bluuebunny/crossref_metadata_2025 huggingface dataset:
Wellness Opportunities for Migrant Beginnings, Kansas City, Missouri
Authors: Sekhon Subhjit , Smith Lucy , Morales Pedro
Published: May 2023

OBJECTIVE:

To create a collaboration among health care professionals and community organizers to advance health equity and increase access to high-quality perinatal health care for Afghan refugees.

PROJECT SUMMARY:

This project was developed to create relationships among the health care industry, community partners, and nonprofit organizations to improve the perinatal health status of the refugee population of Kansas City, Missouri. Meetings were held among leaders of three medical systems (Samuel U. Rodgers Clinic, Swope Health, and University Health) and the two major resettlement agencies (Della Lamb and Jewish Vocational Services) to discuss barriers to care. These included communication, coordination of care, time limitations, and misunderstandings of the system. The following focus areas were identified, and interventions then were implemented:

1. Education

 a. Seminars for health care professionals regarding specific perinatal health care needs

 b. Tours and classes for refugees during which they were introduced to the facility, including labor and delivery, and prenatal, antenatal, and postpartum care

2. Communication

 a. Medical passports for patients to better facilitate perinatal care among organizations, because all facilities provide care but deliveries occur only at University Health

3. Research

 a. Performing surveillance activities and disseminating findings to aid other communities

 The project is now expanding to include all refugee populations in the Kansas City area. Regular meetings are held quarterly with community leaders for continued quality improvement.

OUTCOME:

Primary outcomes focus on our refugee patients: increased patient autonomy, adherence to prenatal and postpartum visits, and developing trust in the system. Secondary outcomes include improved communication between clinics and resettlement agencies and improved cultural awareness among obstetric care professionals.

RELEVANCE TO WOMEN'S HEALTH:

Equity in perinatal care requires individualized services when serving a diverse population. Refugees in particular have a unique perspective and unique needs. Through collaboration, we were able to improve the health status of the most vulnerable members of our community.
Addressing Adverse Childhood and Adult Experiences During Prenatal Care
Authors: Johnson Sara , Kasparian Nadine A. , Cullum Arlene S. , Flanagan Tracy , Ponting Carolyn , Kowalewski Leslie , Main Elliott K.
Published: May 2023

Adverse childhood and adult experiences can affect health outcomes throughout life and across generations. The perinatal period offers a critical opportunity for obstetric clinicians to partner with patients to provide support and improve outcomes. This article draws on stakeholder input, expert opinion, and available evidence to provide recommendations for obstetric clinicians' inquiry about and response to pregnant patients' past and present adversity and trauma during prenatal care encounters. Trauma-informed care is a universal intervention that can proactively address adversity and trauma and support healing, even if a patient does not explicitly disclose past or present adversity. Inquiry about past and present adversity and trauma provides an avenue to offer support and to create individualized care plans. Preparatory steps to adopting a trauma-informed approach to prenatal care include initiating education and training for practice staff, prioritizing addressing racism and health disparities, and establishing patient safety and trust. Inquiry about adversity and trauma, as well as resilience factors, can be implemented gradually over time through open-ended questions, structured survey measures, or a combination of both techniques. A range of evidence-based educational resources, prevention and intervention programs, and community-based initiatives can be included within individualized care plans to improve perinatal health outcomes. These practices will be further developed and improved by increased clinical training and research, as well as through broad adoption of a trauma-informed approach and collaboration across specialty areas.
Efficacy of the combination of tadalafil and tamsulosin versus tadalafil alone as a medical expulsive therapy for stone L1/3 ureter 10 mm or less: A prospective comparative placebo-controlled study
Authors: Reda Ahmed , Kamel Mostafa , Loay Mohamed , Abdelsalam Yaser M. , Zarzour Mohamed A.
Published: May 2023

Background

The lifetime occurrence of urinary stones is approximately 1%–15%, and the peak age of occurrence is 30 years. Approximately one fifths of urinary tract stones are found in the ureter, of which two thirds are in the distal ureter. Many drugs, including phosphodiesterase-5 inhibitors (PDE5Is) and α-blockers, are used to relax the smooth muscles in medical expulsive therapy (MET). We aimed to compare the combination of tadalafil and tamsulosin versus tadalafil alone as MET for stones in the L1/3 ureter of 10 mm or less.

Materials and methods

A total of 150 patients with L1/3 ureteric stones measuring 10 mm or less were enrolled in the study and randomly assigned to one of 3 equal groups using a computer-generated random number. Patients in group A prescribed tadalafil 10 mg/d. However, those in group B were prescribed tamsulosin 0.4 mg and tadalafil 10 mg/d, whereas those in group C received a placebo once daily. Stone expulsion rate and pain recurrence were evaluated after 14 days.

Results

The stone expulsion rate was significantly higher in the tadalafil and tamsulosin groups and the tamsulosin group than in the placebo group in the current study by 68% in the combination group, 64% in the tadalafil alone group, and 42% in the placebo group (p = 0.019). In the current study, a combination was associated with lower pain recurrence than tadalafil alone or placebo, with means of 1.06, 1.9, 2.98 (with a p value of 0.001). Stone size was not effective in any group.

