bluuebunny/crossref_metadata_2025 huggingface dataset:
Healthcare Trajectories and Outcomes in the First Year After Tracheostomy Based on Patient Characteristics*
Authors: Mehta Anuj B. , Matlock Daniel D. , Shorr Andrew F. , Douglas Ivor S.
Published: August 2023

OBJECTIVES:

To define healthcare trajectories after tracheostomy to inform shared decision-making efforts for critically ill patients.

DESIGN:

Retrospective epidemiologic cohort study.

SETTING:

California Patient Discharge Database 2018–2019.

PATIENTS:

Patients who received a tracheostomy.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We tracked 1-year outcomes after tracheostomy, including survival and time alive in and out of a healthcare facility (HCF. Patients were stratified based on surgical status (did the patient require a major operating room procedure or not), age (65 yr old or older and less than 65 yr), pre-ICU comorbid states (frailty, chronic organ dysfunction, cancer, and robustness), and the need for dialysis during the tracheostomy admission. We identified 4,274 nonsurgical adults who received a tracheostomy during the study period with 50.9% being 65 years old or older. Among adults 65 years old or older, median survival after tracheostomy was less than 3 months for individuals with frailty, chronic organ dysfunction, cancer, or dialysis. Median survival was 3 months for adults younger than 65 years with cancer or dialysis. Most patients spent the majority of days alive after a tracheostomy in an HCF in the first 3 months. Older adults had very few days alive and out of an HCF in the first 3 months after tracheostomy. Most patients who ultimately died in the first year after tracheostomy spent almost all days alive in an HCF.

CONCLUSIONS:

Cumulative mortality and median survival after a tracheostomy were very poor across most ages and groups. Older adults and several subgroups of younger adults experienced high rates of prolonged hospitalization with few days alive and out of an HCF. This information may aid some patients, surrogates, and providers in decision-making.
Retrospective Analysis of Axial Length Changes in Overnight Orthokeratology in an Academic Myopia Control Clinic
Authors: Holmes Michelle , Liu Maria , Singh Sarah
Published: August 2023

SIGNIFICANCE

Although the myopia control efficacy of orthokeratology lenses has been established with clinical trials, reports of axial length change in non–study-based patient care are scarce. This study investigates the use of orthokeratology lenses for myopia control in a clinical population and compares axial elongation against those published in recent clinical investigations.

PURPOSE

This study aimed to investigate factors affecting axial elongation during use of orthokeratology lenses for myopia control in an academic clinical setting.

METHODS

This study was a retrospective consecutive case series from the Myopia Control Clinic at the Herbert Wertheim School of Optometry at the University of California, Berkeley (Berkeley, CA). Patients ranging from 5 to 18 years old using orthokeratology for at least 1 year were included in the study. Data from 102 patients' eyes were analyzed at baseline (before the initiation of treatment) and after 1 year of wear (12 ± 3 months). Multivariate analysis was undertaken to identify factors significantly associated with axial elongation over this period.

RESULTS

Mean (±standard deviation) spherical equivalent refraction and axial length at baseline were −2.54 (±1.21) D and 24.53 (±0.82) mm, respectively. By the 1-year follow-up, eyes had shown significant axial elongation (0.18 ± 0.24 mm; P < .001), which was found to be inversely correlated with age (P < .001). Race, sex, baseline axial length, and baseline refraction were not significantly associated with axial elongation.

CONCLUSIONS

Factors influencing axial length and the magnitude of axial elongation in our orthokeratology patient population are consistent with orthokeratology treatment groups from published randomized clinical trials and support the use of these lenses for myopia control in a clinical practice setting.
Publication Trends of Research on Head and Neck Squamous Cell Carcinoma During 2002 to 2022: A 20-Year Bibliometric Study
Authors: Xu Mingpeng , Gu Xiang , Yang Ludi , Ge Shengfang , Zhao Peiquan
Published: August 2023

Background:

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Our study attempted to analyze the research trends in HNSCC and compare contributions from different countries, institutions, journals, and authors.

Materials and Methods:

The authors extracted publications in this field from 2002 to 2022 from the Web of Science database. Microsoft Excel and VOSviewer were performed to collect data on publication numbers, analyze publication trends, and visualize relevant results.

Results:

A total of 1903 publications were screened. In the past 20 years, the United States contributed the most publications and citations in the HNSCC research. China ranked second in the number of publications. The Ophthalmic Plastic and Reconstructive Surgery was the most productive journal concerning HNSCC. ESMAELIB of the University of Texas System and ROSENTHAL EL of Stanford University had published the most publications in this field. Keywords were categorized into 3 clusters: basic study, clinical feature study, and treatment-related study. The keywords “reflectance confocal microscopy”, “raman-spectroscopy”, and “confocal laser endomicroscopy” were most frequently emerged in the recent years. Management-related research has been recognized as a potential focus in the HNSCC.
Improving Quality of Life in The Constipated Older Person
Authors: Güven Şefika Dilek
Published: August 2023

