bluuebunny/crossref_metadata_2025 huggingface dataset:
Impacts of different reconstruction methods on the image quality of cadmium–zinc–telluride-based single photon emission computed tomography/computed tomography pulmonary perfusion imaging
Authors: Wu Weiming , Zhang Ruyi , Zhou Yaqian , Wang Shen , Shen Yiming , Li Ning , Tan Jian , Zheng Wei , Jia Qiang , Meng Zhaowei
Published: May 2023

Objective

The objective was to evaluate the impacts of different reconstruction methods [filtered back projection (FBP) and ordered subset expectation maximization (OSEM)] and different filters (Butterworth filter and Gaussian filter) on the image quality in cadmium–zinc–telluride (CZT)-based single photon emission computed tomography (SPECT)/computed tomography (CT) pulmonary perfusion imaging.

Methods

A combinations including FBP with Butterworth filter, OSEM with Butterworth filter (OSEM + Butterworth filter ), and OSEM with Gaussian filter (OSEM + Gaussian filter) were used during SPECT image reconstruction. Visual and quantitative parameters [root mean square (RMS) noise, contrast and contrast-to-noise ratio (CNR)] were used to evaluate image quality.

Results

The OSEM + Gaussian filter had better RMS noise and CNR than those of the FBP + Butterworth filter or OSEM + Butterworth filter, while the OSEM + Butterworth filter had the best contrast. The highest visual scores were obtained by OSEM + Gaussian filter (P < 0.0001). In the lesion size <2 cm group, the contrast (P < 0.01) and visual scores (P < 0.001) of OSEM + Butterworth filter were better than those of the other two groups. In the lesion size ≥2 cm group, the RMS noise and visual scores of OSEM + Gaussian filter were better than those of the other two groups.

Conclusion

In CZT SPECT/CT pulmonary perfusion imaging, this study recommended the clinical use of the OSEM + Gaussian filter combination for reconstruction in both conventional and larger lesions, the OSEM + Butterworth filter image postprocessing method might be advantageous in small lesions.
The Experience of Peripheral Neuropathy Symptoms in Breast Cancer Survivors With Diabetes
Authors: Storey Susan , Draucker Claire , Haunert Laura , Von Ah Diane
Published: May 2023

Background

Diabetes (type 2) is a risk factor for developing peripheral neuropathy (PN) symptoms in breast cancer survivors (BCS). Because PN symptoms are associated with deficits in physical functioning and quality of life, more information is needed about the effects of PN symptoms on the lives of BCS with diabetes.

Objective

The aim of this study was to describe the experiences of PN among BCS with diabetes from their own perspectives.

Interventions/Methods

This substudy is part of a larger investigation examining factors associated with cancer-related cognitive impairment in cancer survivors. Female early-stage (stage I–III) BCS with diabetes and PN symptoms were eligible to participate. A qualitative descriptive approach using purposive sampling and semistructured interviews was used. Participant narratives were summarized using standard content analytic techniques.

Results

Eleven BCS with diabetes and PN symptoms were interviewed. Participants described PN symptoms that were varied, were often persistent, and had troublesome effects on their physical functioning and quality of life. Participants used a variety of self-management strategies and prescription and over-the-counter medications to manage their PN symptoms. Some said that having both cancer and diabetes exacerbated the PN symptoms and complicated symptom management.

Conclusion

Peripheral neuropathy symptoms can have a profound effect on the lives of BCS with diabetes and should be addressed by healthcare providers.

Implications for Practice

Clinical care for this population should include ongoing assessment of PN symptoms, conversations about the effects of these symptoms on everyday life, evidence-based treatment for the symptoms, and support for symptom self-management.
Retrospective Review of Antecustodial Deaths Referred for Medicolegal Autopsy at the Medical University of South Carolina
Authors: Sullivan Christopher , Presnell S. Erin , Madory James E. , Phillips Angelina I.
Published: May 2023

Deaths occurring in police custody have dominated public discourse over recent years. However, deaths occurring after law enforcement have initiated nonphysical contact but before active restraint or containment lie outside the strict definition of “in custody.” These “antecustodial” deaths demonstrate a unique population and interaction with law enforcement.

A retrospective analysis of medicolegal cases referred to the Medical University of South Carolina from September 1, 2012, to April 28, 2022 was performed. Deaths during nonphysical interaction with or during evasion of law enforcement occurred in 78 cases and were categorized by demographic data, cause of death, manner of death, the presence of drugs and/or alcohol, and circumstances surrounding the interaction.

Antecustodial deaths occurred primarily during law enforcement pursuit and deescalation scenarios. Decedents were predominantly male (92.3%) with a Black-to-White ratio of 1.1:1. The average age of male and female decedents was 35.7 and 32.2 years, respectively. The most common causes of death were gunshot wounds and blunt trauma sustained in motor vehicle crashes. The most common manner of death was homicide (43.6%), followed by suicide (28.2%) and accident (28.2%).
Short and Long-term Efficacy of 3-dimensional Laparoscopic-assisted D2 Radical Gastrectomy Under the Guidance of Membrane Anatomy for Locally Advanced Gastric Cancer
Authors: Lin Huimei , Cai Zhiming , Xu Yanchang , Guo Zipei , Wu Haiyan , Li Zhixiong
Published: May 2023

Background:

Both 3-dimensional (3D) laparoscopy and membrane anatomy are topics of great interest in the treatment of gastric cancer. The purpose of this study was to evaluate the safety, feasibility, and efficacy of 3D laparoscopic-assisted D2 radical gastrectomy for locally advanced gastric cancer (LAGC) under the guidance of membrane anatomy.

