bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and development of a noninvasive ocular pressure estimator
Authors: Karthikeyan Siddharth K. , Sundaram Swaminathan M. , Ve Ramesh S. , Souza Donson D. , Biswas Sayantan , Shetty Mayur U.
Published: March 2024

SIGNIFICANCE

A snapshot intraocular pressure (IOP) is ineffective in identifying the IOP peak and fluctuation, especially during sleep. Because IOP variability plays a significant role in the progression of glaucoma, monitoring the IOP, especially during sleep, is essential to capture the dynamic nature of IOP.

PURPOSE

We aimed to design an ocular pressure estimator (OPE) that can reliably and accurately measure the IOP noninvasively over closed-eyelid condition.

METHODS

Ocular pressure estimator works on the principle that the external pressure applied by raising the IOP of the eyeball is transmitted through a compressible septum to the pressure sensor, thus recording the IOP. A fluid-filled pouch with a pressure sensor was placed over a rubber glove mimicking the eyelid (septum), covering the cornea of enucleated goat eyeballs. A pressure-controlled setup was connected to a goat cadaver eye, which was validated by a rebound tonometer. Cannulation of eyeballs through the lower limbus had the least difference from the control setup values documented using rebound tonometer, compared with cannulation through the optic nerve. Intraocular pressures ranging from 3 to 30 mmHg was induced, and the outputs recorded using OPE were amplified and recorded for 10 minutes (n = 10 eyes). We stratified the randomization of the number of times and the induced pressures.

RESULTS

The measurements recorded were found to be linear when measured against an IOP range of 3 to 30 mmHg. The device has excellent reliability (intraclass correlation coefficient, 0.998). The repeatability coefficient and coefficient of variations were 4.24 (3.60 to 4.87) and 8.61% (7.33 to 9.90), respectively. The overall mean difference ± SD between induced IOP and the OPE was 0.22 ± 3.50 (95% confidence interval, −0.35 to 0.79) mmHg across all IOP ranges.

CONCLUSIONS

Ocular pressure estimator offers a promising approach for reliably and accurately measuring IOP and its fluctuation noninvasively under a condition mimicking a closed eye.
The epidemiology of eye illness in Para athletes in the Winter and Summer settings- a systematic review
Authors: Kunorozva Lovemore , Runciman Phoebe , Ganai Ali , Derman Wayne E.
Published: March 2024

The aim of this systematic review was to evaluate eye illnesses in para athletes in the winter and summer settings. A search was conducted using PubMed-Medline, EbscoHost, and Web of Science for full-text original research articles published anytime until November 2022. Studies that reported quantitative data on eye illness in highly active individuals and para athletes, at any level of performance (elite/nonelite/recreational), aged 15–75 yrs were included. Of the eight studies included, two reported eye pathologies in athletes with visual impairment only, and six studies reported specific factors associated with eye illnesses in various impairments. Illnesses in the eye and adnexa were more prevalent in winter (incidence: 1.6–2.2/1000 athlete days) compared to summer (incidence: 0.3–0.5/1000 athlete days) settings. Eye illnesses were reported in athletes with limb deficiency (33.5%), spinal cord injury (29.4%), visual impairment (10.6%), and central neurologic impairment (15.2%). The findings of this review indicate that: (1) eye illness in para athletes is an understudied area; and (2) eye illnesses are present in athletes with impairments other than visual impairment. There is a need for further research on eye illness, particularly in winter sports settings to understand the types and nature of eye illness affecting para athletes during competition and training settings.
Medical Metaphors That May Reinforce Misconceptions Are Associated With Increased Trust in the Clinician
Authors: Chandler Calvin , Azarpey Ali , Brinkman Niels , Ring David , Reichel Lee , Ramtin Sina
Published: March 2024

Background and Objectives:

This study measured patient reactions to medical metaphors used in musculoskeletal specialty offices and asked: (1) Are there any factors associated with patient thoughts and emotions in response to common metaphors? (2) Is there a difference between patient ratings of metaphors rated as potentially reinforcing misconceptions and those that are more neutral?

