bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex-specific central regulation of reproductive activity revealed by the use of deslorelin in the grey mouse lemur,Microcebus murinus
Authors: Noiret Aude , Aujard Fabienne , Terrien Jeremy
Published: September 2023

Deslorelin is a GnRH agonist used in veterinary medicine to temporarily inhibit reproduction in domestic animals and is sometimes tested in captive species in zoo to control population or tame aggressive behaviours in males. However, some studies have revealed the inefficacy of deslorelin specifically in males, contrary to females that follow a classic long-term inhibition of the reproductive hypothalamic-pituitary axis through sexual steroid negative feedback. We implanted 5 males and 6 females grey mouse lemurs (Microcebus murinus), long-day breeders that display a complete inhibition of the reproductive system during winter, at the end of the short-day period, a few weeks before the breeding season. Contrary to females, which exhibited a classic inhibitory response to deslorelin, males testosterone levels increased as well as their testis size, which suggests a sex-specific sensitivity to the negative feedback of sexual steroids before the mating period. We propose that this sex-imbalance is related to the different life-history of males as opposed to females concerning reproductive tasks and behaviour.
Challenging age-structured and first order transition cell cycle models of cell proliferation
Authors: Ubezio Paolo
Published: September 2023

Uncontrolled cell proliferation is the key feature of tumours. Because experimental measures provide only a partial view to the underlying proliferative processes, such as cell cycling, cell quiescence and cell death, mathematical modelling aims to provide a unifying view of the data with a quantitative description of the contributing basic processes. Modelling approaches to proliferation of cell populations can be divided in two main categories: those based on first order transitions between successive compartments and those including a structure of the cells’ life cycle. Here we challenge basic models belonging to the two categories to fit time course data sets, from our laboratory experience, obtained observing the proliferative phenomenon with different experimental techniques in a cancer cell line. We disclose the limitations of too simple models. At the minimal complexity level accounting for all available data the two approaches converge and suggest similar scenarios for the underlying proliferation process, in both untreated conditions and after treatment.
The rural urban divide, insights from immuno-genetic profiles and implications for health
Authors: Hamad Reem , Eid Nahid A , Aboswar Safa A.E , Saeed Azza , Hussein Ayman A , Elhassan Ibrahim M , Rockett Kirk A , Kwiatkowski Dominic P , Ibrahim Muntaser E , Elhassan Ahmed M
Published: September 2023

Population disparities in health and disease, has been observed, and amply documented. While often attributable to genetic underpinnings, such disparities, extends beyond population genetic predisposition to include environmental and geographic determinants most pronouncedly the division between rural and urban lifestyles. Under such influences, genes and gene products may become affected by epigenetic factors, microbial modifiers including infections and the body microbiome that ultimately shapes the outcome of complex milieu of protein networks. Retrospective, demographic, genotype, and expression data of two rural populations from eastern Sudan were analysed for genotype, allele frequency distribution, Hardy Weinberg Equilibrium and expression profiles using an array panel of Th1, Th2 and Th3 genes in a subset of rural population sample against matched urban control.

Differences between urban and rural samples were observed in the departure from HWE with excess of heterozygosity in the rural sample. In the Th1, Th2 and Th3 array, cytokines were consistently overexpressed in the rural as compared to urban cohort and was replicated in 7 selected genes that are associated with chronic diseases amongst urban dwellers in contrast to rural village inhabitants. IgE levels as feature of parasitic infections is one other difference to include in that dichotomy.

Gene expression appears to be more exposing to an overall outcome of genetic variations, including the interaction with environmental influences within and outside the body. Here, it may be gathered from the contrast in the expression patterns between the rural and urban samples. The presence of signals of natural selection in genes that are key to certain biological functions as CD40L and FasL, and the sharp contrast between urban and rural populations in gene variants distribution and expression patterns may provide important clues towards understanding the disparity between human communities in non-communicable diseases of lifestyle as well as some of the emerging infectious diseases.
Moonless night sky increasesIsistiusspecies and live human contact
Authors: Minaglia Steven , Liegl Melodee
Published: September 2023

The nocturnal feeding behavior and zoogeographical habitat of cookiecutter sharksIsistius brasiliensisandIsistius plutodus(Isistius spp.) greatly reduces interaction of this species with live humans. Attacks on live humans are exceedingly rare with 7 cases reported worldwide, 6 of them in Hawai‘i, and 5 of these occuring among channel swimmers. Published research suggests that periods of bright moonlight may increaseIsistius spp. contact with live humans and does not otherwise identify significant trends or risk factors. Yet 5 of the 6Isistius spp. bites on live humans in Hawai‘ian waters occurred with the moon set and after nautical twilight end and before nautical twilight start. From 1961-2023 in Hawai‘i, 129 successful solo channel crosses and 5Isistius spp. related injuries in the habitat of cookiecutter sharks were analyzed across two groups: one where both the moon and sun were set (dark group) and one where the moon and/or sun was in the sky (light group). There was a significant difference for swimmers bitten byIsistius spp. in the dark 4 (12%) versus light groups 1 (1%), p=0.012, RR 12.6 (95% confidence interval: 1.5-108.9). Swim start time and year was also significant (Pearson correlation 0.566, p <0.001). Swimmer gender and use of shark deterrent devices and artificial illumination were not significant. The growing popularity of channel swimming in Hawai‘i and swim start times have contributed to an increasing likelihood of live human andIsistius spp. contact and a moonless night sky is a significant risk factor for this interaction.
Phylogenetic diversity and regionalization of root nodule symbiosis
Authors: Folk R.A , Belitz M.W. , Siniscalchi C.M. , Kates H.R. , Soltis D.E. , Soltis P.S. , Guralnick R.P. , Borges L.M.
Published: September 2023