Patients and Methods:

Retrospectively analyzed the clinical data of 210 patients who underwent 2-dimensional (2D)/3D laparoscopic-assisted D2 radical gastrectomy under the guidance of membrane anatomy for LAGC. Compared the differences between the two groups in surgical outcomes, postoperative recovery, postoperative complications, and 2-year overall survival and disease-free survival.

Results:

The baseline data of the 2 groups were comparable (P > 0.05). The amount of intraoperative bleeding in the 2D and 3D laparoscopy groups was 100.1 ± 48.75 mL and 74.29 ± 47.33 mL, respectively, with a significant difference between the two groups (P < 0.001). The time to first exhaust and first liquid diet intake and length of postoperative hospital stay was shorter in the 3D laparoscopy group, with significant differences between the two groups [3 (3-3) days vs 3(3-2) days, P = 0.009; 7 (8-7) days vs 6 (7-6) days, P < 0.001; and 13 (15-11) days vs 10 (11-9) days, P < 0.001]. There were no significant differences in operation time, number of lymph node dissections, incidence of postoperative complications, or 2-year overall survival and disease-free survival between the two groups (P > 0.05).

Conclusions:

Three-dimensional laparoscopic-assisted D2 radical gastrectomy for LAGC under the guidance of membrane anatomy is safe and feasible. It can reduce intraoperative bleeding, accelerate postoperative recovery, and does not increase operative complications, the long-term prognosis is similar to that of the 2D laparoscopy group.
Complex Urethral Diverticulectomy: Is a Synchronous Prophylactic Autologous Fascial Sling Needed?
Authors: Schaaf Amanda L. , Lee Yeonsoo S. , Myers Amanda A. , Schommer Jared , Gonzalez Giovanni , Chen Anita , Petrou Steven
Published: May 2023

Importance

Urethral diverticulectomy is performed with or without concomitant pubovaginal sling (PVS). Patients with complex UD are more frequently offered concomitant PVS. However, there is paucity of literature comparing postoperative incontinence rates for patients with simple versus complex UD.

Objective

The objective of this study is to examine postoperative stress urinary incontinence (SUI) rates after Urethral Diverticulectomy without concomitant PVS for both complex and simple cases.

Study Design

A retrospective cohort study was conducted among 55 patients who underwent Urethral Diverticulectomy from 2007 to 2021. Preoperative SUI was patient-reported and confirmed with cough stress test result. Complex cases were defined as circumferential or horseshoe configurations, prior diverticulectomy, and/or anti-incontinence procedure. Primary outcome was postoperative SUI. Secondary outcome was interval PVS. Complex and simple cases were compared using the Fisher exact test.

Results

Median age was 49 years (interquartile range, 36–58 years). Median follow-up was 5.4 months (IQR, 2–24 months). Thirty of 55 (55%) cases were simple, and 25 of 55 (45%) complex. Preoperative SUI was present in 19/57 (35%) (11 complex vs 8 simple, P = 0.25). Stress urinary incontinence persisted postoperatively in 10 of 19 (52%) (6 complex vs 4 simple, P = 0.48). De novo SUI occurred in 7 of 55, 12% (4 complex vs 3 simple, P = 0.68). Overall, 17 of 55 (31%) patients had postoperative SUI (10 complex vs 7 simple, P = 0.24). Of those, 8 of 17 underwent subsequent PVS placement (P = 0.71) and 9 of 17 had resolution of pad use after physical therapy (P = 0.27).

Conclusions

We did not find evidence of an association between complexity and postoperative SUI. Age at surgery and preoperative frequency were the strongest predictors of postoperative SUI in this cohort. Our findings suggest successful complex urethral diverticulum repair does not require concomitant PVS.
Deceased Donor Kidney Nonuse: A Systematic Approach to Improvement
Authors: Bunnapradist Suphamai , Rosenthal J. Thomas , Huang Edmund , Dafoe Donald , Seto Tom , Cohen Aaron , Danovitch Gabriel
Published: May 2023

Background.

A large number of procured kidneys continue not to be transplanted, while the waiting list remains high.

Methods.

We analyzed donor characteristics for unutilized kidneys in our large organ procurement organization (OPO) service area in a single year to determine the reasonableness of their nonuse and to identify how we might increase the transplant rate of these kidneys. Five experienced local transplant physicians independently reviewed unutilized kidneys to identify which kidneys they would consider transplanting in the future. Biopsy results, donor age, kidney donor profile index, positive serologies, diabetes, and hypertension were risk factors for nonuse.

Results.

Two-thirds of nonused kidneys had biopsies with high degree of glomerulosclerosis and interstitial fibrosis. Reviewers identified 33 kidneys as potentially transplantable (12%).

Conclusions.