This study is a randomized comparative trial designed to determine the effects of reflexology and abdominal massage on the improvement of constipation and quality of life of older persons. Participants were randomized to the reflexology group (n = 50) or abdominal massage group (n = 50). Data were collected by using a descriptive information form, the Standardized Mini-Mental Test (SMMT), the Katz Daily Life Activity Scale (Katz ADL), the Constipation Severity Scale (CSS), and the Constipation Quality of Life Questionnaire (CQOLQ). The comparison of the mean scores of participants from the total CSS and the total CQOLQ before and after reflexology and abdominal massage application indicated that the mean post-intervention scores on the total CSS and the total CQOLQ decreased significantly compared with preintervention scores (p < .05). When the mean scores of the reflexology and abdominal massage groups for the total CSS and the total CQOLQ were compared, there was no significant difference between the groups (p < .05). Both interventions improved the constipation problem of these older persons and their quality of life. The effects of both reflexology and abdominal massage were similar in improving constipation and quality of life in older persons.
Toxic neuropathies
Authors: Rossor Alexander M. , Manji Hadi
Published: August 2023

Purpose of review

Immunotherapy has had a significant impact on the treatment of an increasing number of cancers as well as in inflammatory, rheumatological and gastroenterological conditions.

Recreational nitrous oxide use is now a global epidemic. Linezolid is now recommended for the treatment of drug-resistant tuberculosis (TB); neuropathy is a significant cause of morbidity.

Global warming will result in increasing toxin exposure, such as ciguatera, in previously unaffected areas.

Recent findings

With increasing experience, the pathophysiology underlying the neuropathic complications of these drugs has become clear with guidelines now available, for the complications of immune check-point inhibitors and nitrous oxide toxicity. The optimum dose and duration of treatment for resistant TB with regimens, including linezolid, has been ascertained.

Although neuropathic complications with immunotherapy are relatively rare, it is essential that they are recognized and treated early. Nitrous oxide toxicity should be in the differential diagnosis for all patients, particularly those of younger age, presenting with a neuropathy or myleo-neuropathy. Ciguatera toxicity is under recognized and its geographical spread will increase due to global warming. Further research is necessary on the mechanisms and treatment of both acute and chronic effects, which at present, are only symptomatic.
Immune and behavioral correlates of protection against symptomatic post-vaccination SARS-CoV-2 infection
Authors: Goguet Emilie , Olsen Cara H. , Meyer William A. , Ansari Sara , Powers John H. , Conner Tonia L. , Coggins Si’Ana A. , Wang Wei , Wang Richard , Illinik Luca , Edwards Margaret Sanchez , Jackson-Thompson Belinda M. , Hollis-Perry Monique , Wang Gregory , Alcorta Yolanda , Wong Mimi A. , Saunders David , Mohammed Roshila , Balogun Bolatito , Kobi Priscilla , Kosh Lakeesha , Bishop-Lilly Kimberly , Cer Regina Z. , Arnold Catherine E. , Voegtly Logan J. , Fitzpatrick Maren , Luquette Andrea E. , Malagon Francisco , Ortega Orlando , Parmelee Edward , Davies Julian , Lindrose Alyssa R. , Haines-Hull Hannah , Moser Matthew S. , Samuels Emily C. , Tso Marana S. , Graydon Elizabeth K. , Malloy Allison M.W. , Tribble David R. , Burgess Timothy H. , Campbell Wesley , Robinson Sara , Broder Christopher C. , O’Connell Robert J. , Weiss Carol D. , Pollett Simon , Laing Eric D. , Mitre Edward
Published: August 2023

We sought to determine pre-infection correlates of protection against SARS-CoV-2 post-vaccine infections (PVI) acquired during the first Omicron wave in the United States. Serum and saliva samples from 176 vaccinated adults were collected from October to December of 2021, immediately before the Omicron wave, and assessed for SARS-CoV-2 Spike-specific IgG and IgA binding antibodies (bAb). Sera were also assessed for bAb using commercial assays, and for neutralization activity against several SARS-CoV-2 variants. PVI duration and severity, as well as risk and precautionary behaviors, were assessed by questionnaires. Serum anti-Spike IgG levels assessed by research assay, neutralization titers against Omicron subvariants, and low home risk scores correlated with protection against PVIs after multivariable regression analysis. Commercial assays did not perform as well as research assay, likely due to their lower dynamic range. In the 32 participants that developed PVI, anti-Spike IgG bAbs correlated with lower disease severity and shorter duration of illness.
Stabilization of epithelial β-catenin compromises mammary cell fate acquisition and branching morphogenesis
Authors: Satta Jyoti Prabha , Lan Qiang , Taketo Makoto Mark , Mikkola Marja Liisa
Published: August 2023