Methods:

In a cross-sectional study, 228 patients presenting to multiple musculoskeletal specialty offices rated reactions to 4 metaphors presented randomly from a set of 14. Two were categorized as potentially reinforcing common misconceptions and 2 as relatively neutral. Bivariate tests and multivariable regression identified factors associated with patient ratings of levels of emotion (using the standard assessment manikins) and aspects of experience (communication effectiveness, trust, and feeling comfortable rated on 11-point ordinal scales) in response to each metaphor.

Results:

Levels of patient unhelpful thinking or distress regarding symptoms were not associated with patient ratings of patient emotion and experience in response to metaphors. Metaphors that reinforce misconceptions were associated with higher ratings of communication effectiveness, trust, and comfort (P < .05).

Conclusion:

The observation that metaphors that validate a person’s understanding of his or her illness may elicit trust even if those metaphors have the potential to reinforce misconceptions may account for the common usage of such metaphors. Clinicians can work to incorporate methods for building trust without reinforcing misconceptions.
Effectiveness of Huddles in Improving the Patient Safety Attitudes Among Clinical Team Members
Authors: Lai Yi-Hung , Chang Ching-Wein , Wu Ming-Ju , Chen Hsin-Hua , Lin Shih-Ping , Chin Chun-Shih , Lin Cheng-Hsien , Shiu Sz-Iuan , Wu Chun-Yi , Lin Ying-Cheng , Chen Hui-Chi , Hou Shu-Chin , Lin Hung-Ru
Published: March 2024

Background and Objectives:

Huddles among members of interdisciplinary medical teams involve short stand-up sessions and allow team members to focus on existing or emerging patient safety issues, thereby facilitating team communication. Hospital managers are able to recognize the current situation of the organization through patient safety attitudes, strengthen team members’ awareness of patient safety, and improve the quality of health care. The purpose of this study was to determine the effects of huddles on improving team members’ attitudes toward patient safety.

Methods:

We used a quasi-experimental design and selected 2 adult wards with similar properties as the experimental and comparison groups by convenience sampling. Data collection was from December 1, 2021, to June 30, 2022, at a teaching hospital in central Taiwan. Team members of the ward performing huddles formed the experimental group, and they participated 2 times per week in 15-minute huddles from 8:15 to 8:30 am for a total of 4 weeks. The comparison group adopted the routine team care process. Both groups completed the Safety Attitudes Questionnaire during the pre- and post-tests of the study.

Results:

The experimental group scored significantly higher in the post-test than in the pre-test in all aspects of safety attitudes, with the exception of stress recognition. These improved aspects were teamwork climate (76.47 ± 15.90 vs 83.29 ± 13.52, P < .001), safety climate (75.94 ± 16.14 vs 82.81 ± 13.74, P < .001), job satisfaction (74.34 ± 20.22 vs 84.40 ± 17.22, P <.001), perceptions of management (78.02 ± 19.99 vs 85.51 ± 15.97, P < .001), and working conditions (78.85 ± 17.87 vs 86.81 ± 14.74, P < .001).

Conclusion:

Through the huddles, clinical team members improved their understanding of different aspects of safety attitudes. Such a study provided ward units with real-time improvement and adjustment in terms of patient safety during their medical work processes with better patient safety.
Transition to Adult Rheumatology Care: A Disease-Specific Guide
Authors: Cintron Dahima , Chang Joyce C. , Sadun Rebecca E.
Published: March 2024