Conclusions

The combination of PDE5Is and α-blockers effectively increases the expulsion of lower ureteric stones (5–10 mm), but with the same effect as PDE5Is alone, with the advantage of decreasing pain recurrence. Stone size did not affect the expulsion rate in patients who received MET for stones less than 1 cm in size.
The Prognostic Effect of IKZF1 Deletions in ETV6::RUNX1 and High Hyperdiploid Childhood Acute Lymphoblastic Leukemia
Authors: Østergaard Anna , Enshaei Amir , Pieters Rob , Vora Ajay , Horstmann Martin A. , Escherich Gabriele , Johansson Bertil , Heyman Mats , Schmiegelow Kjeld , Hoogerbrugge Peter M. , den Boer Monique L. , Kuiper Roland P. , Moorman Anthony V. , Boer Judith M. , van Leeuwen Frank N.
Published: May 2023

IKZF1 deletions are an established prognostic factor in childhood acute lymphoblastic leukemia (ALL). However, their relevance in patients with good risk genetics, namely ETV6::RUNX1 and high hyperdiploid (HeH), ALL remains unclear. We assessed the prognostic impact of IKZF1 deletions in 939 ETV6::RUNX1 and 968 HeH ALL patients by evaluating data from 16 trials from 9 study groups. Only 3% of ETV6::RUNX1 cases (n = 26) were IKZF1-deleted; this adversely affected survival combining all trials (5-year event-free survival [EFS], 79% versus 92%; P = 0.02). No relapses occurred among the 14 patients with an IKZF1 deletion treated on a minimal residual disease (MRD)-guided protocols. Nine percent of HeH cases (n = 85) had an IKZF1 deletion; this adversely affected survival in all trials (5-year EFS, 76% versus 89%; P = 0.006) and in MRD-guided protocols (73% versus 88%; P = 0.004). HeH cases with an IKZF1 deletion had significantly higher end of induction MRD values (P = 0.03). Multivariate Cox regression showed that IKZF1 deletions negatively affected survival independent of sex, age, and white blood cell count at diagnosis in HeH ALL (hazard ratio of relapse rate [95% confidence interval]: 2.48 [1.32-4.66]). There was no evidence to suggest that IKZF1 deletions affected outcome in the small number of ETV6::RUNX1 cases in MRD-guided protocols but that they are related to higher MRD values, higher relapse, and lower survival rates in HeH ALL. Future trials are needed to study whether stratifying by MRD is adequate for HeH patients or additional risk stratification is necessary.
The Role of Interleukin 6 in Substance Use Disorder Treatment Failure
Authors: Techau Aimee
Published: May 2023

Substance use disorders (SUDs) are often misunderstood as a reflection of an individual's lack of motivation or willpower or as a moral failing. SUDs are complex and require a biopsychosocial lens to understand the phenomenon, particularly treatment failure, which is described as a deficit in patients' willpower/self-regulation or dedication to managing their condition.

Recent evidence has implicated inflammatory cytokines such as interleukin 6 (IL-6) in the action of substance use by impairing executive functioning, which is an essential aspect of self-regulatory control. Emerging research indicates that inflammation may also shape social behavior, including social withdrawal and approach, thus having potential implications on health-seeking and health-sustaining behaviors often interpreted as a dedication to managing health conditions.

The aim of this two-part biobehavioral synthesis is to (a) examine the scientific evidence of the role of IL-6 in self-regulatory failure, (b) explore IL-6 as a common inflammatory mechanism across SUDs, and (c) investigate the role of IL-6 in social withdrawal and approach to gain an understanding of how this determinant may impact treatment failure.

Overall, the evidence supports a new paradigm of treatment failure that stresses the influence of IL-6 on self-regulatory failure by way of dual cognitive processing and the role of IL-6 in shaping social behavior central to health-seeking and health-sustaining behaviors. This discovery will help to minimize stigma and blame. Understanding the role of IL-6 in treatment failure may elucidate novel targets for intervention, improve treatment outcomes, and break the social disconnection cycle often seen in SUDs.
The Combined Effect of Delirium and Falls on Length of Stay and Discharge
Authors: Kalivas Benjamin , Zhang Jingwen , Harper Kristine , Dulin Jennifer , Heincelman Marc , Marsden Justin , Hunt Kelly J. , Mauldin Patrick D. , Moran William P. , Thomas Meghan K.
Published: May 2023

Introduction:

Delirium or a fall are associated with many negative outcomes including increased length of stay (LOS) and discharge to a facility; however, this relationship is incompletely understood.

Methods:

A cross-sectional study of all hospitalizations in a large, tertiary care hospital evaluated the effect of delirium and a fall on the outcomes of LOS and risk of being discharged to a facility.

