter exposure and right ventricle-pulmonary artery conduit patency
Authors: Yue Chao , Li Jin , Zhang Jiaqi , Wang Qiang , Wang Xu
Published: March 2023

Background

Ambient air pollution is a leading risk factor for cardiovascular diseases. No study has investigated the association between fine particulate matter (PM2.5) exposure and prognosis of patients undergoing right ventricle-pulmonary (RV-PA) artery conduit surgery. We hypothesized that PM2.5can lead to stenosis of the conduit by stimulating inflammatory response in the conduit lumen.

Methods

From 2013 to 2020, patients with six complicated congenital heart defects and had undergone RV-PA operation in Beijing Fuwai Hospital were selected. Four conduit materials were used: bovine jugular vein graft (BJV), pulmonary homograft (PHG), aortic homograft (AHG), and handmade tri-leaflet expanded polytetrafluoroethylene (ePTFE) conduit. Telephone interviews were used to confirm the patients’ postoperative addresses. The monthly averages of PM2.5concentrations were obtained from the ChinaHighPM2.5dataset using patients’ places of residence. By comparing findings of echocardiography performed prior to patients’ return to their residence and during re-examination, we defined the trans-conduit peak velocity increase of ≥1.5 m/s as the study endpoint.

Results

232 patients were included in the study. Logistic analysis identified the female gender to be a protective factor against conduit velocity increase (Odd Ratio (OR) 0.270 (95% confidential interval (CI): 0.094–0.780), P = 0.016). Compared with BJV conduits, homografts (AHGs and PHGs) (0.052 (95% CI: 0.005–0.558), P = 0.015) and ePTFE conduits (0.009 (95% CI: 0.002–0.054), P <0.001) were protective factors. The cumulative monthly PM2.5concentration (unit 10μg/m3) was a risk factor (1.014 (95% CI: 1.001–1.026), P = 0.028). Winter experience was a risk factor (1.971 (95% CI: 1.021–3.804, P = 0.043). In the subgroup analysis, Spearman correlation analysis identified BJV conduits (r = 0.680, P <0.001), PHGs (r = 0.559, P = 0.020), AHGs (r = 0.745, P = 0.021) had medium-to-high positive correlations between the cumulative PM2.5concentration and conduit velocity change. For ePTFE, the correlation was weak and not significant (r = 0.222, P = 0.073).

Conclusion

Postoperative PM2.5exposure affects the patency of biologic prosthetic conduits, especially the xenograft. The ePTFE conduit velocity increase is not associated with PM2.5exposure which is a suitable material for patients living in high pollutant concentration areas.
On-chip human lymph node stromal network for evaluating dendritic cell and T-cell trafficking
Authors: Kwee Brian J. , Akue Adovi , Sung Kyung E.
Published: March 2023

The lymph node paracortex, also known as the T-cell zone, consists of a network of fibroblastic reticular cells (FRCs) that secrete chemokines to induce T-cell and dendritic cell trafficking into the paracortex. To model the lymph node paracortex, we utilized multi-channel microfluidic devices to engineer a 3D lymph node stromal network from human cultured FRCs embedded in a collagen I-fibrin hydrogel. In the hydrogel, the FRCs self-assembled into an interconnected network, secreted the extracellular matrix proteins entactin, collagen IV, and fibronectin, as well as expressed an array of immune cell trafficking chemokines. Although the engineered FRC network did not secrete characteristic CCR7-ligand chemokines (i.e. CCL19 and CCL21), human primary TNF-α matured monocyte-derived dendritic cells, CD45RA+T-cells, and CD45RA-T-cells migrated toward the lymph node stromal network to a greater extent than toward a blank hydrogel. Furthermore, the FRCs co-recruited dendritic cells and antigen-specific T-cells into the lymph node stromal network. This engineered lymph node stromal network may help evaluate how human dendritic cells and T-cells migrate into the lymph node paracortex via CCR7-independent mechanisms.
Geographic variation in evolutionary rescue in a predator-prey system under climate change: an example with aphids and ladybird beetles
Authors: Ge Xuezhen , Newman Jonathan A. , Griswold Cortland K.
Published: March 2023