Young adults with childhood-onset rheumatic diseases are more frequently establishing and continuing care with adult rheumatologists. The transfer of care can be challenging for both the young adult patients and their adult rheumatologists, in large part due to differences between pediatric-onset rheumatic diseases and their adult-onset counterparts, or due to the rarity of some pediatric-onset rheumatic conditions. Other challenges are due to cultural differences between pediatric and adult medical care and to the young adult needing to increasingly perform self-management skills that were previously managed by parents or other caregivers. In this review, we will provide a summary of strategies for working effectively with young adults as they transition to adult care. We will then discuss a subset of childhood-onset rheumatic diseases—including juvenile idiopathic arthritis, localized scleroderma, autoinflammatory diseases, pediatric-onset systemic lupus erythematosus, juvenile-onset dermatomyositis, and autoimmune encephalitis—for which clinical manifestations, management, and prognosis frequently differ between pediatric onset and adult onset. Our aim is to highlight differences that make caring for this population of transitioning young adults unique, providing tools and knowledge to empower the adult rheumatologist to care for these young adults in ways that are evidence-based, effective, efficient, and rewarding.
ZIP Code to Genomic Code
Authors: Goel Neha , Hernandez Alexandra E. , Antoni Michael H. , Kesmodel Susan , Pinheiro Paulo S. , Kobetz Erin , Merchant Nipun , Cole Steve
Published: March 2024

Objective:

To determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer (BCa) tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes.

Summary Background Data:

ND is associated with shorter BCa recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS.

Methods:

We quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology—pro-inflammatory activity (NF-kB, AP-1), sympathetic nervous system (SNS) activity (CREB), and protective cellular responses (IRF, STAT). To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively.

Results:

Increasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB, AP-1, down-regulated IRF, STAT) and SNS activation (up-regulated CREB). Increasing subjective ND (e.g., threat to safety), was associated with up-regulated NF-kB and CREB and down-regulated IRF. These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS.

Conclusions:

In the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort.
Obesity and Native Tissue Repairs: A Secondary Analysis of the OPTIMAL Trial
Authors: Hagedorn Meghan K. , Locklear Tonja M. , Evans Sarah , Karp Natalie E. , Greer W. Jerod
Published: March 2024

Importance

The Operations and Pelvic Muscle Training in the Management of Apical Support Loss (OPTIMAL) Trial compared sacrospinous ligament fixation (SSLF) and uterosacral ligament suspension (ULS) surgical outcomes. Increasing body mass index (BMI) is associated with an increased risk of pelvic organ prolapse, and the prevalence of obesity is increasing worldwide.

Objective

The purpose of this study was to better understand the effect of obesity on the results of native tissue vaginal apical suspension procedures.

Study Design

This was a secondary analysis of the OPTIMAL Trial data set. Subgroup analysis was performed to compare surgical failure rates between SSLF and ULS across BMI subgroups after 2 years.

Results

There were 75, 120, 63, and 39 patients in the normal, overweight, class 1 obesity, and class 2 obesity or greater BMI subgroups, respectively. There were no statistically significant differences in surgical failure rates between SSLF and ULS within BMI subgroups; however, failure rates increased in the ULS group between the nonobese and obese groups (normal, 35.9% SSLF vs 30.6% ULS [P = 0.81]; overweight, 38.6% vs 30.2% [P = 0.44]; class 1 obesity, 38.7% vs 40.6% [P = 0.92]; class 2 obesity or greater, 21.1% vs 45% [P = 0.21]).

Conclusions

The risk of surgical failure between SSLF and ULS was not significant across BMI subgroups. Additional investigation is required to further elucidate whether SSLF or ULS is a more reliable option for obese patients.
Vaginal Estrogen Prescribing and Cost Trends Among Medicare Part D Beneficiaries
Authors: Tabakin Alexandra L. , Lee Wai , Winkler Harvey A. , Shalom Dara F.
Published: March 2024

Importance

In 2016, the American College of Obstetricians and Gynecologists issued a Committee Opinion on the safety of vaginal estrogen (VE) in estrogen-dependent breast cancer patients. Since that time, prescribing trends of VE have not been studied.

Objective

Our objective was to analyze expenditure and prescribing trends of VE from 2016 to 2020 for Medicare Part D beneficiaries.

Study Design

In this retrospective review, we queried the Medicare Part D Spending and Prescriber Datasets from 2016 to 2020 to identify claims for VE. Trends regarding claims, expenditures, beneficiaries, and prescribers were examined. A subanalysis of the Medicare Part D Prescriber Dataset was performed for obstetrician-gynecologist-specific trends. Statistical analysis was done with the Kruskal-Wallis test.