Reducing the rate of unutilized kidneys in this OPO service area will be achieved by setting acceptable expanded donor characteristics, identifying suitable well-informed recipients, defining acceptable outcomes, and systematically evaluating the results of these transplants. Because the improvement opportunity will vary by region, to achieve a significant impact on improving the national nonuse rate, it would be useful for all OPOs, in collaboration with their transplant centers, to conduct a similar analysis.
Moorella caeni sp. nov., isolated from thermophilic anaerobic sludge from a methanol-fed reactor
Authors: Vecchini Santaella Nicolás , Sousa Diana Z. , Stams Alfons J. M.
Published: May 2023

Strain AMPT has been previously suggested as a strain of the species

Moorella thermoacetica

Jiang et al. 2009 (based on the high 16S rRNA gene identity, 98.3 %). However, genome-based phylogenetic analysis of strain AMPT reveals that this bacterium is in fact a novel species of the genus

Moorella

. Genome relatedness indices between strain AMPT and

Moorella thermoacetica

DSM 521T were below the minimum threshold values required to consider them members of the same species (digital DNA–DNA hybridization, 52.2 % (<70%); average nucleotide identity, 93.2 % (<95%)). Based on phylogenetic and phenotypic results we recommend that strain AMPT (DSM 21394T=JCM 35360T) should be classified as representing new species, for which we propose the name Moorella caeni sp. nov.
The Lasting Effects of the Pandemic: A Time Series Analysis of First-time Pediatric Speech Delays
Authors: Cartwright Brianna M. Goodwin , Smits Peter D , Stewart Sarah , Rodriguez Patricia J , Gratzl Samuel , Baker Charlotte , Stucky Nicholas
Published: May 2023

Given the profound effects of the COVID-19 pandemic on the way individuals interact, we sought to understand if there was an increase in pediatric first-time speech and language delay diagnoses. We identified children under five years of age with a first-time speech delay diagnosis between January 1, 2018 and February 28, 2023, in Truveta Data. We calculated the monthly rate of first-time speech delay diagnoses per children with an encounter within the last year and no previous speech delay diagnosis. The Seasonal-Trend decomposition using LOESS (STL) method was used to adjust for seasonality. We also compared the difference in means between the 2018/2019 and 2021/2022 time periods. Significant increases in the mean of rates between 2018/2019 and 2021/2022 exist for the overall population and each age strata (p<0.001). Likely the causes of these trends are multifaceted and future research is needed to understand the specific drivers at play.
Discovery and Detection of Dry Eye Disease Protein Biomarkers Using Soft Contact Lens Tear Sampling
Authors: Roden Robert K. , Jiang Fangfang , Nitz Alyssa , Zuniga Nathan , Burlett Rebecca S. , Patil Leena M. , Farnsworth Holly , Ackroyd P. Christine , Payne Samuel H. , Price John C. , Christensen Kenneth A.
Published: May 2023

Dry eye disease (DED) affects up to half of the world’s population and causes blur, eye pain, decreased quality of life. Unfortunately, many people do not receive proper treatment due to current challenges associated with DED diagnoses. To address this issue, point-of-care (PoC) clinical tear film diagnostics are beginning to be used for rapid in-office testing. However, these diagnostics also have significant obstacles, including challenges associated with tear sampling. We previously demonstrated how soft contact lenses (SCLs) can be used to capture and concentrate tear proteins on the eye. Given the low tear volume associated with DED subjects, SCL sampling holds great potential to improve DED PoC diagnostics and facilitate prompt treatment for patients. Here we show the detection of new and established DED protein biomarkers using our SCL sampling method. Our analysis revealed associations between DED tear proteins and the immune system, ferroptosis, salivary secretion, and calcium binding proteins. We also identified correlations between clinical DED testing and proteomics, emphasizing the power and importance of translational medicine research. These experiments lay the foundation for both SCL sampled tear protein biomarker discovery as well as improved diagnostic testing to improve DED patient care.

Abstract Figure
The secretory IgA (sIgA) response in human milk against the SARS-CoV-2 Spike is highly durable and neutralizing for at least 1 year of lactation post-infection
Authors: Yang Xiaoqi , Fox Alisa , DeCarlo Claire , Pineda Nicole , Powell Rebecca L.R.
Published: May 2023

Although in the early pandemic period, COVID-19 pathology among young children and infants was typically less severe compared to that observed among adults, this has not remained entirely consistent as SARS-CoV-2 variants have emerged. There is an enormous body of evidence demonstrating the benefits of human milk antibodies (Abs) in protecting infants against a wide range of enteric and respiratory infections. It is highly plausible that the same holds true for protection against SARS-CoV-2, as this virus infects cells of the gastrointestinal and respiratory mucosae. Understanding the durability of a human milk Ab response over time after infection is critical. Previously, we examined the Abs present in milk of those recently infected with SARS-CoV-2, and concluded that the response was secretory IgA (sIgA)-dominant and that these titers were highly correlated with neutralization potency. The present study aimed to monitor the durability of the SARS-CoV-2 IgA and secretory Ab (sAb) response in milk from COVID-19-recovered lactating individuals over 12 months, in the absence of vaccination or re-infection. This analysis revealed a robust and durable Spike-specific milk sIgA response, that at 9-12 months after infection, 88% of the samples exhibited titers above the positive cutoff for IgA and 94% were above cutoff for sAb. Fifty percent of participants exhibited less than a 2-fold reduction of Spike-specific IgA through 12 months. A strong significant positive correlation between IgA and sAb against Spike persisted throughout the study period. Nucleocapsid-specific Abs were also assessed, which revealed significant background or cross reactivity of milk IgA against this immunogen, as well as limited/inconsistent durability compared to Spike titers. These data suggests that lactating individuals are likely to continue producing Spike-specific Abs in their milk for 1 year or more, which may provide critical passive immunity to infants against SARS-CoV-2 throughout the lactation period.
Development of Cas13a-based Assays forNeisseria gonorrhoeaeDetection and Gyrase A Determination
Authors: Allan-Blitz Lao-Tzu , Shah Palak , Adams Gordon , Branda John A. , Klausner Jeffrey D. , Goldstein Robert , Sabeti Pardis C. , Lemieux Jacob E.
Published: May 2023