The Wnt/β-catenin pathway plays a critical role in cell fate specification, morphogenesis, and stem cell activation across diverse tissues, including the skin. In mammals, the embryonic surface epithelium gives rise to the epidermis, as well as the associated appendages including hair follicles and mammary glands, both of which depend on epithelial Wnt/β-catenin activity for initiation of their development. Later on, Wnts are thought to enhance mammary gland growth and branching while in hair follicles, they are essential for hair shaft formation. Here we report a strong downregulation of epithelial Wnt/β-catenin activity as the mammary bud progresses to branching. We show that forced activation of epithelial β-catenin severely compromises embryonic mammary gland branching. However, the phenotype of conditionalLef1deficient embryos implies that a low level of Wnt/β-catenin activity is necessary for mammary cell survival. Transcriptomic profiling suggests that sustained high β-catenin activity leads to maintenance of mammary bud gene signature at the expense of outgrowth/branching signature. In addition, it leads to upregulation of epidermal differentiation genes. Strikingly, we find a partial switch to hair follicle fate early on upon stabilization of β-catenin suggesting that the level of epithelial Wnt/β-catenin signaling activity may contribute to the choice between skin appendage identities.
Mapping threatened Thai bovids provides opportunities for improved conservation outcomes in Asia
Authors: Horpiencharoen Wantida , Muylaert Renata L. , Marshall Jonathan C. , John Reju Sam , Lynam Antony J. , Riggio Alex , Godfrey Alexander , Ngoprasert Dusit , Gale George A. , Ash Eric , Bisi Francesco , Cremonesi Giacomo , Clements Gopalasamy Reuben , Yindee Marnoch , Shwe Nay Myo , Pin Chanratana , Gray Thomas N. E. , Aung Saw Soe , Nakbun Seree , Manka Stephanie G. , Steinmetz Robert , Phoonjampa Rungnapa , Seuaturien Naret , Phumanee Worrapan , Hayman David T. S.
Published: August 2023

Wild bovids provide important ecosystem functions throughout their ranges. Five wild bovids remain in Thailand: gaur (Bos gaurus), banteng (Bos javanicus), wild water buffalo (Bubalus arnee), mainland serow (Capricornis sumatraensis) and Chinese goral (Naemorhedus griseus). However, their populations and habitats have declined substantially and become fragmented. Here, we identify potentially suitable habitat for these threatened bovids using ecological niche models and quantify how much suitable area remains within protected areas. We combined species occurrence data with environmental variables and used spatially-restricted Biotic-Abiotic-Mobility frameworks with species-specific and single large accessible areas. We used ensembles from eight algorithms for generating maps and out-of-sample predictions to validate model performance against new data. Gaur, banteng, and buffalo models performed well throughout the entire distribution (≥62%) and in Thailand (≥80%). Mainland serow and Chinese goral performed poorly for the entire distribution and in Thailand, though a 5 km movement buffer markedly improved model performance for serow. Particularly large suitable areas were in Thailand and India for gaur, Cambodia and Thailand for banteng, and India for buffalo. Over 50% of overall suitable habitat is located outside protected areas, with just 9% for buffalo in Thai protected areas, highlighting area for potential habitat management and conflict mitigation.
AlphaFold2 predicts interactions amidst confounding structural compatibility
Authors: Martin Juliette
Published: August 2023

Predicting physical interactions is one of the holy grails of computational biology, galvanized by rapid advancements in deep learning. AlphaFold2, although not developed with this goal, seems promising in this respect. Here, I test the prediction capability of AlphaFold2 on a very challenging data set, where proteins are structurally compatible, even when they do not interact. AlphaFold2 achieves high discrimination between interacting and non-interacting proteins, and the cases of misclassifications can either be rescued by revisiting the input sequences or can suggest false positives and negatives in the data set. Alphafold2 is thus not impaired by the compatibility between protein structures and has the potential to be applied at large scale.
Systematic creation and phenotyping of Mendelian disease models inC. elegans: towards large-scale drug repurposing
Authors: O’Brien Thomas J. , Barlow Ida L. , Feriani Luigi , Brown André E.X.
Published: August 2023

There are thousands of Mendelian diseases with more being discovered weekly and the majority have no approved treatments. To address this need, we require scalable approaches that are relatively inexpensive compared to traditional drug development. In the absence of a validated drug target, phenotypic screening in model organisms provides a route for identifying candidate treatments. Success requires a screenable phenotype, however the right phenotype and assay may not be obvious for pleiotropic neuromuscular disorders. Here we show that high-throughput imaging and quantitative phenotyping can be conducted systematically on a panel ofC. elegansdisease model strains. We used CRISPR genome-editing to create 25 worm models of human Mendelian diseases and phenotyped them using a single standardised assay. All but two strains were significantly different from wild-type controls in at least one feature. The observed phenotypes were diverse, but mutations of genes predicted to have related functions in their human orthologs led to similar behavioural differences in worms. As a proof-of-concept, we performed a drug repurposing screen of an FDA approved compound library, and identified two compounds that rescued the behavioural phenotype of a model of UNC80 deficiency. Our results show that a single assay to measure multiple phenotypes can be applied systematically to diverse Mendelian disease models. The relatively short time and low cost associated with creating and phenotyping multiple strains suggests that high-throughput worm tracking could provide a scalable approach to drug repurposing commensurate with the number of Mendelian diseases.
Sandy: A user-friendly and versatile NGS simulator to facilitate sequencing assay design and optimization
Authors: Miller Thiago L. A. , Conceição Helena B. , Mercuri Rafael L. , Santos Felipe R. C. , Barreiro Rodrigo , Buzzo José Leonel , Rego Fernanda O. , Guardia Gabriela , Galante Pedro A. F.
Published: August 2023