Results

From 2016 to 2020 for all specialties, the number of VE claims decreased annually from 945,331 in 2016 to 320,571 in 2020. Most claims were for Estrace (49.5%) followed by Yuvafem (23.3%), Vagifem (14.5%), and Estring (12.7%). The number of VE prescribers decreased from 20,216 to 5,380, with obstetrician-gynecologists comprising 60% of all prescribers. Beneficiaries decreased by more than 70% from 439,210 to 123,318, whereas average spending per beneficiary increased from $688.52 to $1,027.55. Total annual spending on VE decreased from $277,891,645 to $106,679,580. However, average spending per claim increased from $293.40 to $355.28 and increased for all products besides Yuvafem.

Conclusions

Vaginal estrogen claims, beneficiaries, and total expenditures across all provider types have decreased from 2016 to 2020. However, spending per beneficiary and VE claims have increased. Our data suggest that utilization and accessibility of vaginal estrogen may be influenced, in part, by cost.
Aspartate aminotransferase and alanine aminotransferase elevation in suspected physical abuse: Can the threshold to obtain an abdominal computed tomography be raised?
Authors: Lee Ji Young , Coombs Carmen , Clarke Jennifer , Berger Rachel
Published: March 2024

BACKGROUND

Identification of abdominal injury (AI) in children with concern for physical abuse is important, as it can provide important medical and forensic information. Current recommendations are to obtain screening liver function tests (LFTs) in all children with suspected physical abuse and an abdominal computed tomography (CT) when the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is >80 IU/L. This threshold to obtain an abdominal CT is lower than general trauma guidelines, which use a cutoff of AST >200 IU/L or ALT >125 IU/L.

METHODS

This was a retrospective review of children aged 0 to 60 months at a single pediatric tertiary care center who were evaluated for physical abuse and had AST or ALT >80 IU/L. Subjects were then stratified into two groups: midrange (AST ≤200 IU/L and ALT ≤125 IU/L) and high-range (AST >200 IU/L and/or ALT >125 IU/L) LFTs.

RESULTS

Abdominal CTs were performed in 55% (131 of 237) of subjects, 38% (50 of 131) with midrange LFTs and 62% (81 of 131) with high-range LFTs. Abdominal injury was identified in 19.8% (26 of 131) of subjects. Subjects with AI were older than those without AI (mean [SD] age, 18.7 [12.5] vs. 11.6 [12.2] months; p = 0.009). The highest yield of abdominal CTs positive for AI was in the group with high-range LFTs with signs or symptoms of AI at 52.0% (13 of 25; 95% confidence interval, 31.3–72.2%). The negative predictive value of having midrange LFTs and no signs or symptoms of AI was 100% (95% confidence interval, 97.0–100%).

CONCLUSION

Our data suggest that abdominal CT may not be necessary in children being evaluated for physical abuse who have AST ≤200 IU/L and ALT ≤125 IU/L and do not have signs or symptoms of AI. This could limit the number of abdominal CTs performed.

LEVEL OF EVIDENCE

Diagnostic Test/Criteria; Level IV.
Shifting our attention earlier in the multiple sclerosis disease course
Authors: Epstein Samantha E. , Longbrake Erin E.
Published: March 2024

Purpose of review

Revisions of multiple sclerosis (MS) diagnostic criteria enable clinicians to diagnose patients earlier in the biologic disease course. Prompt initiation of therapy correlates with improved clinical outcomes. This has led to increased attention on the earliest stages of MS, including the MS prodrome and radiologically isolated syndrome (RIS). Here, we review current understanding and approach to patients with preclinical MS.

Recent findings

MS disease biology often begins well before the onset of typical MS symptoms, and we are increasingly able to recognize preclinical and prodromal stages of MS. RIS represents the best characterized aspect of preclinical MS, and its diagnostic criteria were recently revised to better capture patients at highest risk of conversion to clinical MS. The first two randomized control trials evaluating disease modifying therapy use in RIS also found that treatment could delay or prevent onset of cli

nical disease.