Background

Neisseria gonorrhoeaeis one of the most common bacterial sexually transmitted infections. The emergence of antimicrobial-resistantN. gonorrhoeaeis an urgent public health threat. Currently, diagnosis ofN. gonorrhoeaeinfection requires expensive laboratory infrastructure, while antimicrobial susceptibility determination requires bacterial culture, both of which are infeasible in low-resource areas where prevalence is highest. Recent advances in molecular diagnostics, such as Specific High-sensitivity Enzymatic Reporter unLOCKing (SHERLOCK) using CRISPR-Cas13a and isothermal amplification, have the potential to provide low-cost detection of pathogen and antimicrobial resistance.

Methods and Results

We designed and optimized RNA guides and primer-sets for SHERLOCK assays capable of detectingN. gonorrhoeaevia theporA gene and of predicting ciprofloxacin susceptibility via a single mutation in the gyrase A (gyrA) gene. We evaluated their performance using both synthetic DNA and purifiedN. gonorrhoeaeisolates. ForporA, we created both a fluorescence-based assay and lateral flow assay using a biotinylated FAM reporter. Both methods demonstrated sensitive detection of 14N. gonorrhoeaeisolates and no cross-reactivity with 3 non-gonococcalNeisseriaisolates. ForgyrA, we created a fluorescence-based assay that correctly distinguished between 20 purifiedN. gonorrhoeaeisolates with phenotypic ciprofloxacin resistance and 3 with phenotypic susceptibility. We confirmed thegyrA genotype predictions from the fluorescence-based assay with DNA sequencing, which showed 100% concordance for the isolates studied.

Conclusion

We report the development of Cas13a-based SHERLOCK assays that detectN. gonorrhoeaeand differentiate ciprofloxacin-resistant isolates from ciprofloxacin-susceptible isolates.
Archaic introgression contributed to shape the adaptive modulation of angiogenesis and cardiovascular traits in human high-altitude populations from the Himalayas
Authors: Ferraretti Giulia , Abondio Paolo , Alberti Marta , Dezi Agnese , Sherpa Phurba T. , Cocco Paolo , Tiriticco Massimiliano , di Marcello Marco , Gnecchi-Ruscone Guido Alberto , Natali Luca , Corcelli Angela , Marinelli Giorgio , Peluzzi Davide , Sarno Stefania , Sazzini Marco
Published: May 2023

It is well established that severalHomo Sapienspopulations experienced admixture with extinct human species during their evolutionary history. Sometimes, such a gene flow could have played a role in modulating their capability to cope with a variety of selective pressures, thus resulting in archaic adaptive introgression events. A paradigmatic example of this evolutionary mechanism is offered by theEPAS1gene, whose most frequent haplotype in Himalayan highlanders was proved to reduce their susceptibility to chronic mountain sickness and to be introduced in the gene pool of their ancestors by admixture with Denisovans. In this study, we aimed at further expanding the investigation of the impact of archaic introgression on more complex adaptive responses to hypobaric hypoxia evolved by populations of Tibetan/Sherpa ancestry, which have been plausibly mediated by soft selective sweeps and/or polygenic adaptations rather than by hard selective sweeps. For this purpose, we used a combination of composite-likelihood and gene network-based methods to detect adaptive loci in introgressed chromosomal segments from Tibetan whole genome sequence data and to shortlist those presenting Denisovan-like derived alleles that participate to the same functional pathways and are absent in populations of African ancestry, which are supposed to do not have experienced Denisovan admixture. According to this approach, we identified multiple genes putatively involved in archaic introgression events and that, especially as regardsTBC1D1,RASGRF2,PRKAG2, andKRAS, have plausibly contributed to shape the adaptive modulation of angiogenesis and of certain cardiovascular traits in high-altitude Himalayan peoples. These findings provided unprecedented evidence about the complexity of the adaptive phenotype evolved by these human groups to cope with challenges imposed by hypobaric hypoxia, offering new insights into the tangled interplay of genetic determinants that mediates the physiological adjustments crucial for human adaptation to the high-altitude environment.
Telomeric repeat evolution in the phylum Nematoda revealed by high-quality genome assemblies and subtelomere structures
Authors: Lim Jiseon , Kim Wonjoo , Kim Jun , Lee Junho
Published: May 2023

Telomeres are composed of tandem arrays of telomeric-repeat motifs (TRMs) and telomere-binding proteins (TBPs), which are responsible for ensuring end-protection and end-replication of chromosomes. TRMs are highly conserved due to the sequence specificity of TBPs, but significant alterations in TRM have also been observed in several taxa, except Nematoda. We used public whole-genome sequencing datasets to analyze putative TRMs of 100 nematode species and determined that two distinct branches included specific novel TRMs, suggesting that evolutionary alterations in TRMs occurred in Nematoda. We focused on one of the two branches, the Panagrolaimidae family, and performed ade novoassembly of four high-quality draft genomes of the canonical (TTAGGC) and novel TRM (TTAGAC)-containing isolates; the latter genomes revealed densely clustered arrays of the novel TRM. We then comprehensively analyzed the subtelomeric regions of the genomes to infer how the novel TRM evolved. We identified DNA damage–repair signatures in subtelomeric sequences that were representative of consequences of telomere maintenance mechanisms by alternative lengthening of telomeres. We propose a hypothetical scenario in which TTAGAC-containing units are clustered in subtelomeric regions and pre-existing TBPs capable of binding both canonical and novel TRMs aided the evolution of the novel TRM in the Panagrolaimidae family.
Bridging the translational neuroscience gap: Development of the ‘shiftability’ paradigm and an exemplar protocol to capture psilocybin-elicited ‘shift’ in neurobiological mechanisms in autism
Authors: Whelan Tobias P. , Daly Eileen , Puts Nicolaas A. , Malievskaia Ekaterina , Murphy Declan G.M. , McAlonan Grainne M.
Published: May 2023