Aim

Here we determine centers of species richness (SR), relative phylogenetic diversity (RPD) and centers of paleo- and neo-endemism, and regionalizations of phylogenetic diversity in the mimosoid clade of the legumes to understand the distribution and environmental associates of mimosoids lacking RNS (root nodule symbiosis).

Location

Global.

Time period

Present.

Major taxa studied

Mimosoid legumes.

Methods

We built a phylogenetic tree of 1313 species and high-quality species distribution models for 1128 species representing the phylogenetic breadth of the mimosoid clade to identify the geographic distribution of RNS. Centers of significant RPD and endemism were identified using a randomization approach, the latter using CANAPE. Phylogenetic regionalization used a distance-based phylogenetic beta-diversity approach.

Results

We recognized nine areas of contiguous high SR as distinct SR hotspots. Non-RNS species occur mainly outside hotspots but are closely correlated with high RPD. Absence of RNS was best predicted by high precipitation, and represents multiple independent phylogenetic assemblages in different biogeographic areas.

Main conclusions

SR hotspots are partly incongruent with centers of RPD and phylogenetic endemism. Lineages lacking RNS are distributed in SR hotspots in Africa and the Americas, belong to biogeographically separate species assemblages, and are, in most cases, associated with relatively moist tropical environments with low temperature seasonality and high available soil nitrogen.
Transferable Coarse Graining via Contrastive Learning of Graph Neural Networks
Authors: Airas Justin , Ding Xinqiang , Zhang Bin
Published: September 2023

Coarse-grained (CG) force fields are essential for molecular dynamics simulations of biomolecules, striking a balance between computational efficiency and biological realism. These simulations employ simplified models grouping atoms into interaction sites, enabling the study of complex biomolecular systems over biologically relevant timescales. Efforts are underway to develop accurate and transferable CG force fields, guided by a bottom-up approach that matches the CG energy function with the potential of mean force (PMF) defined by the finer system. However, practical challenges arise due to many-body effects, lack of analytical expressions for the PMF, and limitations in parameterizing CG force fields. To address these challenges, a machine learning-based approach is proposed, utilizing graph neural networks (GNNs) to represent CG force fields and potential contrasting for parameterization from atomistic simulation data. We demonstrate the effectiveness of the approach by deriving a transferable GNN implicit solvent model using 600,000 atomistic configurations of six proteins obtained from explicit solvent simulations. The GNN model provides solvation free energy estimations much more accurately than state-of-the-art implicit solvent models, reproducing configurational distributions of explicit solvent simulations. We also demonstrate the reasonable transferability of the GNN model outside the training data. Our study offers valuable insights for building accurate coarse-grained models bottom-up.
Dietary burden of phosphorus and aluminum in ready-to-eat wheat flour tortillas exceed that of corn tortillas: Implications for patients with renal or cardiovascular disease
Authors: Chiang Kate C. , Yokel Robert A. , Unrine Jason M. , Kalantar-Zadeh Kamyar , Gupta Ajay
Published: September 2023

Ready-to-eat, shelf-stable tortillas contain several phosphorus- and aluminum-containing additives that may increase the risk of adverse events in patients with chronic kidney disease (CKD). The present study analyzes and compares the elemental content of wheat flour and corn tortillas with special reference to dietary aluminum and phosphorus burden. Twenty-one elements were quantified by ICP-MS and ICP-OES in 14 corn and 13 wheat flour tortilla brands purchased from local supermarkets in Southern California. The aluminum and phosphorus concentrations of many ready-to-eat tortilla brands can present a daily dietary load of up to approximately 100 mg aluminum and 700 mg phosphorus based on an average daily tortilla intake of 330 grams. Ready-to-eat wheat flour tortillas generally had more phosphorus than corn tortillas. Tortillas with aluminum listed as a food additive contained a higher aluminum content than those without such listing, exceeding the tolerable weekly intake. Despite conventional wisdom that CKD patients should avoid phosphorus-rich corn tortillas, ready-to-eat wheat flour tortillas consistently had a higher aluminum and phosphorus content due to additives. CKD patients and healthcare providers should pay attention to food labels, and regulatory authorities should monitor the use of approved food additives and mandate food label warnings for patients at risk.
In Silico Analysis of Drug Off-Target Effects on Diverse Isoforms of Cervical Cancer for Enhanced Therapeutic Strategies
Authors: Iqbal Azhar , Ali Faisal , Aziz Moawaz , Shakil Asad Ullah , Choudhary Shanza , Qayyum Adiba , Arshad Fiza , Ashraf Sarah , Sehgal Sheikh Arslan , Hussain Momina , Sajid Muhammad
Published: September 2023