Next-generation sequencing (NGS) is currently the gold standard technique for large-scale genome and transcriptome studies. However, the downstream processing of NGS data is a critical bottleneck that requires difficult decisions regarding data analysis methods and parameters. Simulated or synthetic NGS datasets are practical and cost-effective alternatives for overcoming these difficulties. Simulated NGS datasets have known true values and provide a standardized scenario for driving the development of data analysis methodologies and tuning cut-off values. Although tools for simulating NGS data are available, they have limitations in terms of their overall usability and documentation. Here, we present Sandy, an open-source simulator that generates synthetic reads that mimic DNA or RNA next-generation sequencing on the Illumina, Oxford Nanopore, and Pacific Bioscience platforms. Sandy is designed to be user-friendly, computationally efficient, and capable of simulating data resembling a wide range of features of real NGS assays, including sequencing quality, genomic variations, and gene expression profiles per tissue. To demonstrate Sandy’s versatility, we used it to address two critical questions in designing an NGS assay: (i) How many reads should be sequenced to ensure unbiased analysis of gene expression in an RNA sequencing run? (ii) What is the lowest genome coverage required to identify most (90%) of the single nucleotide variants and structural variations in whole-genome sequencing? In summary, Sandy is an ideal tool for assessing and validating pipelines for processing, optimizing results, and defining the costs of NGS assays. Sandy runs on Linux, MacOS, and Microsoft Windows and can provide feasible results, even on personal computers. Availability: Sandy is freely available athttps://galantelab.github.io/sandy.
Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy
Authors: Joers Valerie , Murray Benjamin C , McLaughlin Caroline , Oliver Danielle , Staley Hannah , Coronado Jazmyn , Achat-Mendes Cindy , Golshani Sanam , Kelly Sean D. , Goodson Matthew , Lee Danica , Manfredsson Fredric P. , Moore Bob M. , Tansey Malú Gámez
Published: August 2023

Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson’s disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) alpha-synuclein in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes.In vitroanalysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodoE. colibioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies.
The genome of the colonial hydroidHydractiniareveals their stem cells utilize a toolkit of evolutionarily shared genes with all animals
Authors: Schnitzler Christine E. , Chang E. Sally , Waletich Justin , Quiroga-Artigas Gonzalo , Wong Wai Yee , Nguyen Anh-Dao , Barreira Sofia N. , Doonan Liam , Gonzalez Paul , Koren Sergey , Gahan James M. , Sanders Steven M. , Bradshaw Brian , DuBuc Timothy Q. , Febrimarsa  , Jong Danielle de , Nawrocki Eric P. , Larson Alexandra , Klasfeld Samantha , Gornik Sebastian G. , Moreland R. Travis , Wolfsberg Tyra G. , Phillippy Adam M. , Mullikin James C. , Simakov Oleg , Cartwright Paulyn , Nicotra Matthew , Frank Uri , Baxevanis Andreas D.
Published: August 2023

Hydractiniais a colonial marine hydroid that exhibits remarkable biological properties, including the capacity to regenerate its entire body throughout its lifetime, a process made possible by its adult migratory stem cells, known as i-cells. Here, we provide an in-depth characterization of the genomic structure and gene content of twoHydractiniaspecies,H. symbiolongicarpusandH. echinata, placing them in a comparative evolutionary framework with other cnidarian genomes. We also generated and annotated a single-cell transcriptomic atlas for adult maleH. symbiolongicarpusand identified cell type markers for all major cell types, including key i-cell markers. Orthology analyses based on the markers revealed thatHydractinia’s i-cells are highly enriched in genes that are widely shared amongst animals, a striking finding given thatHydractiniahas a higher proportion of phylum-specific genes than any of the other 41 animals in our orthology analysis. These results indicate thatHydractinia’s stem cells and early progenitor cells may use a toolkit shared with all animals, making it a promising model organism for future exploration of stem cell biology and regenerative medicine. The genomic and transcriptomic resources forHydractiniapresented here will enable further studies of their regenerative capacity, colonial morphology, and ability to distinguish self from non-self.
Long-term impacts on estuarine benthic assemblages 4.2 years after a mine tailing spill in SE Brazil
Authors: Coppo Gabriel C. , Gabriel Fabrício A. , Mazzuco Ana Carolina A. , Queiroz Hermano M. , Barcellos Diego , Ferreira Tiago O. , Bernardino Angelo F.
Published: August 2023