Results:

The study included 29,655 hospital admissions. A total of 3,707 (12.5%) patients screened positive for delirium and 286 (0.96%) had a reported fall. After adjustment for covariates, relative to patients without delirium or a fall, patients with delirium only had a 1.64-fold longer LOS; patients with fall only had a 1.96-fold longer LOS; and patients who had delirium and fall had a 2.84-fold longer LOS. The adjusted odds of discharge to a facility, relative to those without delirium or a fall, was 8.98 times higher in those with delirium and a fall.

Conclusions:

Delirium and falls influence LOS and likelihood of being discharged to a facility. The joint impact of falls and delirium on LOS and facility discharge was more than additive. Hospitals should consider the integrated management of delirium and falls.
Apathy Among Persons Living With HIV Is Associated With Lower Self-efficacy for Health Care Provider Interactions
Authors: Babicz Michelle A. , Matchanova Anastasia , Woods Steven Paul
Published: May 2023

Apathy is common in persons with HIV (PWH) and has been associated with a variety of health outcomes. We examined the association between apathy and self-efficacy for health care provider interactions in 142 PWH. A composite score comprised of the apathy subscale of the Frontal Systems Behavioral Scale and the vigor-activation scale of the Profile of Mood States was used to measure apathy. Self-efficacy for health care provider interactions was measured using the Beliefs Related to Medication Adherence – Dealing with Health Professional subscale. Higher levels of apathy were associated with lower self-efficacy for health care provider interactions at a medium effect size, independent of mood disorders, health literacy, and neurocognition. Findings suggest that apathy plays a unique role in self-efficacy for health care provider interactions and support the importance of assessment and management of apathy to maximize health outcomes among PWH.
Experiences of nurse practitioners working during the COVID-19 pandemic: A metasynthesis of qualitative studies
Authors: Twist Ida Laura , Moxham Lorna , Tillott Sarah , Fernandez Ritin
Published: May 2023

Background:

The impact of the COVID-19 pandemic forced global changes to how nurses practice. Nurse practitioners adjusted their scope, changed how they delivered their service, and worked with limited resources. For some services, patient access was also compromised.

Objectives:

To synthesize, combine, and present current evidence on the experiences of nurse practitioners working during the COVID-19 pandemic.

Data sources:

CINAHL, Embase, and MEDLINE electronic databases were used to perform a structured search strategy.

Conclusion:

During the COVID-19 pandemic, health care services had to leverage their workforce skills to accelerate COVID-19 identification, treatment, and care. Nurse practitioners rapidly found themselves at the forefront and were concerned about infecting others. They also identified the need for support and were able to adapt to the changing environment. Nurse practitioners also recognized the impact on their well-being. Having insight into nurse practitioner's experiences during the pandemic is valuable for future health care workforce planning. Understanding how they coped will help with critical preparedness and response actions to other health care crises.

Implications for practice:

Having insight into nurse practitioner's experiences during the pandemic is valuable for future health care workforce planning because, as we know, the nurse practitioner workforce is one of the most rapidly growing professions in primary health care. Any future work in this space will help inform future nurse practitioner education and also help by informing critical preparedness and response actions to future health care crises, whether global or local or clinical or nonclinical.
Education standards, accreditation, certification, and regulation of nurse practitioner practice
Authors: Savin Michele K. , Newberry Desi M.
Published: May 2023

Many organizations play a role in creating, supporting, clarifying, and certifying the foundational documents for nurse practitioner (NP) education and practice. Quality standards for NP education are promulgated by the American Association of Colleges of Nursing (AACN) and the National Organization of Nurse Practitioner Faculties (NONPF). Competency-based education, in the form of interactive learning, helps bridge the gap between theory and practice. In 2021, AACN released new competencies that correspond to 10 domains which reflect the uniqueness of the nursing profession and guide professional nursing education. The NONPF and AACN are co-facilitators of a multi-organizational group called the National Task Force (NTF) on quality nurse practitioner education that standardizes the general evaluation of NP education. In 2022, the NTF updated the evaluation standards in response to the new competencies. Schools are accredited by one of three agencies: The Commission on Collegiate Nursing Education, The Accreditation Commission for Education in Nursing, and The National League for Nursing Commission for Nursing Education Accreditation. The eight NP specialties each have their own certifying bodies. The National Council of State Boards of Nursing is involved in regulation of NPs. The purpose of this article is to update stakeholders, including NPs, preceptors, and nurse faculty, about the various agencies and guidelines that inform education standards, accreditation, certification, and regulation of NP practice. A review of recently published guidelines with a summary of implications is also presented.
Great debates in trauma biomechanics
Authors: Glatt Vaida , O'Toole Robert , Mehta Samir , Kandemir Utku , Ricci William , Nauth Aaron , Schemitsch Emil , Hast Michael W.
Published: May 2023