Despite progress in our understanding of the earliest stages of the MS disease course, additional research is needed to systematically identify patients with preclinical MS as well as capture those at risk for developing clinical disease. Recent data suggests that preventive immunomodulatory therapies may be beneficial for high-risk patients with RIS; though management remains controversial.
Evolutionary trajectory of TRPM2 channel activation by adenosine diphosphate
ribose and calcium
Authors: Ma Cheng , Luo Yanping , Zhang Congyi , Cheng Cheng , Hua Ning , Liu Xiaocao , Wu Jianan , Qin Luying , Yu Peilin , Luo Jianhong , Yang Fan , Jiang Lin-Hua , Zhang Guojie , Yang Wei
Published: March 2024

Ion channel activation upon ligand gating triggers a myriad of biological
events and, therefore, evolution of ligand gating mechanism is of fundamental
importance. TRPM2, a typical ancient ion channel, is activated by adenosine
diphosphate ribose (ADPR) and calcium and its activation has evolved from a
simple mode in invertebrates to a more complex one in vertebrates, but the
evolutionary process is still unknown. Molecular evolutionary analysis of TRPM2s
from more than 280 different animal species has revealed that, the C-terminal
NUDT9-H domain has evolved from an enzyme to a ligand binding site for
activation, while the N-terminal MHR domain maintains a conserved ligand binding
site. Calcium gating pattern has also evolved, from one
Ca2+-binding site as in sea anemones to three sites as
in human. Importantly, we identified a new group represented by olTRPM2, which
has a novel gating mode and fills the missing link of the channel gating
evolution. We conclude that the TRPM2 ligand binding or activation mode evolved
through at least three identifiable stages in the past billion years from simple
to complicated and coordinated. Such findings benefit the evolutionary
investigations of other channels and proteins.
Data science and its future in large neuroscience collaborations
Authors: Schottdorf Manuel , Yu Guoqiang , Walker Edgar Y.
Published: March 2024

The rise of large scientific collaborations in neuroscience requires systematic, scalable, and reliable data management. How this is best done in practice remains an open question. To address this, we conducted a data science survey among currently active U19 grants, funded through the NIH’s BRAIN Initiative. The survey was answered by both data science liaisons and Principal Investigators, speaking for ∼500 researchers across 21 nation-wide collaborations. We describe the tools, technologies, and methods currently in use, and identify several shortcomings of current data science practice. Building on this survey, we develop plans and propose policies to improve data collection, use, publication, re-use and training in the neuroscience community.
Unbiased complexome profiling and global proteomics analysis reveals mitochondrial impairment and potential changes at the intercalated disk in presymptomatic R14Δ/+mice hearts
Authors: Foo Brian , Amedei Hugo , Kaur Surmeet , Jaawan Samir , Boshnakovska Angela , Gall Tanja , de Boer Rudolf A. , Silljé Herman H.W. , Urlaub Henning , Rehling Peter , Lenz Christof , Lehnart Stephan E.
Published: March 2024

Background

Phospholamban (PLN) is a sarco-endoplasmic reticulum (SER) membrane protein that regulates cardiac contraction/relaxation by reversibly inhibiting the SERCA2a Ca2+-reuptake pump. The R14Δ-PLN mutation causes severe cardiomyopathy that is resistant to conventional treatment. Protein complexes and higher-order supercomplexes such as intercalated disk components and Ca+2-cycling domains underlie many critical cardiac functions, a subset of which may be disrupted by R14Δ-PLN.

Methods

We developed an improved complexome profiling (CP) workflow specifically geared towards identifying disruption of very high molecular-weight (>2 MDa) protein complexes and supercomplexes in presymptomatic R14Δ/+mice hearts. Ventricular tissues were homogenized under non-denaturing conditions, fractionated by size-exclusion chromatography (SEC) and subjected to quantitative data-independent acquisition mass spectrometry (DIA-MS) proteomics analysis. Systematic analysis of CP data using conventional strategies yielded limited insights, likely due to underrepresentation of cardiac-specific complexes in the curated protein complex databases used as ground-truth for analysis. We thus developed PERCOM: a novel data analysis strategy that does not rely upon protein complex databases and can, furthermore, be implemented on widely available spreadsheet software.