Under climate change, species can adapt to changing environments through phenotypic plasticity and natural selection, and this kind of evolutionary adaptation can vary geographically. Most species distribution models (SDMs) are built upon the “Niche conservatism” assumption. They often ignore the possibility of “evolutionary rescue” and underestimate species’ future range limits under climate change. Here, we select aphids and ladybirds as model species and develop an eco-evolutionary model to explore evolutionary rescue in a predator-prey system under climate change. We model the adaptive change of species thermal performance, accounting for biotic interactions of unique life-history trait. Our results show that there is geographic variation in evolutionary rescue for ladybirds (the predator) across different locations in the United States, with ladybirds being more likely to be rescued from extinction in southeastern locations. The possibility of rescue is primarily influenced by the change in seasonality. Our findings also indicate the additive genetic variance of predators has a stronger influence on the phenotype evolution and population dynamics of both prey and predators, compared to the additive genetic variance of the prey. Our research emphasizes the importance of incorporating evolutionary adaptation when predicting species range shift under climate change. The eco-evolutionary model framework can be applied to study the effect of evolution on interacting species’ population abundance and geographic distribution under climate change.
Mixing selects for predation resistance in lab-evolved communities of bacterial prey and social predatorMyxococcus xanthus
Authors: Saha Saheli , Bhat Bhoomika , Laloo Jessica Mellicent , Goyal Akshit , Pande Samay
Published: March 2023

Population mixing, and transmission modes strongly influence social interactions. However, the impact of repeated mixing on the evolutionary dynamics of microbial predator-prey interactions remains underexplored1,2. Hence, we conducted a laboratory evolution experiment with bacterial predator-prey communities under two transfer regimens: repeated mixing (horizontal transfer) versus no mixing (vertical transfer). For this,Myxococcus xanthusserved as the generalist predator3,4andEscherichiacoli as prey. We show that prey populations from vertical regimen were less resistant to predation than the ones from horizontal regimen. This was because prey isolates in the vertical treatment showed varying resistance levels relative to ancestors, while those in the horizontal treatment demonstrated less variation. Moreover, analysis of prey populations over evolutionary time revealed that the populations from horizontal treatment showed increasing levels of resistance to predation over time, whereas the ones from vertical treatment did not show similar trend. The differences in the outcomes of the two treatments was because the variants better at intraspecies competition, can only be maintained in the vertical treatment, whereas in horizontal treatment the benefits of superior intraspecies competitive fitness are nullified because of population mixing, as predicted by mathematical modeling approach. These predictions were empirically confirmed. Moreover, contrary to our expectations, predatory efficiency of evolvedM. xanthusisolates was either the same or lesser than the ancestor. Together, we demonstrate that mixing affects the evolution of prey bacteria but has little effect on the hunting ability of the social predatorM. xanthus.
Inhibition of CDK12 elevates cancer cell dependence on P-TEFb by stimulation of RNA polymerase II pause release
Authors: Wang Zhijia , Himanen Samu V. , Haikala Heidi M. , Friedel Caroline C. , Vihervaara Anniina , Barborič Matjaž
Published: March 2023

P-TEFb and CDK12 facilitate transcriptional elongation by RNA polymerase II. Given the prominence of both kinases in cancer, gaining a better understanding of their interplay could inform the design of novel anti-cancer strategies. While down-regulation of DNA repair genes in CDK12-targeted cancer cells is being explored therapeutically, little is known about mechanisms and significance of transcriptional induction upon inhibition of CDK12. We show that selective targeting of CDK12 in colon cancer-derived cells activates P-TEFb via its release from the inhibitory 7SK snRNP. In turn, P-TEFb stimulates Pol II pause release at thousands of genes, most of which become newly dependent on P-TEFb. Amongst the induced genes are those stimulated by hallmark pathways in cancer, including p53 and NF-κB. Consequently, CDK12-inhibited cancer cells exhibit hypersensitivity to inhibitors of P-TEFb. While blocking P-TEFb triggers their apoptosis in a p53-dependent manner, it impedes cell proliferation irrespective of p53 by preventing induction of genes downstream of the DNA damage-induced NF-κB signaling. In summary, stimulation of Pol II pause release at the signal-responsive genes underlies the functional dependence of CDK12-inhibited cancer cells on P-TEFb. Our study establishes the mechanistic underpinning for combinatorial targeting of CDK12 with either P-TEFb or the induced oncogenic pathways in cancer.
Using interactive platforms to encode, manage and explore immune-related adverse outcome pathways
Authors: Mazein Alexander , Shoaib Muhammad , Alb Miriam , Sakellariou Christina , Sommer Charline , Sewald Katherina , Reiche Kristin , Gogesch Patricia , Roser Luise A , Ortega Iannazzo Samira , Sheth Sapna , Schiffmann Susanne , Waibler Zoe , Neuhaus Vanessa , Dehmel Susann , Satagopam Venkata , Schneider Reinhard , Ostaszewski Marek , Gu Wei
Published: March 2023