At the 2021 annual meeting of the Orthopaedic Trauma Association, the Basic Science Focus Forum hosted its first ever debate-style symposium focused on biomechanics and fracture repair. The 3 subjects of debate were “Mechanics versus Biology—Which is ‘More Important’ to Consider?” “Locked Plate versus Forward Dynamization versus Reverse Dynamization—Which Way Should I Go?” and “Sawbones versus Cadaver Models—What Should I Believe Most?” These debates were held because fracture healing is a highly organized synergistic response between biological factors and the local mechanical environment. Multiple studies have demonstrated that both factors play roles in governing bone healing responses, and the causal relationships between the 2 remain unclear. The lack of clarity in this space has led to a spectrum of research with the common goal of helping surgeons make good decisions. Before reading further, the reader should understand that the questions posed in the debate titles are unanswerable and might represent a false choice. Instead, the reader should appreciate that the debates were held to gain a more thorough understanding of these topics based on the current state of the art of experimental and clinical studies, by using an engaging and thought-provoking format.
Orthopaedic infections: what have we learned?
Authors: Lee Christopher , Mayer Erik , Bernthal Nicholas , Wenke Joseph , O'Toole Robert V.
Published: May 2023

Orthopaedic infections remain challenging complications to treat, with profound economic impact in addition to patient morbidity. The overall estimates of infection after orthopaedic surgery with internal devices has been estimated at 5%, with hospital costs eight times that of those without fracture-related infections and with significantly poorer functional and pain interference PROMIS scores. Orthopaedic infection interventions have been focused on prevention and treatment options. The creation of new modalities for orthopaedic infection treatment can benefit from the understanding of the temporal relationship between bacterial colonization and host–cell integration, a concept referred to as “the race for the surface.” Regarding prevention, host modulation and antibiotic powder use have been explored as viable options to lower infection rates. Orthopaedic infection treatment has additionally continued to evolve, with PO antibiotics demonstrating equivalent efficacy to IV antibiotics for the treatment of orthopaedic infections in recent studies. In conclusion, orthopaedic infections remain difficult clinical dilemmas, although evolving prevention and treatment modalities continue to emerge.
Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) birth cohort: study protocol
Authors: Kicic-Starcevich Elizabeth , Hancock David G , Iosifidis Thomas , Agudelo-Romero Patricia , Caparros-Martin Jose A , Silva Desiree , Turkovic Lidija , Le Souef Peter N , Bosco Anthony , Martino David J , Kicic Anthony , Prescott Susan L , Stick Stephen M
Published: May 2023

Introduction

Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities,in uteroexposures, and respiratory exposures in the first year of life.

Methods and Analysis

The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to five years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to six weeks, one, three, and five years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities andin uteroexposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal sampling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses.

Ethics and Dissemination

Ethical approval has been obtained from Ramsey Health Care HREC WA-SA (#1908). Results will be disseminated through open-access peer-reviewed manuscripts, conference presentations, and through different media channels to consumers, ORIGINS families, and the wider community.
ESKtides: a comprehensive database and mining method for ESKAPE-derived peptides
Authors: Li David Runze , Wu Hongfang , Zou Geng , Li Xuejian , Zhang Yue , Zhou Yang , Chen Huanchun , Li Jinquan
Published: May 2023

Under the concept of one health, Super-drug resistant bacteria are getting more and more attention from scientists, in particular, ESKAPE bacteria directly killed more than 1,270,000 people in 2019. Recent studies have proposed that phage PGHs(peptidoglycan hydrolases) and antimicrobial peptides can be the new antibacterial agents against multi-drug resistant bacteria. However, Methods for mining antimicrobial peptides based on phages or phages PGHs are in need to develop. Here, using ESKAPE strains and ESKAPE phages in total of 6,809 samples from National Center for Biotechnology Information (NCBI), PhagesDB, Microbe Versus Phage (MVP) and Virus-Host Database, we systematically identified PGHs across ESKAPE strains prophages and phages, mined peptides and scored peptides based on PGHs. As a result, a total of 1,000 high antibacterial activity peptides and 1,200 medium antibacterial activity peptides were identified. In order to reduce the impact of different methods on comments, we used a unified process to comment ESKAPE strains and phages. In addition, we designed an online tool to predict the peptides antibacterial activity. Calculations of peptides phylogeny, peptides physicochemical property and peptides secondary structure are also included into our online tools. Finally, we developed ESKtides, a user-friendly and intuitive database (http://www.phageonehealth.cn:9000/ESKtides) for data browsing, searching, and downloading. ESKtides will significantly provide a rich peptide library based on ESKAPE strains and phages.
Estimating the proportion of beneficial mutations that are not adaptive in mammals
Authors: Latrille Thibault , Joseph Julien , Hartasanchez Diego A. , Salamin Nicolas
Published: May 2023