The Rio Doce estuary was critically impacted in 2015 by the world’s largest mining tailing spill, with still unclear long-term effects. Here we present a long-term (2015 to 2020) assessment of estuarine benthic assemblages, where Annelida and Mollusca were dominant (52.6% and 26.3%, respectively). Our results demonstrated that the density and richness of benthic taxa decreased in response to an increase in potentially toxic elements concentrations, suggesting a chronic pollution effect that lasted for at least 4.2 years in the estuary. Our data demonstrated that despite the decline in sediment potentially toxic elements concentration over time, there was a continued low habitat quality for the benthic fauna characterized by a reduction of 96% on macroinvertebrate density and 48% on species richness. The long-term impacts on benthic macrofauna highlight that water quality levels can misguide impact assessment programs, and reveal that mine tailings impacts persist for many years in estuarine ecosystems.
Synchronicity in zebrafish locomotive circuit development mediated by electrical pacemaker interneurons
Authors: Miles Kaleb D. , Barker Chase M. , Appel Bruce H. , Doll Caleb A.
Published: August 2023

The earliest motor output in vertebrate animals is generated by clusters of early-born motor neurons that occupy distinct regions of the spinal cord, innervating stereotyped muscle groups. Even the simplest movements require coordinated activity across these motor pools, yet motor neurons are not directly interconnected and instead project to the periphery. Instead, emerging motor circuits might be synchronized by pacemaker interneurons. We hypothesize that pacemaker interneurons are required for synchronization of motor neuron activity throughout the spinal cord, coupling motor pools through electrical gap junctions to ultimately drive coordinated motor behavior. With functional imaging in the embryonic zebrafish spinal cord, we show that ipsilateral caudal interneurons possess periodic activity profiles prior to widespread motor circuit activity that transition to synchronized Ca2+events in motor neurons throughout the spinal cord. Importantly, we also show that blockade of electrical gap junctions and ablation of pioneer pacemakers leads to desynchronization in developing motor circuits. Further, we use a genetic model of hyperactivity to gain critical insight into the consequences of errors in motor circuit formation and function, finding that Fragile X syndrome (FXS) model mutant zebrafish are hyperexcitable from the earliest phases of spontaneous behavior, show reduced sensitivity to blockade of electrical gap junctions, and have increased expression of the gap junction protein Connexin 36. Taken together, our work highlights the importance of pacemakers in the development of motor circuits and suggests that the origins of hyperactivity in neurodevelopmental disorders may be established during the initiation of motor circuit formation.
Niche-specific macrophage loss promotes skin capillary aging
Authors: Mesa Kailin R , O'Connor Kevin A. , Ng Charles , Salvatore Steven , Dolynuk Alexandra , Rivera Lomeli Michelle , Littman Dan R
Published: August 2023

All mammalian organs depend upon resident macrophage populations to coordinate repair processes and facilitate tissue-specific functions. Recent work has established that functionally distinct macrophage populations reside in discrete tissue niches and are replenished through some combination of local proliferation and monocyte recruitment. Moreover, decline in macrophage abundance and function in tissues has been shown to contribute to many age-associated pathologies, such as atherosclerosis, cancer, and neurodegeneration. Despite these advances, the cellular mechanisms that coordinate macrophage organization and replenishment within an aging tissue niche remain largely unknown. Here we show that capillary-associated macrophages (CAMs) are selectively lost over time, which contributes to impaired vascular repair and tissue perfusion in older mice. To investigate resident macrophage behavior in vivo, we have employed intravital two-photon microscopy to non-invasively image in live mice the skin capillary plexus, a spatially well-defined model of niche aging that undergoes rarefication and functional decline with age. We find that CAMs are lost with age at a rate that outpaces that of capillary loss, leading to the progressive accumulation of capillary niches without an associated macrophage in both mice and humans. Phagocytic activity of CAMs was locally required to repair obstructed capillary blood flow, leaving macrophage-less niches selectively vulnerable to both homeostatic and injury-induced loss in blood flow. Our work demonstrates that homeostatic renewal of resident macrophages is not as finely tuned as has been previously suggested. Specifically, we found that neighboring macrophages do not proliferate or reorganize sufficiently to maintain an optimal population across the skin capillary niche in the absence of additional cues from acute tissue damage or increased abundance of growth factors, such as colony stimulating factor 1 (CSF1). Such limitations in homeostatic renewal and organization of various niche-resident cell types are potentially early contributors to tissue aging, which may provide novel opportunities for future therapeutic interventions.
CNTN4 modulates neural elongation through interplay with APP
Authors: Bamford Rosemary A. , Zuko Amila , Sprengers Jan J. , Post Harm , Taggenbrock Renske L. R. E. , Mehr Annika , Jones Owen J. R. , Kudzinskas Aurimas , Gandawijaya Josan , Eve Madeline , Müller Ulrike C. , Kas Martien J. , Burbach J. Peter H. , Oguro-Ando Asami
Published: August 2023

The neuronal cell adhesion molecule contactin-4 (CNTN4) has been genetically linked to autism spectrum disorders (ASD) and other psychiatric disorders. TheCntn4-deficient mouse model has previously shown that CNTN4 has important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex have not yet been investigated.