We address the need for modelling and predicting adverse outcomes in immunotoxicology to improve non-clinical assessments of immunomodulatory therapy safety and efficacy. The integrated approach includes, first, the adverse outcome pathway concept established in the toxicology field, and, second, the systems medicine disease map approach for describing molecular mechanisms involved in a particular pathology. The proposed systems immunotoxicology workflow is demonstrated with CAR T cell treatment as a use case. To this end, the linear adverse outcome pathway (AOP) is expanded into a molecular interaction model in standard systems biology formats. Then it is shown how knowledge related to immunotoxic events can be integrated, encoded, managed and explored to benefit the research community. The map is accessible online via the MINERVA Platform for browsing, commenting and data visualisation (https://minerva.pages.uni.lu). Our work transforms a graphical illustration of an AOP into a digitally structured and standardised form, featuring precise and controlled vocabulary and supporting reproducible computational analyses. Because of annotations to source literature and databases, the map can be further expanded to match the evolving knowledge and research questions.
Effects of recurrent summer droughts on arbuscular mycorrhizal and total fungal communities in experimental grasslands differing in plant diversity and community composition
Authors: Albracht Cynthia , Eisenhauer Nico , Vogel Anja , Wagg Cameron , Buscot François , Heintz-Buschart Anna
Published: March 2023

Biodiversity loss and climate change have been determined as major global drivers affecting ecosystems and their functioning. In this context, drought was shown to have negative effects on ecosystems by disrupting ecological processes, which could be buffered in more biodiverse systems. Many studies, however, focus on effects on aboveground communities of single drought events, while dynamics of soil-borne communities are still widely unclear, despite their important roles in ecosystem functioning.

To elucidate the effect of recurrent summer drought periods on fungal communities in a long-term grassland biodiversity experiment, roof shelters were installed on grassland plots ranging in plant species richness from 1 to 16 species and plant functional group richness (1-4 groups) and composition. After 9 years of summer droughts, bulk soil was sampled and used for Illumina sequencing of the ITS2 and SSU genes to characterize the total fungal and arbuscular mycorrhizal fungal (AMF) communities, respectively.

We found shifts of AMF and total fungi community structures caused by recurrent drought and plant species richness, but no buffering of drought effects by plant diversity. Alpha-diversity (VT or ASV richness) of both AMF and total fungi increased with plant species richness but was not significantly affected by drought. Even though drought overall had minimal long-lasting effects, we foundDiversisporaandParaglomusamong the AMF andPenicilliumamong total fungal communities to be more abundant after the drought treatment. AMF communities were affected by the presence of individual plant functional groups, reacting stronger to presence of legumes under drought, while total fungal interaction with plant communities were similar under drought as control. AMF α-diversity differed between plant functional groups in control conditions but was independent of plant community composition under drought. In contrast, total fungi α-diversity was increased by presence of herbs and legumes only under drought.

From our results, we conclude that recurring moderate summer droughts do not strongly affect soil fungal communities. All shifts can be explained by indirect effects through the plant community and its top-down effect on soils altered by drought. Further, AMF are not less affected than total fungal communities, but rather respond differently by interacting more strongly with legumes in response to drought. Consequently, not plant species richness, but plant functional composition, dominates in shaping fungal communities under recurrent droughts.
Energy-Saving Pretreatments Affect PelagicSargassumComposition and DNA Metabarcoding Analysis Reveals the Microbial Community Involved in Methane Yield
Authors: Salgado-Hernández Enrique , Alvarado-Lassman Alejandro , Martínez-Hernández Sergio , Velázquez-Fernández Jesús B. , Dorantes-Acosta Ana E. , Rosas-Mendoza Erik S. , Ortiz-Ceballos Ángel I.
Published: March 2023