Mutations can be beneficial by bringing innovation to their bearer, allowing them to adapt to environmental change. These mutations are typically unpredictable since they respond to an unforeseen change in the environment. However, mutations can also be beneficial because they are simply restoring a state of higher fitness that was lost due to genetic drift in a stable environment. In contrast to adaptive mutations, these beneficial non-adaptive mutations can be predicted if the underlying fitness landscape is stable and known. The contribution of such non-adaptive mutations to molecular evolution has been widely neglected mainly because their detection is very challenging. We have here reconstructed protein-coding-gene fitness landscapes shared between mammals, using mutation-selection models and a multi-species alignments across 87 mammals. These fitness landscapes have allowed us to predict the fitness effect of polymorphisms found in 28 mammalian populations. Using methods that quantify selection at the population level, we have confirmed that beneficial non-adaptive mutations are indeed positively selected in extant populations. Our work confirms that deleterious substitutions are accumulating in mammals and are being reverted, generating a balance in which genomes are damaged and restored simultaneously at different loci. We observe that beneficial non-adaptive mutations represent between 15% and 45% of all beneficial mutations in 24 of 28 populations analyzed, suggesting that a substantial part of ongoing positive selection is not driven solely by adaptation to environmental change in mammals.
VEGF-C overexpression in kidney progenitor cells is a model of renal lymphangiectasia
Authors: Donnan Michael D. , Deb Dilip K. , David Valentin , Quaggin Susan E.
Published: May 2023

Background

Lymphangiogenesis is believed to be a protective response in the setting of multiple forms of kidney injury and mitigates the progression of interstitial fibrosis. To augment this protective response, promoting kidney lymphangiogenesis is being investigated as a potential treatment to slow the progression of kidney disease.

As injury related lymphangiogenesis is driven by signaling from the receptor VEGFR-3 in response to the cognate growth factor VEGF-C released by tubular epithelial cells, this signaling pathway is a candidate for future kidney therapeutics. However, the consequences to kidney development and function to targeting this signaling pathway remains poorly defined.

Methods

We generated a new mouse model expressingVegf-Cunder regulation of the nephron progenitor Six2Cre driver strain (Six2Vegf-C). Mice underwent a detailed phenotypic evaluation. Whole kidneys were processed for histology and micro computed tomography 3-dimensional imaging.

Results

Six2Vegf-Cmice had reduced body weight and kidney function compared to littermate controls.Six2Vegf-Ckidneys demonstrated large peripelvic fluid filled lesions with distortion of the pelvicalcyceal system which progressed in severity with age. 3D imaging showed a 3-fold increase in total cortical vascular density. Histology confirmed a substantial increase in LYVE1+/PDPN+/VEGFR3+ lymphatic capillaries extending alongside EMCN+ peritubular capillaries. There was no change in EMCN+ peritubular capillary density.

Conclusions

Kidney lymphangiogenesis was robustly induced in theSix2Vegf-Cmice. There were no changes in peritubular blood capillary density despite these endothelial cells also expressing VEGFR-3. The model resulted in a severe cystic kidney phenotype that resembled a human condition termed renal lymphangiectasia. This study defines the vascular consequences of augmenting VEGF-C signaling during kidney development and provides new insight into a mimicker of human cystic kidney disease.
Plant inositol transport influences bacterial colonization phenotypes
Authors: O’Banion Bridget S. , Jones Piet , Demetros Alexander A. , Kelley Brittni R. , Wagner Andrew S. , Chen Jin-Gui , Muchero Wellington , Reynolds Todd B. , Jacobson Daniel , Lebeis Sarah L.
Published: May 2023

Plant microbiomes are assembled and modified through a complex milieu of biotic and abiotic factors. Despite dynamic and fluctuating contributing variables, specific host metabolites are consistently identified as important mediators of microbial interactions. We combine information from a large-scale metatranscriptomic dataset from natural poplar trees and experimental genetic manipulation assays in model Arabidopsis seedlings to converge on a conserved role for transport of the plant metabolitemyo-inositol in mediating host-microbe interactions. While microbial catabolism of this compound is often linked to increased host colonization, we identify motility phenotypes that occur independently of catabolism, suggesting that inositol may additionally serve as a eukaryotic-derived signaling molecule to modulate microbial activities. Our data suggests host control of this compound and resulting microbial behavior are important mechanisms at play surrounding the host metabolite inositol.
Inverse blebs operate as hydraulic pumps during mouse blastocyst formation
Authors: Schliffka Markus F. , Dumortier Julien G. , Pelzer Diane , Mukherjee Arghyadip , Maître Jean-Léon
Published: May 2023

During preimplantation development, mouse embryos form a fluid-filled lumen, which sets their first axis of symmetry1,2. Pressurized fluid breaks open cell-cell contacts and accumulates into pockets, which gradually coarsen into a single lumen3–5. During coarsening, the adhesive and contractile properties of cells are thought to guide intercellular fluid (IF) but what cell behavior may control fluid movements is unknown. Here, we report large fluid-filled spherical membrane intrusions called inverse blebs6,7growing into cells at adhesive contacts. At the onset of lumen coarsening, we observed hundreds of inverse blebs throughout the embryo, each dynamically filling with IF and retracting within a minute. We find that inverse blebs grow due to pressure build-up resulting from luminal fluid accumulation and cell-cell adhesion, which locally confines fluid. Inverse blebs then retract due to actomyosin contraction, which effectively redistributes fluid within the intercellular space. Importantly, inverse blebs show topological specificity and only occur at contacts between two cells, not at contacts formed by multiple cells, which essentially serve as fluid sinks. Manipulating the topology of the embryo reveals that, in the absence of sinks, inverse blebs pump fluid into one another in a futile cycle. We propose that inverse blebs operate as hydraulic pumps to promote luminal coarsening, thereby constituting an instrument used by cells to control fluid movement.
Natural and engineered isoforms of the inflammasome adaptor ASC form non-covalent, pH-responsive hydrogels
Authors: Gaspar-Morales Eduardo A. , Waterston Anthony , Diaz-Parga Pedro , Smith Ariell M. , Sadqi Mourad , Gopinath Arvind , Andresen Eguiluz Roberto C. , de Alba Eva
Published: May 2023