Results

SEC-DIA-MS coupled with PERCOM identified 296 proteins with disrupted elution profiles in presymptomatic 28wk-old R14Δ/+mice. Hits were significantly enriched for mitochondrial and intercalated disk (ICD) components. Alterations to mitochondrial and ICD supercomplexes were observed in mice as young as 9wks of age and were associated with reduced expression of mitochondrial proteins and maximal oxygen consumption rate.

Conclusion

Using a novel CP workflow, we identify mitochondrial alterations as an early-stage R14Δ-PLN event and provide preliminary data showing effects at the ICD. These molecular components underlie critical cardiac functions and their alteration at a young age may contribute to R14Δ-PLN pathogenesis.
Reassembly of a tropical rainforest ecosystem: A new chronosequence in the Ecuadorian Chocó tested with the recovery of tree attributes
Authors: Escobar Sebastián , Newell Felicity L. , Endara María-José , Guevara-Andino Juan E. , Landim Anna R. , Neuschulz Eike Lena , Nußer Ronja , Müller Jörg , Pedersen Karen M. , Schleuning Matthias , Tremlett Constance J. , Villa-Galaviz Edith , Schaefer H. Martin , Donoso David A , Blüthgen Nico
Published: March 2024

From hunting and foraging to clearing land for agriculture, humans modify forest biodiversity, landscapes, and climate. Forests constantly undergo disturbance–recovery dynamics and understanding them is a major objective of ecologists and conservationists. Chronosequences are a useful tool for understanding global restoration efforts. They represent a space-for-time substitution approach suited for the quantification of theresistanceof ecosystem properties to withstand disturbance and theresilienceof these properties until reaching pre-disturbance levels. Here we introduce a newly established chronosequence with 62 plots (50 ⍰ 50 m) in active cacao plantations and pastures, early and late regeneration, and mature old-growth forests, across a 200 km2 area in the extremely wet Chocó rainforest. Our chronosequence covers by far the largest total area of plots compared to others in the Neotropics. Plots ranged from 159–615 masl in a forested landscape with 74 ± 2.8 % forest cover within a 1-km radius including substantial old-growth forest cover. Land-use legacy and regeneration time were not confounded by elevation. We tested how six forest structure variables (maximum tree height and DBH, basal area, number of stems, vertical vegetation heterogeneity, and light availability), aboveground biomass (AGB), and rarefied tree species richness change along our chronosequence. Forest structure variables, AGB, and tree species richness increased with regeneration time and are predicted to reach similar levels to those in old-growth forests after ca. 30–116, 202, and 108 yrs, respectively. Compared to previous work in the Neotropics, old-growth forests in Canandé accumulate high AGB that takes one of the largest time spans reported until total recovery. Our chronosequence comprises one of the largest tree species pools, covers the largest total area of regenerating and old-growth forests, and has higher forest cover than other Neotropical chronosequences. Hence, our chronosequence can be used to determine the time for recovery and stability (resistance and resilience) of different taxa and ecosystem functions, including species interaction networks. This integrative effort will ultimately help to understand how one of the most diverse forests on the planet recovers from large-scale disturbances.
DNA damage drives antigen diversification through mosaic Variant Surface Glycoprotein (VSG) formation inTrypanosoma brucei
Authors: Smith Jaclyn E. , Wang Kevin J. , Kennedy Erin M. , Hakim Jill M.C. , So Jaime , Beaver Alexander K. , Magesh Aishwarya , Gilligan-Steinberg Shane D. , Zheng Jessica , Zhang Bailin , Moorthy Dharani Narayan , Akin Elgin Henry , Mwakibete Lusajo , Mugnier Monica R.
Published: March 2024