Sargassumspp. floods the Caribbean coastlines, causing damage to the local economy and environment. These macroalgae have a low methane yield that makes the anaerobic digestion (AD) process unviable, so low-cost pretreatments are required. This research investigated the efficiency of energy-saving pretreatments, such as water washing, that had not been evaluated for these species. The microbial communities involved in AD of the best and worst-performing systems were also analyzed by high-throughput sequencing. The results showed that water washing pretreatment modified the content of inorganic compounds, fibers, and C:N ratio and increased the methane yield by 38%. The bacterial phyla Bacteroidota, Firmicutes, and Thermotogota, as well as the archaea generaMethanosarcina,RumEn_M2, andBathyarchaeia, dominated the microbial communities. This study is the first to show the microbial community structure involved in the AD ofSargassumspp. The pretreatments presented in this study may help overcome the previously reported limitations.
A tale of two pumps: Blue light and ABA alter Arabidopsis leaf hydraulics via bundle sheath cells’ H+-pumps and channels
Authors: Torne-Srivastava Tanmayee , Grunwald Yael , Rosenwald Mercedes , Dalal Ahan , Yaaran Adi , Shebtaev Veronica , Moshelion Menachem , Moran Nava
Published: March 2023

This study focuses on the cellular mechanism underlying the co-regulation of the leaf hydraulic conductance (Kleaf) by blue light (BL) and the stress hormone ABA inArabidopsis thaliana. Our previous work has demonstrated that (1) Kleafincreased by BL signaling within the leaf bundle sheath cells (BSCs), which activated their plasmalemma (PM) H+-ATPase (AHA2), acidifying the xylem sap; (2) external acidification enhanced the BSCs’ Kleafand their osmotic water permeability (Pf); (3) ABA decreased both Kleafand Pfby reducing the BSCs’ PM aquaporins activity.

We now show, using pH and EM(membrane potential) probes combined with H+-pumps inhibitors and manipulations of cytosolic and external Ca2+concentrations ([Ca2+]CYT,[Ca2+]EXT,respectively), that, in the BSCs: (a) under BL, ABA inhibits AHA2, depolarizing the BSCs and alkalinizing the xylem sap, (b) ABA stimulates the BSCs’ vacuolar H+-ATPase (VHA), alkalinizing their cytosol; (c) each pumpstimulation, AHA2 by BL and VHA by ABA, requires [Ca2+]CYTelevation. ABA-effect-mimicking conditions in patch-clamp experiments activate the BSCs’ K+-release channels (SKOR and/or GORK). ABA decreased the Kleafofskormutants less than WT’s, while during water deprivation stress,skorplants transpired more and their leaves lost relatively less K+than WT. This suggests a role for SKOR in water conservation under drought.
Personalized Neuroimaging Reveals the Impact of Children’s Interests on Language Processing in the Brain
Authors: Olson Halie A. , Johnson Kristina T. , Nishith Shruti , Frosch Isabelle R. , Gabrieli John D.E. , D’Mello Anila M.
Published: March 2023

Cognition is shaped by individual experiences and interests. However, to study cognition in the brain, researchers typically use generic stimuli that are the same across all individuals. Language, in particular, is animated and motivated by several highly personal factors that are typically not accounted for in neuroimaging study designs, such as “interest” in a topic. Due to its inherently personal and idiosyncratic nature, it is unknown how interest in a topic modulates language processing in the brain. We conducted functional magnetic resonance imaging (fMRI) in 20 children (ages 6.98-12.01 years, mean(SD)=9.35(1.52), 5 female/15 male) as they listened to personalized narratives about a topic of specific interest, as well as to non-personalized generic narratives. We found that personalized narratives about a topic of interest increased activation in canonical language areas, as well as in reward and self-reference regions. Strikingly, we found that activation patterns elicited by topics of personal interest were more consistent across children, despite their idiosyncratic nature, than activation patterns elicited by narratives about an identical generic topic. These results reinforce the critical role that personal interests play in language processing in the human brain, and demonstrate the feasibility of using a personalized neuroimaging approach to study the effects of individually-varying factors such as interest in the brain.
Epidermal GIGANTEA adjusts the response to shade at dusk by directly impinging on PHYTOCHROME INTERACTING FACTOR 7 function
Authors: Martínez-Vasallo Carlos , Cole Benjamin , Gallego-Bartolomé Javier , Chory Joanne , Kay Steve A. , Nohales Maria A.
Published: March 2023