The protein ASC polymerizes into intricate filament networks to assemble the inflammasome, a filamentous multiprotein complex that triggers the inflammatory response. ASC carries two Death Domains integrally involved in protein self-association for filament assembly. We have leveraged this behavior to create non-covalent, pH-responsive hydrogels of full-length, folded ASC by carefully controlling the pH as a critical factor in the polymerization process. We show that natural variants of ASC (ASC isoforms) involved in inflammasome regulation also undergo hydrogelation. To further demonstrate this general capability, we engineered proteins inspired in the ASC structure that successfully form hydrogels. We analyzed the structural network of the natural and engineered protein hydrogels using transmission and scanning electron microscopy, and studied their viscoelastic behavior by shear rheology. Our results reveal one of the very few examples of hydrogels created by the self-assembly of globular proteins and domains in their native conformation and show that Death Domains can be used alone or as building blocks to engineer bioinspired hydrogels.
Computational and experimental hunt for expansion prone tandem CNG repeats in human genomes
Authors: Suroliya Varun , Uppili Bharathram , Kumar Manish , Jha Vineet , Srivastava Achal K , Faruq Mohammed
Published: May 2023

Introduction

Spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders. Tandem repeat expansion is the pathogenic mutation in most of SCA cases. The pathophysiology of SCAs is still not completely defined due to the lack of genetic mutation in around 50% of cases worldwide. These uncharacterized cases must be genetically diagnosed for a better understanding and future treatment purposes. In this study, we tried a combination of computational and experimental approaches to find out novel CNG repeat loci that may be associated with SCAs.

Methodology

We investigate the human reference genome (hg-37) to find out all the possible CNG repeats present in more than 3 continuous uninterrupted units and annotated their functional locations. For experiment purposes, we targeted 52 loci from exonic and UTR regions and screened them in our 100 control samples through fragment analysis to know their polymorphic status. All the highly polymorphic loci were further investigated in 100 patient samples to know any large repeat expansion.

Results

There are 15069 CNG repeat loci present in the human genome. After the examination of 52 loci in the control samples, 19 loci showed a highly polymorphic repeat pattern and were screened in patients. The 1000 genome different population data also suggested the polymorphic status in the available 15 loci data. From the GTEx database, 18 loci proposed the expression in the brain, suggesting any variation in these genes may cause neurological disorders.

Conclusion

We tried a different kind of approach to find out tandem repeat expansion mutation in a cost-effective manner. Although we were unable to identify any disease-causing mutation in our patient cohort recently, various studies from different populations of the world have vouched for the genetic changes in these genes like GLS, RAI1, GIPC1, and CNKSR2 resulted in neurological disorders. Moreover, publications on the same identified repeats in GIPC1 for OPMD and GLS for ataxia with developmental delay, confirm the hypothesis to evaluate these repeat loci in different populations and other neurological disorders to identify novel targets.
How well do models of visual cortex generalize to out of distribution samples?
Authors: Ren Yifei , Bashivan Pouya
Published: May 2023

Unit activity in particular deep neural networks (DNNs) are remarkably similar to the neuronal population responses to static images along the primate ventral visual cortex. Lin-ear combinations of DNN unit activities are widely used to build predictive models of neu-ronal activity in the visual cortex. Nevertheless, prediction performance in these models is often investigated on stimulus sets consisting of everyday objects under naturalistic set-tings. Recent work has revealed a generalization gap in how predicting neuronal responses to synthetically generated out-of-distribution (OOD) stimuli. Here, we investigated how the recent progress in improving DNNs’ object recognition generalization, as well as various DNN design choices such as architecture, learning algorithm, and datasets have impacted the generalization gap in neural predictivity. We came to a surprising conclusion that the performance on none of the common computer vision OOD object recognition benchmarks is predictive of OOD neural predictivity performance. Furthermore, we found that adver-sarially robust models often yield substantially higher generalization in neural predictivity, although the degree of robustness itself was not predictive of neural predictivity score. These results suggest that improving object recognition behavior on current benchmarks alone may not lead to more general models of neurons in the primate ventral visual cortex.
Externally provided rewards increase internal preference, but not as much as preferred ones without extrinsic rewards
Authors: Zhu Jianhong , Katahira Kentaro , Hirakawa Makoto , Nakao Takashi
Published: May 2023