Clinical trials of pharmacological approaches targeting the core features of autism have failed. This is despite evidence from preclinical studies, genetics, post-mortem studies and correlational analyses linking peripheral and central markers of multiple candidate neurochemical systems to brain function in autism. Whilst this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way todirectlyestablish that a neurotransmitter or neuromodulator is involved in a candidate brain function is tochangeit and observe ashiftin that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is very little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. As a result, our understanding of how neurochemical differences contribute to neurodiversity is limited and impedes our ability to translate findings from animal studies into humans.

Here, we begin by introducing our “shiftability” paradigm, an approach to bridge the translational gap in autism research. We then provide an overview of the methodologies used and explain our most recent choice of psilocybin as a pharmacological probe of the serotonin systemin vivo. Finally, we provide a summary of the protocol for ‘PSILAUT’, an exemplar “shiftability” study which uses psilocybin to directly test the hypothesis that the serotonin system functions differently in autistic and non-autistic adults.
In vivolong-term voltage imaging by genetically encoded voltage indicator reveals spatiotemporal dynamics of neuronal populations during development
Authors: Shiraishi Asuka , Hayashi Ayane , Fukuda Narumi , Hishinuma Mari , Miyazawa Hiroaki , Tsuda Sachiko
Published: May 2023

A central question in brain development lies in how individual neurons emerge and organize communities to acquire various functions. Voltage imaging provides unique approaches to addressing this by enabling simultaneous, non-invasive, in vivo recording of voltage dynamics from a population of cells. Recently, genetically encoded voltage indicators (GEVIs) facilitate cell-type specific imaging of voltage dynamics. However, it has not been applied to brain development. Here, we applied ArcLight, a GEVI utilizing voltage-sensitive domain, to zebrafish and established experimental approaches for analyzing voltage and morphology of neuron populations during development, focusing on the spinal cord and cerebellum. We initially demonstrated that Arclight was widely distributed in the neural tissues. With voltage imaging, we successfully visualized the coordinated, spontaneous activity of spinal cord neurons in their early stage of development at a high spatiotemporal resolution, at subcellular and population levels. Hyperpolarization and subthreshold signals were also detected. Finally, long-term voltage imaging during development revealed the process of changes in voltage dynamics in neuron populations, accompanied by axonal outgrowth. Voltage imaging could greatly contribute to our understanding of the functional organization of the nervous system during development.
Ecological Inducers of the Yeast Filamentous Growth Pathway Reveal Environment-Dependent Roles for Pathway Components
Authors: Vandermeulen Matthew D. , Cullen Paul J.
Published: May 2023

Signaling modules, such as MAPK pathways, are evolutionarily conserved drivers of cell differentiation and stress responses. In many fungal species including pathogens, MAPK pathways control filamentous growth, where cells differentiate into an elongated cell type. The convenient model budding yeastSaccharomyces cerevisiaeundergoes filamentous growth by the filamentous growth (fMAPK) pathway; however, the inducers of the pathway remain unclear, perhaps because pathway activity has been mainly studied in laboratory conditions. To address this knowledge gap, an ecological framework was employed, which uncovered new fMAPK pathway inducers, including pectin, a material found in plants, and the metabolic byproduct ethanol. We also show that induction by a known inducer of the pathway, the non-preferred carbon source galactose, required galactose metabolism and induced the pathway differently than glucose limitation or other non-preferred carbon sources. By exploring fMAPK pathway function in fruit, we found induction of the pathway led to visible digestion of fruit rind through a known target,PGU1, which encodes a pectolytic enzyme. Different stimuli revealed different modes of pathway signaling. For example, combinations of inducers (galactose and ethanol) stimulated the pathway to near maximal levels, which showed dispensability of several fMAPK pathway components (e.g. mucin sensor, PAK), but not others (e.g. adaptor, MAPKKK) and required the Ras2-PKA pathway. This included a difference between the transcription factor binding partners for the pathway, as Tec1p, but not Ste12p, was partly dispensable for fMAPK pathway activity. Thus, by exploring ecologically-relevant stimuli, new modes of MAPK pathway signaling were uncovered, perhaps revealing how a pathway can respond differently to specific environments.