Cervical cancer is a severe medical issue as 500,000 new cases of cervical cancer are identified in the world every year. The selection and analysis of the suitable gene target are the most crucial in the early phases of drug design. The emphasis at one protein while ignoring its several isoforms or splice variations may have unexpected therapeutic or harmful side effects. In this work, we provide a computational analysis of interactions between cervical cancer drugs and their targets that are influenced by alternative splicing. By using open-accessible databases, we targeted 45 FDA-approved cervical cancer drugs targeting various genes having more than two distinct protein-coding isoforms. Binding pocket interactions revealed that many drugs do not have possible targets at the isoform level. In terms of size, shape, electrostatic characteristics, and structural analysis have shown that various isoforms of the same gene with distinct ligand-binding pocket configurations. Our results emphasized the risks of ignoring possibly significant interactions at the isoform level by concentrating just on the canonical isoform and promoting consideration of the impacts of cervical cancer drugs on- and off-target at the isoform level to further research.
Genetic Variants That Modify the Neuroendocrine Regulation of Foraging Behavior inC. elegans
Authors: Lee Harksun , Boor Sonia A. , Hilbert Zoë A. , Meisel Joshua D. , Park Jaeseok , Wang Ye , McKeown Ryan , Fischer Sylvia E. J. , Andersen Erik C. , Kim Dennis H.
Published: September 2023

The molecular mechanisms underlying diversity in animal behavior are not well understood. A major experimental challenge is determining the contribution of genetic variants that affect neuronal gene expression to differences in behavioral traits. The neuroendocrine TGF-beta ligand, DAF-7, regulates diverse behavioral responses ofCaenorhabditis elegansto bacterial food and pathogens. The dynamic neuron-specific expression ofdaf-7is modulated by environmental and endogenous bacteria-derived cues. Here, we investigated natural variation in the expression ofdaf-7from the ASJ pair of chemosensory neurons and identified common variants ingap-2, encoding a GTPase-Activating Protein homologous to mammalian SynGAP proteins, which modifydaf-7expression cell-non-autonomously and promote exploratory foraging behavior in a DAF-7-dependent manner. Our data connect natural variation in neuron-specific gene expression to differences in behavior and suggest that genetic variation in neuroendocrine signaling pathways mediating host-microbe interactions may give rise to diversity in animal behavior.
Constraints on avian seed dispersal reduce potential for resilience in degraded tropical forests
Authors: Hatfield Jack H. , Banks-Leite Cristina , Barlow Jos , Lees Alexander C. , Tobias Joseph A.
Published: September 2023

1. Seed dispersal – one of the many services supplied by biodiversity – is a critical process underpinning the resilience of tropical forests. Forest loss or degradation typically leads to defaunation, altering seed transfer dynamics and impairing the ability of forested habitats to regenerate or recover from perturbation. However, the extent of defaunation, and its likely impacts on the seed dispersers needed to restore highly degraded or clear-felled areas, remains poorly understood, particularly in human-modified tropical forest landscapes.

2. To quantify defaunation of seed-dispersing birds, we used field survey data from more than 400 transects in three regions of Brazil, first comparing the recorded assemblages with those predicted by geographic range maps, and then assessing frugivore habitat associations across gradients of land cover modification at local scales.

3. We found that current bird assemblages have lower functional trait diversity than predicted by species range maps in Amazonia (4–6%), with a greater reduction (28%) for the Atlantic Forest region, which has been more heavily deforested for a longer period. These reductions are probably caused by local extinctions of forest-dependent bird species following land-use change.

4. Direct measures of seed dispersal are difficult to obtain, so we instead focused on the potential for seed transfer inferred from shared species occurrence between land cover types. Of 83 predominantly frugivorous bird species recorded in relatively intact forests, we show that 10% were absent from degraded forest, and 57% absent from the surrounding matrix of agricultural land covers, including many of the large-beaked species. Of 112 frugivorous species using degraded forest, 47% were absent from matrix habitats.

5. Our findings suggest that degraded forest can supply seed dispersal services to adjacent cleared lands, and that direct transfer of seeds from intact forest to cleared areas may be limited, particularly for large-seeded trees. We conclude that resilience of tropical forest landscapes is best achieved by protecting a mosaic of forest types, including sufficient core areas of intact forest surrounded by buffer zones of degraded forest.
CodonBERT: Large Language Models for mRNA design and optimization
Authors: Li Sizhen , Moayedpour Saeed , Li Ruijiang , Bailey Michael , Riahi Saleh , Kogler-Anele Lorenzo , Miladi Milad , Miner Jacob , Zheng Dinghai , Wang Jun , Balsubramani Akshay , Tran Khang , Zacharia Minnie , Wu Monica , Gu Xiaobo , Clinton Ryan , Asquith Carla , Skaleski Joseph , Boeglin Lianne , Chivukula Sudha , Dias Anusha , Montoya Fernando Ulloa , Agarwal Vikram , Bar-Joseph Ziv , Jager Sven
Published: September 2023