It is well known that preferences are formed through choices, known as choice-induced preference change (CIPC). However, whether value learned through externally provided rewards influences the preferences formed through CIPC remains unclear. To address this issue, we used tasks for decision-making guided by reward provided by the external environment (externally guided decision-making; EDM) and for decision-making guided by one’s internal preference (internally guided decision-making; IDM). In the IDM task, we presented stimuli with learned value in the EDM and novel stimuli to examine whether the value in the EDM affects preferences. Stimuli reinforced by rewards given in the EDM were reflected in the IDM’s initial preference and further increased through CIPC in the IDM. However, such stimuli were not as strongly preferred as the most preferred novel stimulus in the IDM, indicating the superiority of intrinsically learned values (SIV). The underlying process of this phenomenon is discussed in terms of the fundamental self-hypothesis.

Author Summary

We make decisions based on internal value criteria, which are individual preferences, or based on external value criteria, which are the values learned from the external environment. Although it is known that values are learned in both types of decisions, is there a difference in the nature of these values? Our study uses simulation and fits human behavioral data to address this question. The results showed that stimuli that were learned to be highly valued because of external feedback became preferred in subsequent preference judgments. However, it is interesting to note that such stimuli were not chosen as much as stimuli that were preferred without influence from the external environment. This finding suggests that values formed through one’s own criteria have characteristics distinct from those formed through external environmental influence. Our findings promote an integrated understanding of the decision-making process.
A modified BCG with depletion of enzymes associated with peptidoglycan amidation induces enhanced protection against tuberculosis in mice
Authors: Shaku Moagi T. , Um Peter , Ocius Karl L. , Apostolos Alexis J. , Pires Marcos M. , Bishai William R. , Kana Bavesh D.
Published: May 2023

Mechanisms by whichMycobacterium tuberculosis(Mtb) evades pathogen recognition receptor activation during infection may offer insights for the development of improved tuberculosis (TB) vaccines. Whilst Mtb elicits NOD-2 activation through host recognition of its peptidoglycan-derived muramyl dipeptide (MDP), it masks the endogenous NOD-1 ligand through amidation of glutamate at the second position in peptidoglycan sidechains. As the current BCG vaccine is derived from pathogenic mycobacteria, a similar situation prevails. To alleviate this masking ability and to potentially improve efficacy of the BCG vaccine, we used CRISPRi to inhibit expression of the essential enzyme pair, MurT-GatD, implicated in amidation of peptidoglycan sidechains. We demonstrate that depletion of these enzymes results in reduced growth, cell wall defects, increased susceptibility to antibiotics and altered spatial localization of new peptidoglycan. In cell culture experiments, training of monocytes with this recombinant BCG yielded improved control of Mtb growth. In the murine model of TB infection, we demonstrate that depletion of MurT-GatD in BCG, resulting in unmasking of the D-glutamate diaminopimelate (iE-DAP) NOD-1 ligand, yields superior prevention of TB disease compared to the standard BCG vaccine. This work demonstrates the feasibility of gene regulation platforms such as CRISPRi to alter antigen presentation in BCG in a bespoke manner that tunes immunity towards more effective protection against TB disease.
Evoked Responses to Localized Sounds Suggest Linear Representation of Elevation in Human Auditory Cortex
Authors: Bialas Ole , Maess Burkhard , Schönwiesner Marc
Published: May 2023

The auditory system computes the position of a sound along each of the three spatial axes, azimuth, elevation and distance, from very different acoustical cues. The extraction of sound azimuth from binaural cues (differences in arrival time and intensity between the ears) is well understood, as is the representation of these binaural cues in the auditory cortex of different species. Sound elevation is computed from monaural spectral cues arising from direction-dependent filtering of the pinnae, head, and upper body. The cortical representation of these cues in humans is still debated. We have shown that the fMRI blood-oxigen level-dependent activity in small parts of auditory cortex relates monotonically to perceived sound elevation and tracks listeners internal adaptation to new spectral cues. Here we confirm the previously suggested cortical code with a different method that reflects neural activity rather than blood oxigenation (electroencephalography), show that elevation is represented relatively late in the cortex, with related activity peaking at about 400 ms after sound onset, and show that differences in sound elevation can be decoded from the electroencephalogram of listeners, particularely from those who can distinguish elevations well. We used an adaptation design to isolate elevation-specific brain responses from those to other features of the stimuli. These responses gradually increased with decreasing sound elevation, consistent with our previous fMRI findings and population rate code for sound elevation. The long latency as well as the topographical distribution of the elevation-specific brain response indicates the involvement of higher-level cognitive processes not present for binaural cue representation. The differences between brain responses to sounds at different elevations predicted the listeners sound localization accuracy, suggesting that these responses reflect perceived elevation. This is, to our knowledge, the first study that demonstrates the cortical encoding of sound elevation in humans with high-temporal resolution. Our results agree with previous findings from functional magnetic resonance imaging, providing strong support for the hypothesis that elevation is represented in a population-rate code. This represents a critical advance in our understanding of spatial auditory processing along a dimension that is still poorly understood.
Populating a Continent: Phylogenomics Reveal the Timing of Australian Frog Diversification
Authors: Brennan Ian G. , Lemmon Alan R. , Lemmon Emily Moriarty , Hoskin Conrad J. , Donnellan Stephen C. , Keogh J. Scott
Published: May 2023