Data Availability Statement

All data are in the manuscript and/or supporting information files.
Caenorhabditis elegansgerm granules are present in distinct configurations that differentially associate with RNAi-targeted RNAs
Authors: Uebel Celja J. , Rajeev Sanjana , Phillips Carolyn M.
Published: May 2023

RNA silencing pathways are complex, highly conserved, and perform widespread, critical regulatory roles. InC. elegansgermlines, RNA surveillance occurs through a series of perinuclear germ granule compartments—P granules, Z granules, SIMR foci, andMutatorfoci—multiple of which form via phase separation and exhibit liquid-like properties. The functions of individual proteins within germ granules are well-studied, but the spatial organization, physical interaction, and coordination of biomolecule exchange between compartments within germ granule “nuage” is less understood. Here we find that key proteins are sufficient for compartment separation, and that the boundary between compartments can be reestablished after perturbation. Using super-resolution microscopy, we discover a toroidal P granule morphology which encircles the other germ granule compartments in a consistent exterior-to-interior spatial organization. Combined with findings that nuclear pores primarily interact with P granules, this nuage compa rtment organization has broad implications for the trajectory of an RNA as it exits the nucleus and enters small RNA pathway compartments. Furthermore, we quantify the stoichiometric relationships between germ granule compartments and RNA to reveal discrete populations of nuage that differentially associate with RNAi-targeted transcripts, possibly suggesting functional differences between nuage configurations. Together, our work creates a more spatially and compositionally accurate model ofC. elegansnuage which informs the conceptualization of RNA silencing through different germ granule compartments.
Contrasting synaptic roles of MDGA1 and MDGA2
Authors: Bemben Michael A. , Sandoval Matthew , Le Aliza A. , Won Sehoon , Chau Vivian N. , Lauterborn Julie C. , Incontro Salvatore , Li Kathy H. , Burlingame Alma L. , Roche Katherine W. , Gall Christine M. , Nicoll Roger A. , Diaz-Alonso Javier
Published: May 2023

Neurodevelopmental disorders are frequently linked to mutations in synaptic organizing molecules. MAM domain containing glycosylphosphatidylinositol anchor 1 and 2 (MDGA1 and MDGA2) are a family of synaptic organizers suggested to play an unusual role as synaptic repressors, but studies offer conflicting evidence for their localization. Using epitope-tagged MDGA1 and MDGA2 knock-in mice, we found that native MDGAs are expressed throughout the brain, peaking early in postnatal development. Surprisingly, endogenous MDGA1 was enriched at excitatory, but not inhibitory, synapses. Both shRNA knockdown and CRISPR/Cas9 knockout of MDGA1 resulted in cell-autonomous, specific impairment of AMPA receptor- mediated synaptic transmission, without affecting GABAergic transmission. Conversely, MDGA2 knockdown/knockout selectively depressed NMDA receptor-mediated transmission butenhancedinhibitory transmission. Our results establish that MDGA2 acts as a synaptic repressor, but only at inhibitory synapses, whereas both MDGAs are required for excitatory transmission. This nonoverlapping division of labor between two highly conserved synaptic proteins is unprecedented.

Teaser

MDGAs 1 and 2 independently localize to and modulate excitatory and inhibitory hippocampal synapses by different mechanisms.
Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6
Authors: Ye Xiyun , Zhang Peiyuan , Tao Jason , Wang John C. K. , Mafi Amirhossein , Grob Nathalie M. , Quartararo Anthony J. , Baddock Hannah T. , Foe Ian , Loas Andrei , Eaton Dan L. , Hao Qi , Nile Aaron H. , Pentelute Bradley L.
Published: May 2023

Human papillomavirus (HPV) infections account for nearly all cervical cancer cases, which is the fourth most common cancer in women worldwide. High-risk variants, including HPV16, drive tumorigenesis in part by promoting the degradation of the tumor suppressor p53. This degradation is mediated by the HPV early protein 6 (E6), which recruits the E3 ubiquitin ligase E6AP and redirects its activity towards ubiquitinating p53. Targeting the protein interaction interface between HPV E6 and E6AP is a promising modality to mitigate HPV-mediated degradation of p53. In this study, we designed a covalent peptide inhibitor, termed reactide, that mimics the E6AP LXXLL binding motif by selectively targeting cysteine 58 in HPV16 E6 with quantitative conversion. This reactide provides a starting point in the development of covalent peptidomimetic inhibitors for intervention against HPV-driven cancers.
Anterior chamber depth in mice is controlled by several quantitative trait loci
Authors: Larson Demelza R. , Kimber Allysa J. , Meyer Kacie J. , Anderson Michael G.
Published: May 2023

PURPOSE

Anterior chamber depth (ACD) is a quantitative trait associated with primary angle closure glaucoma (PACG). Although ACD is highly heritable, known genetic variations explain a small fraction of the phenotypic variability. The purpose of this study was to identify additional ACD-influencing loci using strains of mice.

METHODS

Cohorts of 86 N2 and 111 F2 mice were generated from crosses between recombinant inbred BXD24/TyJ and wild-derived CAST/EiJ mice. Using anterior chamber optical coherence tomography, mice were phenotyped at 10-12 weeks of age, genotyped based on 93 genome-wide SNPs, and subjected to quantitative trait locus (QTL) analysis.

RESULTS

In an analysis of ACD among all mice, six loci passed the significance threshold ofp= 0.05 and persisted after multiple regression analysis. These were on chromosomes 6, 7, 11, 12, 15 and 17 (namedAcdq6,Acdq7,Acdq11,Acdq12,Acdq15, andAcdq17, respectively).