For plants adapted to bright light, a decrease in the amount of light received can be detrimental to their growth and survival. Consequently, in response to shade from surrounding vegetation, they initiate a suite of molecular and morphological changes known as the shade avoidance response (SAR) through which stems and petioles elongate in search for light. Under sunlight-night cycles, the plant’s responsiveness to shade varies across the day, being maximal at dusk time. While a role for the circadian clock in this regulation has long been proposed, mechanistic understanding of how it is achieved is incomplete. Here we show that the clock component GIGANTEA (GI) directly interacts with the transcriptional regulator PHYTOCHROME INTERACTING FACTOR 7 (PIF7), a key player in the response to shade. GI represses PIF7 transcriptional activity and the expression of its target genes in response to shade, thereby fine-tuning the magnitude of the response to limiting light conditions. We find that, under light/dark cycles, this function of GI is required to adequately modulate the gating of the response to shade at dusk. Importantly, we also show that GI expression in epidermal cells is sufficient for proper SAR regulation.

SIGNIFICANCE

Plants have a remarkable capacity to adapt to and cope with changes in environmental conditions. Because of the importance of light to their survival, plants have evolved sophisticated mechanisms to optimize responses to light. An outstanding adaptive response in terms of plant plasticity in dynamic light environments is the shade avoidance response which sun-loving plants deploy to escape canopy and grow towards the light. This response is the result of a complex signaling network in which cues from different pathways are integrated, including light, hormone, and circadian signaling. Within this framework, our study provides a mechanistic model of how the circadian clock contributes to this complex response by temporalizing the sensitivity to shade signals towards the end of the light period. In light of evolution and local adaptation, this work gives insights into a mechanism through which plants may have optimized resource allocation in fluctuating environments.
flashfmZoom: a tool for joint fine-mapping and exploration of GWAS results in the UK Biobank
Authors: Zhou Feng , Starr Colin , Butterworth Adam S , Asimit Jennifer Lea
Published: March 2023

flashfmZoom is an all-in-one tool for analysis and interactive visualisation of potential causal genetic variants that underlie associations with quantitative traits from the UK Biobank. It offers a user-friendly interface and guides users in the selection of pleiotropic regions among subsets of 134 quantitative traits, such as cardiometabolic, hematologic, and respiratory traits. Users may then run single-trait fine-mapping, allowing for multiple causal variants, and leverage information between the traits using multi-trait fine-mapping to improve resolution. A series of interactive plots and downloadable tables are generated within flashfmZoom to identify potential causal variants that are shared or distinct between the traits; it also lists relevant literature for the traits and/or variants. Besides exploring traits that are well-known to be related, flashfmZoom encourages interactive exploration for the joint analysis of traits that may not often be considered together. This may reveal common aetiological pathways between traits related to different disorders.
Sequence independent activity of a predicted long disordered segment of the human papillomavirus L2 capsid protein during virus entry
Authors: Oh Changin , Buckley Patrick M , Choi Jeongjoon , Hierro Aitor , DiMaio Daniel
Published: March 2023

The papillomavirus L2 capsid protein protrudes through the endosome membrane into the cytoplasm during virus entry to bind cellular factors required for intracellular virus trafficking. Cytoplasmic protrusion of HPV16 L2, virus trafficking, and infectivity are inhibited by large deletions in an ∼110 amino acid segment of L2 that is predicted to be disordered. The activity of these mutants can be restored by inserting protein segments with diverse compositions and chemical properties into this region, including scrambled sequences, a tandem array of a short sequence, and the intrinsically disordered region of a cellular protein. The infectivity of mutants with small in-frame insertions and deletions in this segment directly correlates with the size of the segment. These results indicate that the length of the disordered segment, not its sequence or its composition, determines its activity during virus entry. Sequence independent but length dependent activity has important implications for protein function and evolution.
Low back pain service utilization and costs: association with timing of first-line services for individuals initially contacting a physician specialist. A retrospective cohort study
Authors: Elton David , Zhang Meng
Published: March 2023

Background

Physician specialists (PS) are often the type of healthcare provider initially contacted by an individual with low back pain (LBP). LBP clinical practice guidelines (CPG) recommend a stepped approach to management with an emphasis on first-line non-pharmaceutical and non-interventional services.

Objective

Examine the association between the incorporation of CPG recommended first-line services, exposure to second- and third-line services and total episode cost for individuals with non-surgical LBP initially contacting a PS.

Design

Retrospective observational study with identical design to previous study focused on primary care physicians.