Abstract

mRNA based vaccines and therapeutics are gaining popularity and usage across a wide range of conditions. One of the critical issues when designing such mRNAs is sequence optimization. Even small proteins or peptides can be encoded by an enormously large number of mRNAs. The actual mRNA sequence can have a large impact on several properties including expression, stability, immunogenicity, and more. To enable the selection of an optimal sequence, we developed CodonBERT, a large language model (LLM) for mRNAs. Unlike prior models, CodonBERT uses codons as inputs which enables it to learn better representations. CodonBERT was trained using more than 10 million mRNA sequences from a diverse set of organisms. The resulting model captures important biological concepts. CodonBERT can also be extended to perform prediction tasks for various mRNA properties. CodonBERT outperforms previous mRNA prediction methods including on a new flu vaccine dataset.
Passivating blunt-ended helices to control monodispersity and multi-subunit assembly of DNA origami structures
Authors: Berengut Jonathan F. , Berg Willi R. , Rizzuto Felix J. , Lee Lawrence K.
Published: September 2023

DNA origami facilitates the synthesis of bespoke nanoscale structures suitable for a wide range of applications. Effective design requires prevention of uncontrolled aggregation, while still permitting directed assembly of multi-subunit superstructures. Uncontrolled aggregation can be caused by base-stacking interactions between arrays of blunt-ended helices on different structures, which are routinely passivated by incorporating disordered regions as either scaffold loops or poly-nucleotide brushes (usually poly-thymine) at the end of DNA helices. Such disordered regions are ubiquitous in DNA origami structures yet their exact design requirements in different chemical environments are ill defined. In this study, we systematically examine the use of scaffold loops and poly-nucleotide brushes for passivation and for controlling multi-subunit assembly. We assess the dependence of length and sequence for preventing aggregation amidst a titration of MgCl2concentrations and the suitability of each strategy for enabling controlled multi-subunit assembly. We then introduce a novel strategy where double-stranded DNA helices run orthogonal to arrays of blunt-ended DNA helices forming a steric shield that prevents base stacking. The results define the limitations of each method and important design considerations for achieving monodispersity. For example, poly-thymine brushes are most effective for achieving monodispersity in the broadest conditions whereas scaffold loops can facilitate directed multi-subunit assembly. Finally, orthogonal DNA helices remove the need for disordered regions altogether, prevent aggregation in a broad range of MgCl2concentrations and facilitate directed multi-subunit assembly. This study expands the design tools available and enables a more informed approach for achieving control of monodispersity and multi-subunit assembly in DNA origami structures.
Spatial molecular profiling of mixed invasive ductal-lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations
Authors: Shah Osama Shiraz , Nasrazadani Azadeh , Foldi Julia , Atkinson Jennifer M. , Kleer Celina G , McAuliffe Priscilla F. , Johnston Tyler J , Stallaert Wayne , da Silva Edaise M , Selenica Pier , Dopeso Higinio , Pareja Fresia , Mandelker Diana , Weigelt Britta , Reis-Filho Jorge S. , Bhargava Rohit , Lucas Peter C. , Lee Adrian V. , Oesterreich Steffi
Published: September 2023

Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially-resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity (e.g., MDLC with TNBC/basal ductal and ER+/luminal lobular regions), distinct enrichment of senescence/dormancy and oncogenic (ER and MYC) signatures, genetic and epigeneticCDH1inactivation in lobular, but not ductal regions, and single-cell ductal and lobular sub-populations with unique oncogenic signatures further highlighting intra-regional heterogeneity. Altogether, we demonstrated that the intra-tumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma.

Significance

MDLC displays both ductal and lobular tumor regions. Our multi-omic profiling approach revealed that these morphologically distinct tumor regions harbor distinct intrinsic subtypes and oncogenic features that may cause prognostic uncertainty and therapeutic dilemma. Thus histopathological/molecular profiling of individual tumor regions may guide clinical decision making and benefit patients with MDLC, particularly in the advanced setting where there is increased reliance on next generation sequencing.
Evaluating Risk Progression in Mental Health Chatbots Using Escalating Prompts
Authors: Heston Thomas F.
Published: September 2023

The safety of large language models (LLMs) as mental health chatbots is not fully established. This study evaluated the risk escalation responses of publicly available ChatGPT conversational agents when presented with prompts of increasing depression severity and suicidality. The average referral point to a human was at the midpoint of escalating prompts. However, most agents only definitively recommended professional help at the highest level of risk. Few agents included crisis resources like suicide hotlines. The results suggest current LLMs may fail to escalate mental health risk scenarios appropriately. More rigorous testing and oversight are needed before deployment in mental healthcare settings.
A Decade’s Experience Performing Forensic Medical and Psychologic Evaluations for Pediatric Asylum Seekers in the United States
Authors: Plesons Marina , Hullfish Haley , Joshi Priyashma , Symes Stephen , Saxena Anjali
Published: September 2023

Background

The number of children seeking asylum in the US has increased substantially in recent years. To add to the limited evidence base related to children seeking asylum in the US, this paper describes the sociodemographic characteristics, nature of human rights violations, and guardianship status of the children served by the Human Rights Clinic of Miami from 2010-2021.

Methods

A retrospective study was conducted on affidavits for pediatric patients seeking forensic medical and psychological evaluation at the Human Rights Clinic of Miami from 2010 to 2021. We determined trends among sociodemographic characteristics and the nature of human rights violations among these patients and used logistic regression to determine factors associated with having a guardian present at the evaluation.