Antigenic variation, using large genomic repertoires of antigen-encoding genes, allows pathogens to evade host antibody. Many pathogens, including the African trypanosomeTrypanosoma brucei,extend their antigenic repertoire through genomic diversification. While evidence suggests thatT. bruceidepends on the generation of new variant surface glycoprotein (VSG) genes to maintain a chronic infection, a lack of experimentally tractable tools for studying this process has obscured its underlying mechanisms. Here, we present a highly sensitive targeted sequencing approach for measuring VSG diversification. Using this method, we demonstrate that a Cas9-induced DNA double-strand break within the VSG coding sequence can induce VSG recombination with patterns identical to those observed during infection. These newly generated VSGs are antigenically distinct from parental clones and thus capable of facilitating immune evasion. Together, these results provide insight into the mechanisms of VSG diversification and an experimental framework for studying the evolution of antigen repertoires in pathogenic microbes.
Attentional modulation of secondary somatosensory and visual thalamus of mice
Authors: Petty Gordon H , Bruno Randy M
Published: March 2024

Each sensory modality has its own primary and secondary thalamic nuclei. While the primary thalamic nuclei are well understood to relay sensory information from the periphery to the cortex, the role of secondary sensory nuclei is elusive. We trained head-fixed mice to ateend to one sensory modality while ignoring a second modality, namely to ateend to touch and ignore vision, or vice versa. Arrays were used to record simultaneously from secondary somatosensory thalamus (POm) and secondary visual thalamus (LP). In mice trained to respond to tactile stimuli and ignore visual stimuli, POm was robustly activated by touch and largely unresponsive to visual stimuli. A different pateern was observed when mice were trained to respond to visual stimuli and ignore touch, with POm now more robustly activated during visual trials. This POm activity was not explained by differences in movements (i.e., whisking, licking, pupil dilation) resulting from the two tasks. Post hoc histological reconstruction of array tracks through POm revealed that subregions varied in their degree of plasticity. LP exhibited similar phenomena. We conclude that behavioral training reshapes activity in secondary thalamic nuclei. Secondary nuclei respond to the same behaviorally relevant, reward-predicting stimuli regardless of stimulus modality.
How do we respond to the next SARS CoV epidemic/pandemic? A bioinformatics approach with the promise of preventing or reducing the severity of future SARS CoV related pandemics
Authors: Geoffrey A S Ben , Gracia Judith
Published: March 2024

In this work, we develop a Bayesian weighted scheme to generate evolutionary lineages of a particular viral protein sequence of interest and through a process of clustering and choosing representative lineages from the different clusters according to an evolutionary fitness objective function, we demonstrate it is possible to have anticipated the emergence of the SARS-CoV 2 (2019) strain from the SARS-CoV 1(2004) strain and having shown this retrospectively, we discuss the possibility of applying this approach along with continuous genomic surveillance of SARS-CoVs to prevent or reduce severity of future SARS-CoV related pandemics by being prepared with broad neutralization strategies for anticipated future lineages of SARS-CoVs identified through bioinformatics approaches such as that reported in this work.
Unexpectedly low recombination rates and presence of hotspots in termite genomes
Authors: Everitt Turid , Rönneburg Tilman , Elsner Daniel , Olsson Anna , Liu Yuanzhen , Larva Tuuli , Korb Judith , Webster Matthew T
Published: March 2024