Setting/Patients

National sample of individuals with non-surgical LBP occurring in 2017-2019.

Measurements

Independent variables were initial contact with a PS, and the timing of incorporation of five types of first-line services. Dependent measures included exposure to thirteen types of health care services and total episode cost.

Results

91,096 individuals were associated with 98,992 episodes of non-surgical LBP. 36.2% of the 33,277 PS initially contacted for an episode of LBP incorporated any first-line service at any time during an episode. A first-line service was provided in 24.0% of episodes with active care (19.5% of episodes), manual therapy (13.7%) and chiropractic manipulative therapy (6.5%) the most common. 7.3% of non-surgical LBP episodes included a first-line service within seven days of initial contact with a PS. These episodes were associated with a reduction in the use of prescription skeletal muscle relaxants (risk ratio (RR) 0.88) and opioids (RR 0.55), spinal injections (RR 0.84), and CT scans (RR 0.71), with no impact on the use of prescription NSAIDs, radiography, or MRI scans. First-line services were associated with an increase in total episode cost at any time of incorporation with chiropractic manipulation associated with the lowest cost increase. Younger individuals from zip codes with higher adjusted gross income were more likely to receive a first-line service in the first seven days of an episode.

Limitations

As a retrospective observational analysis of associations there are numerous potential confounders and limitations.

Conclusions

For individuals with non-surgical LBP PS provide second- or third-line services more frequently and earlier than CPG recommended first-line services. There is an opportunity to improve concordance with LBP CPGs for individuals with LBP initially contacting a PS.
“We are their eyes and ears here on the ground, yet they do not appreciate us”- Factors influencing the performance of Kenyan community health volunteers working in urban informal settlements
Authors: Ogutu Michael O , Kamui Eric , Abuya Timothy , Muraya Kui
Published: March 2023

Community Health Volunteers (CHVs) play a crucial role in linking the community with the formal health system, particularly in low- and middle-income countries. Studies in Kenya have focused on the implementation of the Kenya Community Health Strategy (CHS) in rural, nomadic, and peri-urban areas; with limited information on the factors that influence CHV performance in urban informal settlements. This study therefore explored factors that influence CHV performance in urban informal settlements within Nairobi Kenya and ways in which CHVs can be supported to enhance their wellbeing and strengthen community strategies. The study was undertaken in two urban informal settlements within Nairobi County. Thirteen focus group discussions (total of 123 participants) and three key informant interviews were conducted with a range of respondents. Various topics covering the design of the Community Health Strategy (CHS) and broader contextual factors that affect CHVs’ performance, were discussed and the data analysed using a framework analysis approach. The key programme design factors identified as influencing the performance of CHVs working in urban informal setting included: CHV recruitment; training; the availability of supplies and resources; and the remuneration of CHVs. Health system factors that influenced CHVs performance included: nature of relationship between healthcare workers at local referral facilities and community members; the availability of services and perceived corruption at the referral facilities; and CHV referral outside of the local health facility. Whereas the broader contextual factors that affected CHV performance at the community level included: demand for material or financial support; perceived corruption in community programmes; and neighbourhood insecurity. These findings suggest that like other CHVs working in both the rural and peri-urban settings, CHVs working in urban informal settlements in Kenya face a myriad of challenges that impact on their wellbeing and work performance. Therefore, to enhance CHVs’ well-being and improve their performance, the following should be considered: adequate and timely remuneration for CHVs, appropriate holistic training, adequate supportive supervision, and ensuring a satisfactory supply of resources and supplies. Additionally, at the health facility level, healthcare workers should be trained on appropriate and respectful relations with both the community and the CHVs, clarity of roles and scope of work, ensure availability of services, and safeguard against corrupt practices in public health facilities. Lastly, there is a need for improved and adequate security measures at the community level, to ensure safety of CHVs as they undertake their roles.
Cardiac Health Assessment using a wearable device before and after TAVI
Authors: Eerdekens Rob , Zelis Jo M. , Horst Herman ter , Crooijmans Caia , van ‘t Veer Marcel , Keulards Daniëlle C.J. , Kelm Marcus , Archer Gareth , Kuehne Titus , Brueren Guus R.G. , Wijnbergen Inge , Johnson Nils P. , Tonino Pim A.L.
Published: March 2023

Background

Due to the aging of the population, the prevalence of aortic valve stenosis will increase dramatically in upcoming years. Consequently Transcatheter Aortic Valve Implantation (TAVI) procedures will also expand worldwide. Optimal selection of patients who benefit with improved symptoms and prognosis is key since TAVI is not without risk. Currently we are not able to adequately predict functional outcome after TAVI. Quality of life measurement tools and traditional functional assessment tests do not always agree and can depend on factors unrelated to heart disease. Activity tracking using wearable devices might provide a more comprehensive assessment.