Results

Of the total 64 pediatric patients who received a forensic medical and psychological evaluation, over half were male (56%) and two-thirds were aged 15-17. Honduras was the most common country of origin (53%). Physical violence was the most reported human rights abuse (72%) followed by gang violence (53%), sexual violence (22%), and political violence (3%). The majority of children (87%) reported being detained at the border upon entry into the USA. Only 31% of pediatric patients had a guardian present during the evaluation, with guardianship significantly less likely for older patients (p <0.05).

Conclusions

These findings identified specific challenges unique to the pediatric population, including lack of guardianship among older children. Future efforts may include the development of formal pediatric-specific guidelines for conducting evaluations of children seeking asylum.
A brief report on the of mycobacterial proteins regulated by the loss of PtkA in Mtb-H37Ra
Authors: Jaiswal Swati , Srivasatava Kishore K
Published: September 2023

Kinase-phosphatase signaling plays an important role in cellular signaling pathways. The genome ofMycobacterium tuberculosis, (the causative agent of tuberculosis), is embossed with several kinases and phosphatases. Recently identified protein tyrosine kinase (PtkA) is a novel tyrosine kinase that phosphorylates protein tyrosine phosphatase A (PtpA) and regulates its secretion in the cytosol. PtkA is considered as a regulatory protein. In this study, the mycobacterial proteins regulated due to theptkAgene deletion in Mtb-H37Ra have been studied and highlighted using two-dimensional (2D) gel electrophoresis coupled with MALDI TOF MS/MS analysis. We have identified 13 differentially expressed proteins that play an important role in mycobacterial intracellular survival and pathogenesis.
VAMP2/Munc18-1 domain 3a interaction controls the nanoscale reorganization underpinning vesicular priming
Authors: Jiang Anmin , Gormal Rachel S. , Kasula Ravikiran , Blum Ailisa , Salla-Martret Mercè , Chai Ye Jin , Wallis Tristan P. , Brouillet Julie Z. , Padmanabhan Pranesh , Weeratunga Saroja , Livingstone Emma K. , Mollazade Mahdie , Joensuu Merja , Martínez-Mármol Ramón , Collins Brett M. , Meunier Frédéric A.
Published: September 2023

SNARE-mediated secretory vesicle (SV) exocytosis underpins neuronal communication. Munc18-1 orchestrates SNARE complex formation by controlling the opening of syntaxin-1A. How the SV-plasma membrane interface becomes fusion-competent at the nanoscale level is poorly understood. Here, we propose that the interaction of Munc18-1 with VAMP2 during vesicular docking triggers nanoscale re-organization which renders the SV-plasma membrane interface fusion-competent. We identified and mutated key residues in Munc18-1 domain 3a (A297 and T304) hypothesised to impair its interaction with VAMP2. Munc18-1A297H, and to a lesser extent Munc18-1T304H, constrained SVs on the plasma membrane and reduced stimulated secretion, under re-expression conditions in Munc18-1/2 double knockout neurosecretory cells. Moreover, the de-clustering of Munc18-1 in response to activity was lost for both mutants. The interaction of VAMP2 with the Munc18-1 domain 3a therefore controls the re-organization of the nanoscale environment of the docked SV-plasma membrane interface, fostering syntaxin-1A opening and Munc18-1 release to ensure that SNARE assembly only occurs within the confinement of docked vesicles.
The Origin And Speciation Of Orchids
Authors: Perez-Escobar Oscar A. , Bogarín Diego , Przelomska Natalia A.S. , Ackerman James D. , Balbuena Juan A. , Bellot Sidonie , Bühlmann Roland P. , Cabrera Betsaida , Cano Jose Aguilar , Charitonidou Martha , Chomicki Guillaume , Clements Mark A. , Cribb Phillip , Fernández Melania , Flanagan Nicola S. , Gravendeel Barbara , Hágsater Eric , Halley John M. , Hu Ai-Qun , Jaramillo Carlos , Mauad Anna Victoria , Maurin Olivier , Müntz Robert , Leitch Ilia J. , Li Lan , Negrao Raquel , Oses Lizbeth , Phillips Charlotte , Rincon Milton , Salazar-Chavez Gerardo , Simpson Lalita , Smidt Eric , Solano-Gomez Rodolfo , Parra-Sánchez Edicson , Tremblay Raymond L. , van den Berg Cassio , Villanueva Boris Stefan , Zuluaga Alejandro , Chase Mark W. , Fay Michael F. , Condamine Fabien L. , Forest Felix , Nargar Katharina , Renner Susanne S. , Baker William J. , Antonelli Alexandre
Published: September 2023

⍰ Orchids constitute one of the most spectacular radiations of flowering plants. However, their geographical origin, historical spread across the globe, and hotspots of speciation remain uncertain due to the lack of a broad phylogenomic framework.

⍰ We present a new Orchidaceae phylogeny based on high-throughput and Sanger sequencing datasets, covering all five subfamilies, 17/22 tribes, 40/49 subtribes, 285/736 genera, and ∼7% (1,921) of the currently 29,524 accepted species. We then use it to infer geographic range evolution, diversity, and speciation patterns by adding curated geographical distribution data through the World Checklist of Vascular Plants.