The Australian continent’s size and isolation make it an ideal place for studying the accumulation and evolution of biodiversity. Long separated from the ancient supercontinent Gondwana, most of Australia’s plants and animals are unique and endemic, including the continent’s frogs. Australian frogs comprise a remarkable ecological and morphological diversity categorized into a small number of distantly related radiations. We present a phylogenomic hypothesis based on an exon-capture dataset that spans the main clades of Australian myobatrachoid, pelodryadid hyloid, and microhylid frogs. Our time-calibrated phylogenomic-scale phylogeny identifies great disparity in the relative ages of these groups which vary from Gondwanan relics to recent immigrants from Asia and include arguably the continent’s oldest living vertebrate radiation. This age stratification provides insight into the colonization of, and diversification on, the Australian continent through deep time, during periods of dramatic climatic and community changes. Contemporary Australian frog diversity highlights the adaptive capacity of anurans, particularly in response to heat and aridity, and explains why they are one of the continent’s most visible faunas.
Molecular choreography of primer synthesis by the eukaryotic Pol α-primase
Authors: Yuan Zuanning , Georgescu Roxana , Li Huilin , O’Donnell Michael E.
Published: May 2023

The eukaryotic polymerase α (Pol α) is a dual-function DNA polymerase/primase complex that synthesizes an RNA-DNA hybrid primer of 20-30 nucleotides for DNA replication. Pol α is composed of Pol1, Pol12, Primase 1 (Pri1), and Pri2, with Pol1 and Pri1 containing the DNA polymerase activity and RNA primase activity, respectively, whereas Pol12 and Pri2 serve a structural role. It has been unclear how Pol α hands over an RNA primer made by Pri1 to Pol1 for DNA primer extension, and how the primer length is defined, perhaps due to the difficulty in studying the highly mobile structure. Here we report a comprehensive cryo-EM analysis of the intact 4-subunit yeast Pol α in the apo, primer initiation, primer elongation, RNA primer hand-off from Pri1 to Pol1, and DNA extension states in a 3.5 Å - 5.6 Å resolution range. We found that Pol α is a three-lobed flexible structure. Pri2 functions as a flexible hinge that holds together the catalytic Pol1-core, and the noncatalytic Pol1 CTD that binds to Pol 12 to form a stable platform upon which the other components are organized. In the apo state, Pol1-core is sequestered on the Pol12−Pol1-CTD platform, and Pri1 is mobile perhaps in search of a template. Upon binding a ssDNA template, a large conformation change is induced that enables Pri1 to perform RNA synthesis, and positions Pol1-core to accept the future RNA primed site 50 Å upstream of where Pri1 binds. We reveal in detail the critical point at which Pol1-core takes over the 3’-end of the RNA from Pri1. DNA primer extension appears limited by the spiral motion of Pol1-core while Pri2-CTD stably holds onto the 5’ end of the RNA primer. Since both Pri1 and Pol1-core are attached via two linkers to the platform, primer growth will produce stress within this “two-point” attachment that may limit the length of the RNA-DNA hybrid primer. Hence, this study reveals the large and dynamic series of movements that Pol α undergoes to synthesize a primer for DNA replication.
Structural Insights into the ATP-dependent Activation of NOD-like Receptor with Pyrin 3 (NLRP3) Protein by Molecular Dynamics Simulation
Authors: Sandall Christina F. , MacDonald Justin A.
Published: May 2023

The inflammasome-forming NOD-like receptor containing pyrin-3 (NLRP3) protein is a critical player in the innate immune responses to cellular danger signals. New structural data of NLRP3 provide a framework to probe the conformational impact of nucleotide binding. In this study, microsecond molecular dynamics (MD) simulations were used to detail information on the unique structural conformations adopted by NLRP3 with ATP or ADP binding. Sampling convergence reflected a high degree of confidence in the MD simulations as shown by RMSD and protein-nucleotide concordance, favourable overall MM-PBSA ligand binding energies for both nucleotides and low cosine coefficients of the principal eigenvectors obtained with essential dynamics (ED) analysis. NLRP3-ADP simulations provide relatively stable conformations with few global rearrangements as shown by decreased protein RMSD, Rg, SASA, and solvent accessibility for the ADP-bound structure. In contrast, ATP binding induced increased flexibility and resulted in substantive conformational changes to the NLRP3 structure. Binding of ATP was thermodynamically favourable as shown by the ΔGsolvand MM-PBSA calculations of complex free energies, and these NLRP3-ATP simulations resulted in similar structural transitions as observed in the activated NLRC4 empirical structure. Lastly, the active conformation of NLRP3 critically depends on hinging between the HD2 and LRR domains, whereby ATP binding drives local conformational changes that are conveyed to the global structure.