Using Nissl staining, immunohistochemistry and Golgi staining the motor cortex ofCntn4-/-mice was analysed for abnormalities. Interacting partners of CNTN4 were identified by immunoprecipitation and mass spectrometry. Further analysis of the interaction between CNTN4 and APP utilised knockout human cells generated via CRISPR-Cas9 gene editing.

Our study newly identified reduced cortical thickness in the motor cortex ofCntn4-/-mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, and we confirmed an interaction between CNTN4 and APP. Knockout human cells of CNTN4 and/or APP revealed a relationship between CNTN4 and APP.

This study demonstrates that CNTN4 contributes to cortical development, and that its binding and interplay with APP controls neural elongation. This is an important finding for understanding the function of APP, a target protein for Alzheimer’s disease. The binding between Cntn4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth.
Theoretical minimum uncertainty of modulation enhanced spinning disk confocal microscopy
Authors: Kalisvaart Dylan , Hung Shih-Te , Smith Carlas S.
Published: August 2023

Modulation enhanced single-molecule localization microscopy (meSMLM), where emitters are sparsely activated with patterned illumination, increases the localization precision over SMLM. Furthermore, meSMLM improves the resolution over structured illumination microscopy while reducing the required amount of illumination patterns. These factors motivate enabling meSMLM in existing systems which employ patterned illumination intensity. Here, we introduce SpinFlux: modulation enhanced localization for spinning disk confocal microscopy. SpinFlux uses a spinning disk with pinholes in its illumination and emission paths, to illuminate select regions in the sample during each measurement. The resulting intensity-modulated emission signal is analyzed to localize emitters with improved precision. We derive a statistical image formation model for SpinFlux and we quantify the theoretical minimum uncertainty, in terms of the Cramér-Rao lower bound, for various illumination pattern configurations. We find that SpinFlux requires multiple patterns to improve the localization precision over SMLM, with the maximum improvement being 1.17 when using a single pattern. When using two pinholes on opposing sides of the emitter position, thex-localization precision can locally be improved 2.62-fold over SMLM, whereas they-precision is improved by maximally a factor 1.12. When using pinholes in a triangular configuration around the emitter position, the localization precision is balanced over thexandy-directions at approximately a twofold local improvement over SMLM, at the cost of suboptimal precision in each individual direction. When doughnut-shaped illumination patterns, created with a phase mask in the illumination and emission paths, are used for SpinFlux, the local precision improvement over SMLM is increased 3.5-fold in thex- andy-directions. While localization on ISM data ideally results in an average global improvement of 1.48 over SMLM, or 2.10 with Fourier reweighting, SpinFlux is the method of choice for local refinements of the localization precision.

Why it matters: One of the main objectives of singlemolecule localization microscopy (SMLM) is to improve the precision with which single molecules can be localized. This has been successfully achieved through modulation enhanced SMLM, which uses patterned illumination to increase the information content of signal photons. However, this technique relies on setups with increased technical complexity over SMLM. With SpinFlux, we locally enable a twoto 3.5-fold precision improvement over singlemolecule localization microscopy, which can be achieved with only minor modifications to existing spinning disk confocal microscopy setups (e.g. a phase mask in the illumination and emission paths). In addition, our modeling framework enables evaluation of a wide variety of spinning disk setups and therefore paves the way for optimal spinning disk design.
Generative adversarial networks in cell microscopy for image augmentation. A systematic review
Authors: Lesmes-Leon Duway Nicolas , Dengel Andreas , Ahmed Sheraz
Published: August 2023

Cell microscopy is the main tool that allows researchers to study microorganisms and plays a key role in observing and understanding the morphology, interactions, and development of microorganisms. However, there exist limitations in both the techniques and the samples that impair the amount of available data to study. Generative adversarial networks (GANs) are a deep learning alternative to alleviate the data availability limitation by generating nonexistent samples that resemble the probability distribution of the real data. The aim of this systematic review is to find trends, common practices, popular datasets, and analyze the impact of GANs in image augmentation of cell microscopy images. We used ScienceDirect, IEEE Xplore, PubMed, bioRxiv, and arXiv to select English research articles that employed GANs to generate any kind of cell microscopy images independently of the main objective of the study. We conducted the data collection using 15 selected features from each study, which allowed us to analyze the results from different perspectives using tables and histograms. 32 studies met the legibility criteria, where 18 had image augmentation as the main task. Moreover, we retrieved 21 publicly available datasets. The results showed a lack of consensus with performance metrics, baselines, and datasets. Additionally, we evidenced the relevance of popular architectures such as StyleGAN and losses including Vanilla and Wasserstein adversarial loss. This systematic review presents the most popular configurations to perform image augmentation. It also highlights the importance of design good practices and gold standards to guarantee comparability and reproducibility. This review implemented the ROBIS tool to assess the risk of bias, and it was not registered in PROSPERO.
Utilizing mentorship education to promote a culturally responsive research training environment in the biomedical sciences
Authors: Suiter Sarah , Byars-Winston Angela , Sancheznieto Fátima , Pfund Christine , Sealy Linda
Published: August 2023