CONCLUSIONS

Our findings demonstrate a quantitative multi-genic pattern of ACD inheritance in mice and identify six previously unrecognized ACD-influencing loci. We have taken a unique approach to studying the anterior chamber depth phenotype by using mice as genetic tool to examine this continuously distributed trait.
Voltage dynamics of dendritic integration and back-propagationin vivo
Authors: Wong-Campos J. David , Park Pojeong , Davis Hunter , Qi Yitong , Tian He , Itkis Daniel G. , Kim Doyeon , Grimm Jonathan B. , Plutkis Sarah E. , Lavis Luke , Cohen Adam E.
Published: May 2023

Neurons integrate synaptic inputs within their dendrites and produce spiking outputs, which then propagate down the axon and back into the dendrites where they contribute to plasticity. Mapping the voltage dynamics in dendritic arbors of live animals is crucial for understanding neuronal computation and plasticity rules. Here we combine patterned channelrhodopsin activation with dual-plane structured illumination voltage imaging, for simultaneous perturbation and monitoring of dendritic and somatic voltage in Layer 2/3 pyramidal neurons in anesthetized and awake mice. We examined the integration of synaptic inputs and compared the dynamics of optogenetically evoked, spontaneous, and sensory-evoked back-propagating action potentials (bAPs). Our measurements revealed a broadly shared membrane voltage throughout the dendritic arbor, and few signatures of electrical compartmentalization among synaptic inputs. However, we observed spike rate acceleration-dependent propagation of bAPs into distal dendrites. We propose that this dendritic filtering of bAPs may play a critical role in activity-dependent plasticity.
A Long COVID Risk Predictor Focused on Clinical Workflow Integration
Authors: Bhattacharya Biplab S. , Mitchell Elliot G. , Shetty Gaurav , Delong Grant , Munia Tamanna T. K. , Tariq Abdul A.
Published: May 2023

For the NIH Long COVID Computational Challenge (L3C) in the Fall of 2022, we developed a machine learning model to predict who is at high risk for developing Long COVID, optimized for clinical deployment. Our submission won second prize in the competition. We present lessons learned, with details on the features, model selection and performance, fairness analysis, limitations, and deployment implications.
Selenium supplementation and clinical outcomes: an umbrella review protocol
Authors: Mosanya Adaobi Uchenna , Umeh Ifeoma , Abdullahi Abba Khalid , Ukoha-Kalu Blessing Onyinye , Adibe Maxwell Ogochukwu , Sanmartin Grijalba Carmen
Published: May 2023

Background

Selenium is a trace element essential for the normal functions of different human body systems and its deficiency has been associated with different disease states. In recent years, many systematic reviews of randomized clinical trials in humans have demonstrated various properties of selenium such as antioxidant, anti-inflammatory, increased immunity, blocking tumour invasion and metastasis in various pathological conditions. Therefore, there is need to summarize these recent findings in one single paper to facilitate the decision making of clinicians and policy makers regarding the inclusion of selenium supplementation in routine clinical practice, treatment guidelines and essential medicine list. This study would guide researchers towards future research and design of clinical trials.

Objectives

The objective of this umbrella review is to assess the clinical outcomes of selenium supplementation in different disease states and to determine its therapeutic implications.

Eligibility criteria

Only systematic reviews of randomized clinical trials reporting clinical outcomes after the use of selenium alone as a supplement in the management of diseases will be included. While primary studies, systematic reviews that involved the administration of selenium in combination with other trace elements for the prevention or treatment of diseases will be excluded.

Methods

The following databases will be searched by three independent reviewers: MEDLINE, PUBMED, EMBASE, COCHRANE database of systematic reviews, CINAHL, JBI Evidence synthesis, EPISTEMONIKOS, SCOPUS, Web of Science and TRIP PRO. Unpublished reviews will be searched using ProQuest for dissertations and Theses, Canadian Agency for drugs and Technologies in Health (CADTH) database of Grey matters and GOOGLE scholar. Systematic reviews published in the last 10 years (2013 to 2023). There will be no language restriction. The services of a translator will be employed if studies in other languages were found. Selection of reviews and data extraction will be done by 3 independent reviewers. Summary of findings will be presented in tables accompanied by texts where necessary.

Strengths and limitations of this study

This is the first umbrella review on the use of selenium supplements for disease management. Secondly, the findings from this study would facilitate the decision making of clinicians and policy makers regarding the inclusion of selenium supplementation in routine clinical practice, treatment guidelines and essential medicine list. Nevertheless, a major limitation of this umbrella review would be a reduced scope of eligible studies because only systematic reviews/ or meta-analysis that included randomized clinical trials will be considered.
An intra-oral flavor discrimination task in freely moving mice
Authors: Shiotani Kazuki , Tanisumi Yuta , Osako Yuma , Murata Koshi , Hirokawa Junya , Sakurai Yoshio , Manabe Hiroyuki
Published: May 2023

Flavor plays a critical role in the pleasure of food. Flavor research has mainly focused on human subjects and revealed that many brain regions are involved in flavor perception. However, animal models for elucidating the mechanisms of neural circuits are lacking. Herein, we demonstrate the use of a novel behavioral task in which mice are capable of flavor discrimination. When the olfactory pathways of the mice were blocked, they could not perform the task. However, behavioral accuracy was not affected when the gustatory pathway was blocked by benzocaine. These results indicate that the mice performed this discrimination task mainly based on the intraoral flavor. We conclude that this novel task can contribute to research on the neural mechanisms of flavor perception.
Deep Learning models for retinal cell classification
Authors: Kostałkowski Maciej , Kordecka Katarzyna , Płaczkiewicz Jagoda , Posłuszny Anna , Foik Andrzej
Published: May 2023

Data analysis is equally important as an experimental part of the scientist’s work. Therefore any reliable automatization would accelerate research. Histology is a good example, where scientists work with different cell types. The difficulty level can be severe while trying to distinguish cell types from one another. In this paper, we focus on the retina. The retina consists of eight basic cell types, creating a layered structure. Some types of cells overlap within the layer, and some differ significantly in size. Fast and thorough manual analysis of the cross-section is impossible. Even though Deep Learning models are applied in multiple domains, we observe little effort to automatize retinal analysis. Therefore, this research aims to create a model for classifying retinal cell types based on morphology in a cross-section of retinal cell images.