⍰ Orchid’s most recent common ancestor is traced back to the Late Cretaceous in Laurasia. The modern Southeast Asian range of subfamily Apostasioideae is interpreted as relictual, matching the history of numerous clades that went extinct at higher latitudes following the global climate cooled during the Oligocene. Despite their ancient origins, modern orchid species’ diversity mainly originated over the last 5 Ma, with the fastest speciation rates found in south-eastern Central America.

⍰ Our results substantially alter our understanding of the geographic origin of orchids, previously proposed as Australian, and further pinpoint the role of Central American as a region of recent and explosive speciation.
Hierarchical heuristic species delimitation under the multispecies coalescent model with migration
Authors: Kornai Daniel , Flouri Tomáš , Yang Ziheng
Published: September 2023

The multispecies coalescent (MSC) model accommodates genealogical fluctuations across the genome and provides a natural framework for comparative analysis of genomic sequence data to infer the history of species divergence and gene flow. Given a set of populations, hypotheses of species delimitation (and species phylogeny) may be formulated as instances of MSC models (e.g., MSC for one species versus MSC for two species) and compared using Bayesian model selection. This approach, implemented in the programbpp, has been found to be prone to over-splitting. Alternatively heuristic criteria based on population parameters under the MSC model (such as population/species divergence times, population sizes, and migration rates) estimated from genomic sequence data may be used to delimit species. Here we extend the approach of species delimitation using the genealogical divergence index (gdi) to develop hierarchical merge and split algorithms for heuristic species delimitation, and implement them in a python pipeline calledhhsd. Applied to data simulated under a model of isolation by distance, the approach was able to recover the correct species delimitation, whereas model comparison bybppfailed. Analyses of empirical datasets suggest that the procedure may be less prone to over-splitting. We discuss possible strategies for accommodating paraphyletic species in the procedure, as well as the challenges of species delimitation based on heuristic criteria.
Knockout of the longevity gene Klotho perturbs aging- and Alzheimer’s disease-linked brain microRNAs and tRNA fragments
Authors: Dubnov Serafima , Yayon Nadav , Yakov Or , Bennett David A. , Seshadri Sudha , Mufson Elliott , Tzur Yonat , Bennet Estelle R. , Greenberg David , Kuro-o Makoto , Paldor Iddo , Abraham Carmela R. , Soreq Hermona
Published: September 2023

Introductory paragraph

Overexpression of the longevity gene Klotho prolongs, while its knockout shortens lifespan and impairs cognition via altered fibroblast growth factor signaling that perturbs myelination and synapse formation; however, comprehensive analysis of Klotho’s knockout consequences on mammalian brain transcriptomics is lacking. Here, we report the altered levels under Klotho knockout of 1059 long RNAs, 27 microRNAs (miRs) and 6 tRNA fragments (tRFs), reflecting effects upon aging and cognition. Perturbed transcripts included key neuronal and glial pathway regulators that are notably changed in murine models of aging and Alzheimer’s Disease (AD) and in corresponding human post-mortem brain tissue. To seek cell type distributions of the affected short RNAs, we isolated and FACS-sorted neurons and microglia from live human brain tissue, yielding detailed cell type-specific short RNA-seq datasets. Together, our findings revealed multiple Klotho deficiency-perturbed aging- and neurodegeneration-related long and short RNA transcripts in both neurons and glia from murine and human brain.
Enhanced Omicron subvariant cross-neutralization efficacy of a monovalent SARS-CoV-2 BA.4/5 mRNA vaccine encoding a noncleaved, nonfusogenic spike antigen
Authors: Seo Han Young , Jung Haewon , Woo Hawon , Jung Hae-Gwang , Cho Hee , Bak Yeonju , Lee Se-Young , Son Yu-Min , Yoon Gone , Hwang Seo-Yeon , Park Inho , Shin Jeon-Soo , Oh Jong-Won
Published: September 2023

The rapid emergence of diverse SARS-CoV-2 variants, notably the Omicron variant, poses challenges to vaccine development. Here, we present a noncleaved, nonfusogenic spike (S) protein eliciting robust B- and T-cell immune responses against Omicron BA.5. The antigen incorporates the R685S and R815A mutations, effectively preventing the shedding of the S1 subunit and eliminating fusogenic activity of the resulting S antigen, termed S(SA). Through reverse genetic analysis, we found that the noncleaved form S protein with the R685S mutation enhances ACE2-dependent viral entry in vitro compared to the wild-type S protein, without increasing the virulence of the mutant virus in mice. The mRNA vaccine encoding the Omicron BA.4/5 S(SA) antigen conferred protective immunity in mice following two doses of 1 μg Ψ-UTP- or UTP-incorporated mRNA vaccines. Despite a roughly 6-fold reduction in neutralizing potency, both mRNA vaccines exhibited broad neutralizing efficacy against Omicron subvariants, including the XBB lineage variants XBB.1.5 and XBB.1.16.
Influence of open-source virtual-reality based gaze training on navigation performance in Retinitis pigmentosa patients in a crossover randomized controlled trial
Authors: Neugebauer Alexander , Sipatchin Alexandra , Stingl Katarina , Ivanov Iliya , Wahl Siegfried
Published: September 2023

Motivation

People living with tunnel vision caused by Retinitis pigmentosa (RP) oftentimes face challenges navigating and avoiding obstacles due to a severely decreased Visual Field. Previous studies have shown that gaze training – guided tasks to encourage specific gaze behavior – help improve visual performance in patients with limited Visual Field. We propose a Virtual-Reality based, at-home gaze training – to the best of our knowledge the first of its kind – to increase effective eye movements and navigation performance of RP patients in a real-world obstacle course.