There is an urgent and compelling need for systemic change to achieve diversity and inclusion goals in the biomedical sciences. Since faculty hold great influence in shaping research training environments, faculty development is a key aspect in building institutional capacity to create climates in which persons excluded because of their ethnicity or race (PEERs) can succeed. In this paper, we present a mixed methods case study of one institution’s efforts to improve mentorship of PEER doctoral students as a strategy to improve graduate trainees’ experiences, and as a strategy to positively affect institutional climate with respect to racial and ethnic diversity. We found evidence that our culturally responsive mentorship education increased faculty mentors’ self-reported mentorship competencies, though their valuing of culturally responsive mentoring behaviors were comparatively higher than their confidence to enact those behaviors. PEER doctoral students reported that they noticed mentors’ efforts to address cultural diversity matters and identified some guidance for how to approach such topics. We discuss future directions and implications for using mentorship education to activate systemic change toward inclusive research training environments and promoting the value of mentorship within institutions.
GraphMHC: neoantigen prediction model applying the graph neural network to molecular structure
Authors: Jeong Hoyeon , Cho Young-Rae , Gim Jungsoo , Cha Seung-Kuy , Kim Maengsup , Kang Dae Ryong
Published: August 2023

Neoantigens are biomarkers that can predict the prognosis associated with immune checkpoint inhibition by estimating the binding potential of candidate peptides to somatic mutation and major histocompatibility complex (MHC) proteins. Although deep neural networks have been primarily used for these prediction models, it is difficult to consider the models reported thus far as accurately representing the interactions between biomolecules. In this study, we propose the GraphMHC model, which utilizes a graph neural network model through molecular structure to simulate the binding between MHC proteins and peptide sequences. Amino acid sequences sourced from the immune epitope database (IEDB) undergo conversion into molecular structures. Subsequently, atomic intrinsic informations and inter-atomic connections are extracted and structured as a graph representation. Bindings are classified by feeding them into the GraphMHC network, comprising stacked graph attention and convolution layers. The prediction results from the test set using the GraphMHC model showed a high performance with an area under the receiver operating characteristic curve of 92.2% (91.9-92.5%), surpassing the baseline model. Moreover, by applying the GraphMHC model to melanoma patient data from the Cancer Genome Atlas project, we found a borderline difference in overall survival and a significant difference in stromal score between the high and low neoantigen load groups. This distinction was not present in the baseline model. This study presents the first feature-intrinsic method based on biochemical molecular structure for modeling the binding between MHC protein sequences and neoantigen candidate peptide sequences. The model can provide highly accurate suitability information for cancer patients who want to apply immune checkpoint inhibitors.

Author summary
How frequently are insects wounded in the wild? A case study usingDrosophila melanogaster
Authors: Subasi Bengisu S. , Grabe Veit , Kaltenpoth Martin , Rolff Jens , Armitage Sophie A.O.
Published: August 2023

Wounding occurs across multicellular organisms. There is a deep understanding of infections and immune responses from lab studies, yet wounds remain relatively comparatively understudied in nature. Ecological interactions like predator attacks, intra- and inter-specific competition can lead to wounding. Furthermore, rates of wounding may vary depending on factors such as sex and geographic location, with consequences for host mobility, reproduction, and susceptibility to pathogens.

Wounds initiate an immune response, resulting in the deposition of the brown-black pigment melanin in insects, and they are potential entry points for pathogens. Despite the potential ecological and evolutionary implications of wounding, and the relative abundance of lab immunity studies utilisingDrosophila melanogaster, wounding in the wild in this model is unstudied. Our aim, therefore, was to investigate the prevalence and examine potential causes of wounds in wild-collectedD. melanogaster.

From systematic collections of female and male flies, over three seasons and locations, we found that 31% ofD. melanogasterwere wounded. The abdomen was more frequently wounded than other body parts, and females were more likely to be injured particularly on the ventral abdomen, compared to males. Encapsulated parasitoid egg frequency was just under ten percent. Moreover, just under one percent of Drosophilidae species had mites attached to their body, the majority of which also caused wounds, i.e., were potentially parasitic.