Objectives

Identify objective parameters from a wearable device (the Philips Health Watch) associated with improvement after TAVI for severe aortic stenosis.

Methods and results

100 patients undergoing routine TAVI wore a Philips Health Watch for one week before and after the procedure. Watch data were analyzed offline: 97 before and 75 after TAVI. Parameters like the total number of steps and activity time did not change, in contrast to improvements in the six-minute walking test (6MWT) and physical limitation domain of a questionnaire (transformed WHOQOL-BREF).

Conclusions

These findings in an elderly TAVI population show that watch-based parameters like the number of steps do not change after TAVI, unlike traditional 6MWT and QoL assessments that do improve. Basic wearable device parameters might be less appropriate for measurement of treatment effects from TAVI.
A comparison of live versus kill pitfall traps to assess the diet of carabids through a metabarcoding approach
Authors: Graux Yohann , Querejeta Marina , Gaba Sabrina , Bretagnolle Vincent , Boyer Stéphane
Published: March 2023

Metabarcoding approaches are powerful tools to unravel trophic relationships between predators and prey. To apply metabarcoding analyses on invertebrate gut contents, specimens must be well preserved from DNA degradation, thus the trapping method should be selected accordingly. Dry pitfall traps are commonly assumed to provide a better DNA preservation than traps that use a killing agent. However, this assumption has never been specifically tested for gut content analyses.

In our study, we compared how two types of pitfall trapping, dry vs. with brine, affect the conservation of prey DNA contained in the digestive tract of predators and subsequent metabarcoding analyses. We placed dry and “classic” pitfall traps in oilseed rape fields within an intensive agricultural area in the French Nouvelle-Aquitaine region. Traps were set up in autumn and compared for carabid trapping efficiency as well as our capacity to retrieve dietary information from the digestive tract of the main carabid species,Nebria salinaandCalathus fuscipes.

PCR success rate was higher in dry pitfall traps compared to classic ones forN. salina. We hypothesise that this was due to the presence of PCR inhibitors in the gut of this species. The ability to sequence prey DNA did not differ between specimens caught in both trap types. The list of predated species was similar between both trap types. However, sequencing yielded more prey OTUs from specimens caught in dry pitfall traps, leading to difference in prey community composition and a greater ability to reconstruct prey community

Our analyses also shed light on the prey spectrum ofCalathus fuscipesandNebria salinain oilseed rape in autumn.
Complete male-to-female sex reversal in XY mice lacking themiR-17∼92cluster
Authors: Hurtado Alicia , Mota-Gómez Irene , Lao Miguel , Real Francisca M. , Jedamzick Johanna , Burgos Miguel , Lupiáñez Darío G. , Jiménez Rafael , Barrionuevo Francisco J.
Published: March 2023

In mammals, sex determination is controlled by antagonistic gene cascades operating in embryonic undifferentiated gonads12. The expression of the Y-linked geneSRYis sufficient to trigger the testicular pathway, whereas its absence in XX embryos leads to ovarian differentiation345. Despite this strong genetic component, the involvement of non-coding regulation in determining mammalian sex remains unclear6. Here we show that the deletion of a single microRNA cluster,miR-17∼92, induces complete primary male-to-female sex reversal in XY mice. Time-course analyses revealed thatSryis heterochronically expressed, showing a delay in XYmiR-17∼92knockout gonads, which subsequently activate the ovarian genetic program. Bulk and single cell RNA-seq analyses showed that Sertoli cell differentiation is reduced, delayed and unable to sustain the testicular fate. This disrupted differentiation results from a transient state of sex ambiguity in pre-supporting cells, which is later resolved towards the ovarian fate. Consistent with known mechanisms of miRNA-mediated gene regulation, the expression ofmiR-17∼92target genes is not stabilized in undifferentiated XY mutant gonads, affecting concomitantly the fine regulation of gene networks with critical roles in developing gonads. Our results demonstrate that microRNAs are key components for mammalian sex determination, controlling the timing ofSryexpression and Sertoli cell differentiation.
Upregulated GIRK2 counteracts ethanol-induced changes in excitability & respiration in human neurons
Authors: Prytkova Iya , Liu Yiyuan , Fernando Michael , Gameiro-Ros Isabel , Popova Dina , Kamarajan Chella , Xuei Xiaoling , Chorlian David B. , Edenberg Howard J. , Tischfield Jay A. , Porjesz Bernice , Pang Zhiping P. , Hart Ronald P. , Goate Alison , Slesinger Paul A.
Published: March 2023