Methods

A group of RP patients (n=8) participated in a study consisting of two 4-week-phases, both carried out by the same patient group in randomized order: In the ‘training phase’, participants carried out a Virtual-Reality gaze training for 30 minutes per day; In the ‘control phase’, no training occurred. Before and after each phase, participants were tasked to move through a randomized real-world obstacle course. Navigation performance in the obstacle course as well as eye-tracking data during the trials were evaluated. The study is registered at the German Clinical Trials Register (DRKS) with the ID DRKS00032628.

Results

On average, the time required to move through the obstacle course decreased by 17.0% after the training phase (p <0.001), the number of collisions decreased by 50.0% (p <0.001) and the average visual area observed by participants increased by 4.41% (p <0.001). In comparison, after the control phase, the time required to move through the obstacle course was found to have decreased by 5.9% (p= 0.003), collisions decreased by 10.4% (p= 0.609) and the observed visual area increased by 2.06% (p= 0.0835).

Conclusion

The performance increase over the training phase significantly surpasses the natural learning effect found in the control phase, suggesting that Virtual-Reality based gaze training can improve real-world navigation performance and effective gaze movements of patients with RP. The training is available as work-in-progress open-source software.
Parental Perceptions of Early Childhood Research with In-Home Monitoring: A Qualitative Study
Authors: Smith Gabriella B. , Jones Mickayla D. , Akel Mary J. , Barrera Leonardo , Heffernan Marie , Seed Patrick C. , Macy Michelle L. , Fisher Stephanie A. , Mithal Leena B.
Published: September 2023

Background

Despite growing interest in novel approaches to measure home environmental effects on the developing child (the exposome), parental perceptions remain poorly understood. Parents’ perspectives are important for building trust, assessing feasibility, and increasing participation in research that includes home monitoring technologies. We aimed to explore parents’ perceptions regarding these topics.

Methods

A diverse group of new and expecting mothers participated in semi-structured interviews. A single interviewer conducted all sessions and introduced a hypothetical longitudinal observational early childhood home-based research study including novel home monitoring approaches: 1) wearable devices, 2) audio monitoring, and 3) environmental sampling. Interviews were audio-recorded, transcribed, and coded. A constant comparative approach identified themes from transcripts.

Results

Twenty-four interviews were completed. Emerging themes included 1) Positive Perceptions; 2) Incentives; 3) Transparency and Purpose; 4) Privacy and Safety Concerns; and 5) Logistics and Feasibility. Perceptions were similar across racial, ethnic, and socioeconomic groups. Overall perceptions were positive with several central motivators for hypothetical participation. Participants desired additional information related to feasibility and the purpose of studies. Many had concerns related to wearable device safety and data privacy; a trusting relationship with the research team was a priority.

Conclusion

Many participants had positive sentiments regarding longitudinal observational studies involving pregnancy and infancy with various incentives, yet they expressed concerns about safety, privacy, feasibility, and transparency. These findings can inform future perinatal and early childhood research study design, particularly those that novel home monitoring approaches, to ensure protocols and communication are transparent, inclusive, and appealing to parents.
Flow-mediated dilatation: learning curve study with a novice operator
Authors: Dhar Arko S. , Fisk Marie , McEniery Carmel M. , Cseh Domonkos
Published: September 2023

Introduction

Brachial artery flow-mediated dilatation (FMD) is commonly measured to assess endothelial function in experimental and clinical research studies. However, attaining reproducible results can be challenging, especially among inexperienced operators. Until now, no detailed learning curve study of novice operators has been published.

Methods

We assessed the learning curve of FMD measurement in one novice operator. Following a one-week basic training period, the operator performed duplicate measurements on 6-8 individuals per week, for six weeks. The operator followed the recommendations of the most recent FMD measurement guideline. Duplex ultrasound was used for the simultaneous and continuous measurement of brachial artery diameter and local blood flow velocity. Following a 1-minute recording of baseline diameter (D), FMD was measured after a 5-minute period of occlusion of the proximal forearm vessels. Inter-session coefficient of variation (CV) values for D and FMD were calculated for each week.

Results

The majority of participants did not have any cardiovascular disease history. The number of volunteers assessed each week were the following: 8, 7, 7, 6, 7, 7 individuals, from week 1 to week 6. CV values for both D and FMD exhibited a decreasing trend over the training period, ending at 1.73% for D and 14.24% for FMD at week 6. The CV values at week 6 were within the range outlined in the most recent FMD guideline for proficiency.

Conclusions

Within a reasonable timeframe, and with careful adherence to measurement guidelines, the attainment of sound reproducibility in FMD measurements by a novice operator is feasible.
Glycemic outcomes of a family-focused intervention for adults with type 2 diabetes: Main, mediated, and subgroup effects from the FAMS 2.0 RCT
Authors: Nelson Lyndsay A. , Spieker Andrew J. , Greevy Robert A. , Roddy McKenzie K. , LeStourgeon Lauren M. , Bergner Erin M. , El-Rifai Merna , Aikens James E. , Wolever Ruth Q. , Elasy Tom A. , Mayberry Lindsay S.
Published: September 2023

Aims

Family/friends Activation to Motivate Self-care (FAMS) is a self-care support intervention delivered via mobile phones. We evaluated FAMS effects on hemoglobin A1c (HbA1c) and intervention targets among adults with type 2 diabetes in a 15-month RCT.