Wounding is prevalent inD. melanogaster, and as such it is likely to exert selection pressure on host immunity for two reasons: on a rapid and efficient wound repair, and on responding to opportunistic infections. Wounds are thus expected to be important drivers of immune system evolution and to affect individual fitness and population dynamics.
African elephants address one another with individually specific calls
Authors: Pardo Michael A. , Fristrup Kurt , Lolchuragi David S. , Poole Joyce , Granli Petter , Moss Cynthia , Douglas-Hamilton Iain , Wittemyer George
Published: August 2023

Personal names are a universal feature of human language, yet few analogs exist in other species. While dolphins and parrots address conspecifics by imitating the calls of the addressee1,2, human names are not imitations of the sounds typically made by the name’s owner3. Labeling objects or individuals without relying on imitation of the sounds made by that object or individual is key to the expressive power of language. Thus, if non-imitative name analogs were found in other species, this could have important implications for our understanding of language evolution. Here, we show that wild African elephants address one another with individually specific calls without any evidence of imitating the receiver’s vocalizations. A random forest model correctly predicted receiver identity from call structure better than expected by chance, regardless of whether the calls were more or less similar to the receiver’s calls than typical for that caller. Moreover, elephants differentially responded to playbacks of calls originally addressed to them relative to calls addressed to a different individual, indicating that they can determine from a call’s structure if it was addressed to them. Our findings offer the first evidence for a non-human species individually addressing conspecifics without imitating the receiver.
Competition and the century-long decline of a once common lizard,Sceloporus consobrinus
Authors: Murray Alexander H. , Folfas Edita , Page Morgan A. , Lange Zachary K. , Mruzek Joseph L. , Frishkoff Luke O.
Published: August 2023

Habitat modification and climate change are primary mechanisms responsible for historical and ongoing population declines. Species interactions however, though difficult to study, may be of similar importance. Here we use a combination of historical species records, standardized transect surveys, and staged competition trials to assess the role of competition in recent population trends and distributions of two closely related lizard species: the prairie lizard (Sceloporus consobrinus) and the Texas Spiny lizard (S. olivaceus). Occurrence data reveals divergent population trends.S. consobrinushas decreased whileS. olivaceushas increased in relative frequency over the last 100 years. We analyzed spatially-aggregated records of all lizards within the range ofS. consobrinusto determine the role of climate suitability, climate change, landcover, and species interactions in shaping the occurrence patterns ofS. consobrinus. In contrast to other lizard species, presence ofS. olivaceuswas associated with substantial reductions ofS. consobrinusoccurrence, and explains occurrence patterns better than either climate suitability or landcover. To test whether patterns of broad scale co-occurrence are indicative of local competitive exclusion we conducted 200m transects surveys to assess lizard communities and paired this with staged behavioral trials in the lab. Despite occurring in similar habitats, and across similar regions, transect surveys revealed lower-than-expected abundance ofS. consobrinuson transects containingS. olivaceus, with both species co-occurring on only 2 of 176 transects. Shifts in habitat use implicate competitive displacement, withS. consobrinusoccupying areas with three times less canopy cover at sites withS. olivaceuscompared to those without. Finally, behavioral trials revealed competitive dominance ofS. olivaceus, which controlled the prime basking position, and initiated more interactions that led to retreat or hiding byS. consobrinus. Our study implicates competitive interactions as in important force in structuring species’ distributions and population trends.
Identifying dysregulated regions in amyotrophic lateral sclerosis through chromatin accessibility outliers
Authors: Celik Muhammed Hasan , Gagneur Julien , Lim Ryan G , Wu Jie , Thompson Leslie M. , Xie Xiaohui
Published: August 2023

The high heritability of ALS and similar rare diseases contrasts with their low molecular diagnosis rate post-genetic testing, pointing to potential undiscovered genetic factors. Chromatin accessibility assays quantify the activity of functional elements genome-wide, offering invaluable insights into dysregulated regions. In this research, we introduced EpiOut, a computational toolbox to identify outliers in chromatin accessibility. These outliers represent dysregulated regions where chromatin accessibility uniquely diverges from the population baseline in a single or few samples. Annotation of accessible regions with histone ChIP-seq and Hi-C indicates that outliers are concentrated in functional loci, especially among promoters interacting with active enhancers. Across different omics levels, outliers are robustly replicated, and chromatin accessibility outliers are reliable predictors of gene expression outliers and aberrant protein levels. For example, 59% of gene expression outliers can be linked to aberration in chromatin accessibility. When promoter accessibility does not align with gene expression, our results indicate that molecular aberrations are more likely to be linked to post-transcriptional regulation rather than transcriptional regulation. Our findings demonstrate that the outlier detection paradigm can uncover dysregulated regions in rare diseases. EpiOut is open-sourced and freely available atgithub.com/uci-cbcl/EpiOut.
CoFrEE: An Application to Estimate DNA Copy Number from Genome-wide RNA Expression Data
Authors: Gaenko Anita , Ray Dipankar , Nancarrow Derek J.
Published: August 2023

We introduce CoFrEE, a simple python-based approach to extracting copy number data from expression values that works with either RNAseq or array-based expression data. CoFrEE works best in tumor cohorts that include a subset of non-tumor tissues and is applied to processed (RSEM, RPKM or TPM) expression, rather than raw data. Experiments with real public data suggest CoFrEE can provide copy number estimations comparable to existing RNAseq-based approaches, with the advantage of also being applicable to the multitude of older expression-array cohorts.