In this study, we propose a classification Deep Learning model for retinal cell classification. We implemented two models, each tested in three different approaches: Small dataset, Extended dataset, and One cell type vs. All cell types. Although the problem presented to the trained model was simplified, a significant data imbalance was created from multiclass to binary classification, influencing the models’ performance. Both, Sequential and Transfer Learning models performed best with the Extended dataset. The Sequential model generated the best overall results. The obtained results allow us to place prepared models within the benchmark of published models.

This paper proposes the first Deep Learning tool classifying retinal cell types based on a dataset prepared from publicly available images collated from multiple sources and images obtained in our laboratory. The multiclass approach with an extended dataset showed the best results. With more effort, the model could become an excellent analytical tool.
MDM2 acts as a timer reporting the length of mitosis
Authors: Fulcher Luke J. , Sobajima Tomoaki , Batley Caleb , Gibbs-Seymour Ian , Barr Francis A.
Published: May 2023

Delays in mitosis trigger p53-dependent arrest in G1 of the following cell cycle, enabling cells to respond to changes that would otherwise promote chromosome instability and aneuploidy1–10. We find that MDM2, the p53 ubiquitin ligase, is a key component of the timer mechanism triggering G1 arrest in response to prolonged mitosis. This timer function arises because MDM2 has a short half-life and ongoing protein synthesis is therefore necessary to maintain its steady-state concentration. Due to the attenuation of protein synthesis in mitosis, the amount of MDM2 gradually falls during mitosis, but normally remains above a critical threshold for p53 regulation at the onset of G1. When mitosis is extended by prolonged spindle assembly checkpoint activation, the amount of MDM2 drops below this threshold, stabilising p53. Subsequent p53-dependent p21 accumulation in the following G1 then channels cells into a prolonged cell cycle arrest, whereas abrogation of the response in p53-deficient cells allows them to bypass this crucial defence mechanism.
Goat Discrimination of Emotional Valence in the Human Voice
Authors: Mason Marianne A. , Semple Stuart , Marshall Harry H. , McElligott Alan G.
Published: May 2023

Reading another animal’s emotional state can enable receivers to anticipate their behavioural motivations, which is important in guiding interactions with that individual. For species living closely alongside humans, the emotional cues that people express can be almost as informative as those of conspecifics. Goats can discriminate differences in emotional valence present in another goat’s calls, and we investigated whether this ability extends to human speech. We presented goats with a habituation-dishabituation-rehabituation paradigm, where they experienced multiple playbacks of a familiar or unfamiliar human voice conveying a single emotional valence (e.g., angry; habituation phase), before the valence of the voice changed (e.g., happy; dishabituation phase) and then reversed again in-line with the habituation phase (e.g., angry; rehabituation phase). Over the habituation phase, goat behavioural responses decreased, showing evidence of having habituated to the playback stimuli presented. Following a change in emotional valence (dishabituation phase), although goats were overall less likely to respond, those that did looked for longer, suggesting they had perceived the shift in emotional content conveyed in human voice playbacks. We found no changes in physiological arousal (heart rate or heart rate variability) with shifts in playback valence. Goats, as a domesticated species, may have developed a sensitivity to our cues over their long association with humans, but the differences in individual behaviour towards the playback paradigm could highlight a role for learning and individual experience in particular on interspecific emotional communication.
Identification of the FSH-RH, the other gonadotropin-releasing hormone
Authors: Uehara Shun Kenny , Nishiike Yuji , Maeda Kazuki , Karigo Tomomi , Kuraku Shigehiro , Okubo Kataaki , Kanda Shinji
Published: May 2023

In vertebrates, folliculogenesis and ovulation are regulated by two distinct pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Today, there is an intriguing consensus that a single hypothalamic neurohormone, gonadotropin-releasing hormone (GnRH), regulates the secretion of both FSH and LH, although the required timing and functions of FSH and LH are different. However, recent studies in vertebrates other than mammals indicate that the effect of GnRH on FSH is too weak to explain its regulation. Therefore, to challenge this “solo GnRH model,” we aimed to identify the other gonadotropin regulator, FSH-releasing hormone (FSH-RH), in vertebrates. Here, by using the model teleost medaka, we successfully identified cholecystokinin as the FSH-RH. Our histological andin vitroanalyses demonstrated that hypothalamic cholecystokinin-expressing neurons directly affect FSH cells through the cholecystokinin receptor, Cckbr1, thereby increasing the expression and release of FSH. Remarkably, the knockout of cholecystokinin ligand orcckbr1minimized FSH expression and resulted in a complete failure of folliculogenesis. Our results challenge the longstanding consensus of the solo GnRH model in all vertebrates; instead, we propose the existence of a “dual GnRH model” group in vertebrates that utilizes both FSH-RH and LH-RH. The discovery of the FSH-RH in vertebrates opens not only a new era in neuroendocrinology but also possible applications involving vertebrate reproduction.