Methods

Persons with diabetes (PWDs) and their support persons (family/friend, optional) were randomized to FAMS or control. FAMS included monthly phone coaching and text messages for PWDs, and text messages for support persons over a 9-month intervention period.

Results

PWDs (N=329) were 52% male, 39% from minoritized racial or ethnic groups, with mean HbA1c 8.6±1.7%. FAMS improved HbA1c among PWDs with a non-cohabitating support person (−0.64%; 95% CI [-1.22%, −0.05%]), but overall effects were not significant. FAMS improved intervention targets including self-efficacy, dietary behavior, and family/friend involvement during the intervention period; these improvements mediated post-intervention HbA1c improvements (total indirect effect −0.27%; 95% CI [-0.49%, −0.09%]) and sustained HbA1c improvements at 12 months (total indirect effect −0.19%; 95% CI [−0.40%, −0.01%]).

Conclusions

Despite improvements in most intervention targets, HbA1c improved only among PWDs engaging non-cohabitating support persons suggesting future family interventions should emphasize inclusion of these relationships. Future work should also seek to identify intervention targets that mediate improvements in HbA1c.
Well-being outcomes of a family-focused intervention for persons with type 2 diabetes and support persons: Main, mediated, and subgroup effects from the FAMS 2.0 RCT
Authors: Roddy McKenzie K. , Spieker Andrew J. , Nelson Lyndsay A , Greevy Robert A. , LeStourgeon Lauren M. , Bergner Erin M. , El-Rifai Merna , Elasy Tom A. , Aikens James E. , Wolever Ruth Q. , Mayberry Lindsay S.
Published: September 2023

Aims

Type 2 diabetes self-management occurs within social contexts. We sought to test the effects of Family/friends Activation to Motivate Self-care (FAMS), a self-care support intervention delivered via mobile phones, on psychosocial outcomes for persons with diabetes (PWDs) and their support persons.

Methods

PWDs had the option to enroll with a friend/family member as a support person in a 15-month RCT to evaluate FAMS versus enhanced usual care. FAMS included 9-months of monthly phone coaching and text message support for PWDs, and text message support for enrolled support persons.

Results

PWDs (N=329) were 52% male and 39% from minoritized racial or ethnic groups; 50% enrolled with elevated diabetes distress. Support persons (N=294) were 26% male and 33% minoritized racial or ethnic groups. FAMS improved PWDs’ diabetes distress (d=-0.19) and global well-being (d=0.21) during the intervention, with patterns of larger effects among minoritized groups. Post-intervention and sustained (15-month) improvements were driven by changes in PWDs’ self-efficacy, self-care behaviors, and autonomy support. Among support persons, FAMS improved helpful involvement without increasing burden or harmful involvement.

Conclusions

FAMS improved PWDs’ psychosocial well-being, with post-intervention and sustained improvements driven by improved self-efficacy, self-care, and autonomy support. Support persons increased helpful involvement without adverse effects.
Incidence of and Risk Factors for New-Onset Urinary and Fecal Incontinence After Acute Stroke
Authors: Cruz Enrique , Wells Yvonne , Miller Charne , Lannin Natasha A. , Cloud Geoffrey C.
Published: September 2023

Background and Purpose

Understanding the risk factors for incontinence after acute stroke allows for early identification and treatment of patients who are likely to experience this complication. This study estimates incidence of urinary and fecal incontinence (UI and FI) after stroke in adults and examines the association of risk factors.

Methods

Screening data of a prospective study were analyzed. Included were 652 consecutive patients admitted to an acute stroke unit over a 15-month period beginning May 2021. Those with pre-existing UI or FI were excluded from the analysis. Bivariate analyses examined unadjusted relationships between both UI and FI and age, sex, stroke severity, premorbid disability, stroke type, and stroke anatomical site. Regression analyses were performed to build iterative models.

Results

A total of 418 patients had an acute stroke without pre-existing incontinence. The median age of stroke survivors was 76 years (IQR66-84), 58% were men, and 76% had an ischemic stroke. Within the first 7 days after stroke, 128 (29%) had UI and 115 (26%) had FI. Increasing age, premorbid disability, and stroke severity increased the risk of both new-onset UI and FI after stroke. Those with intraventricular hemorrhage were 2.9 times more likely to develop UI. Women were 1.7 times more likely to have UI after stroke than men. Intraventricular hemorrhage increased the risk of new-onset FI after stroke by 2.9 times, while lobar hemorrhage increased the risk by 2.2 times.

Conclusions

Urinary and fecal incontinence continue to be relatively common after acute stroke, although incidence rates are lower than 20th century estimates. Patients are more likely to require incontinence assessment, monitoring and care if they are older, had higher premorbid disability, and have experienced more severe stroke or intraventricular hemorrhage. Provision of continence care and rehabilitation remain essential components of stroke services.