Genome-wide association analysis (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified non-coding polymorphisms within theKCNJ6gene.KCNJ6encodes GIRK2, a subunit of a G protein-coupled inwardly-rectifying potassium channel that regulates neuronal excitability. How changes in GIRK2 affect human neuronal excitability and the response to repeated ethanol exposure is poorly understood. Here, we studied the effect of upregulatingKCNJ6using an isogenic approach with human glutamatergic neurons derived from induced pluripotent stem cells (male and female donors). Using multi-electrode-arrays, population calcium imaging, single-cell patch-clamp electrophysiology, and mitochondrial stress tests, we find that elevated GIRK2 acts in concert with 7-21 days of ethanol exposure to inhibit neuronal activity, to counteract ethanol-induced increases in glutamate response, and to promote an increase intrinsic excitability. Furthermore, elevated GIRK2 prevented ethanol-dependent changes in basal and activity-dependent mitochondrial respiration. These data support a role for GIRK2 in mitigating the effects of ethanol and a previously unknown connection to mitochondrial function in human glutamatergic neurons.

SIGNIFICANCE STATEMENT

Alcohol use disorder (AUD) is a major health problem that has worsened since COVID, affecting over 100 million people worldwide. While it is known that heritability contributes to AUD, specific genes and their role in neuronal function remain poorly understood, especially in humans. In the current manuscript, we focused on the inwardly-rectifying potassium channel GIRK2, which has been identified in an AUD-endophenotype genome-wide association study. We used human excitatory neurons derived from healthy donors to study the impact of GIRK2 expression. Our results reveal that elevated GIRK2 counteracts ethanol-induced increases in glutamate response and intracellular calcium, as well as deficits in activity-dependent mitochondrial respiration. The role of GIRK2 in mitigating ethanol-induced hyper-glutamatergic and mitochondrial offers therapeutic promise for treating AUD.
Mammalian Esophageal Stratified Tissue Homeostasis is Maintained Distinctively by the Epithelial Pluripotent p63+Sox2+and p63−Sox2+Cell Populations
Authors: Yu Xiaohong , Yuan Hui , Yang Yanan , Zheng Wei , Zheng Xuejing , Lu Shih-Hsin , Jiang Wei , Yu Xiying
Published: March 2023

Self-renewing, damage-repair and differentiation of mammalian stratified squamous epithelia are subject to tissue homeostasis, but the regulation mechanisms remain elusive. Here, we investigate the esophageal squamous epithelial tissue homeostasis in vitro and in vivo. We establish a rat esophageal organoid (rEO) in vitro system and show that the landscapes of rEO formation, development and maturation trajectories can mimic those of rat esophageal epithelia in vivo. Single-cell RNA sequencing (scRNA-seq), snap-shot immunostaining and functional analyses of stratified “matured” rEOs define that the epithelial pluripotent stem-cell determinants, p63 and Sox2, play crucial but distinctive roles for regulating mammalian esophageal tissue homeostasis. We identify two cell populations, p63+Sox2+and p63−Sox2+, of which the p63+Sox2+population presented at the basal layer is the cells of origin required for esophageal epithelial stemness maintenance and proliferation whereas the p63−Sox2+population presented at the suprabasal layers is the cells of origin having a dual role for esophageal epithelial differentiation (differentiation-prone fate) and rapid tissue damage-repair responses (proliferation-prone fate). Given the fact that p63 and Sox2 are developmental lineage oncogenes and commonly overexpressed in ESCC tissues, p63−Sox2+population could not be detected in organoids formed by esophageal squamous cell carcinoma (ESCC) cell lines. Taken together, these findings reveal that the tissue homeostasis is maintained distinctively by p63 and/or Sox2 dependent cell lineage populations required for the tissue renewing, damage-repair and protection of carcinogenesis in mammalian esophagi.