Meiotic recombination is a fundamental evolutionary process that facilitates adaptation and the removal of deleterious genetic variation. Social Hymenoptera exhibit some of the highest recombination rates among metazoans, whereas high recombination rates have not been found among non-social species from this insect order. It is unknown whether elevated recombination rates are a ubiquitous feature of all social insects. In many metazoan taxa, recombination is mainly restricted to hotspots a few kilobases in length. However, little is known about the prevalence of recombination hotspots in insect genomes. Here we infer recombination rate and its fine-scale variation across the genomes of two social species from the insect order Blattodea: the termitesMacrotermes bellicosusandCryptotermes secundus. We used linkage-disequilibrium-based methods to infer recombination rate. We infer that recombination rates are close to 1 cM/Mb in both species, similar to the average metazoan rate. We also observed a highly punctate distribution of recombination in both termite genomes, indicative of the presence of recombination hotspots. We infer the presence of full-lengthPRDM9genes in the genomes of both species, which suggests recombination hotspots in termites might be determined byPRDM9, as they are in mammals. We also find that recombination rates in genes are correlated with inferred levels of germline DNA methylation. The finding of low recombination rates in termites indicates that eusociality is not universally connected to elevated recombination rate. We speculate that the elevated recombination rates in social Hymenoptera are instead promoted by intense selection among haploid males.
Reference-informed prediction of alternative splicing and splicing-altering mutations from sequences
Authors: Xu Chencheng , Bao Suying , Chen Hao , Jiang Tao , Zhang Chaolin
Published: March 2024

Alternative splicing plays a crucial role in protein diversity and gene expression regulation in higher eukaryotes and mutations causing dysregulated splicing underlie a range of genetic diseases. Computational prediction of alternative splicing from genomic sequences not only provides insight into gene-regulatory mechanisms but also helps identify disease-causing mutations and drug targets. However, the current methods for the quantitative prediction of splice site usage still have limited accuracy. Here, we present DeltaSplice, a deep neural network model optimized to learn the impact of mutations on quantitative changes in alternative splicing from the comparative analysis of homologous genes. The model architecture enables DeltaSplice to perform “reference-informed prediction” by incorporating the known splice site usage of a reference gene sequence to improve its prediction on splicing-altering mutations. We benchmarked DeltaSplice and several other state-of-the-art methods on various prediction tasks, including evolutionary sequence divergence on lineage-specific splicing and splicing-altering mutations in human populations and neurodevelopmental disorders, and demonstrated that DeltaSplice outperformed consistently. DeltaSplice predicted ∼15% of splicing quantitative trait loci (sQTLs) in the human brain as causal splicing-altering variants. It also predicted splicing-alteringde novomutations outside the splice sites in a subset of patients affected by autism and other neurodevelopmental disorders, including 19 genes with recurrent splicing-altering mutations. Among the new candidate disease risk genes,MFN1is involved in mitochondria fusion, which is frequently disrupted in autism patients. Our work expanded the capacity ofin silicosplicing models with potential applications in genetic diagnosis and the development of splicing-based precision medicine.
Development and evaluation of a kidney health questionnaire and estimates of chronic kidney disease prevalence in the Cooperative Health Research In South Tyrol (CHRIS) study
Authors: Giulia Barbieri , Lucia Cazzoletti , Roberto Melotti , Essi Hantikainen , Rebecca Lundin , Laura Barin , Martin Gögele , Peter Riegler , Manuel Ferraro Pietro , Paul Pramstaller Peter , Giovanni Gambaro , Elisabetta Zanolin Maria , Cristian Pattaro
Published: March 2024

Introduction

Kidney diseases are a public health burden but, except for chronic kidney disease (CKD), they are poorly investigated in the general population. In light of inadequate survey tools for use in population studies, we developed a novel questionnaire to retrospectively assess the main kidney diseases, integrating it within the Cooperative Health Research In South Tyrol (CHRIS) study conducted between 2011 and 2018 in the Alpine district of Val Venosta/Vinschgau (Italy).

Methods

The questionnaire covers general kidney diseases, reduced kidney function, and renal surgeries. It was applied to the cross-sectional assessment of self-reported kidney health among 11,684 adults, along with measures of fasting estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR). By factor analysis we contextualized the questionnaire content with respect to biochemical measurements. CKD was defined according to KDIGO guidelines, self-reported diagnosis, and their combination. Prevalence estimates were calibrated to the general target population via relative sampling weights.

Results

In this population sample (median age=45 years; median eGFR=98.4 mL/min/1.73 m2; median UACR=5.7 mg/g), 8.3% of participants reported at least one kidney disease. Population-representative prevalence of glomerulonephritis, pyelonephritis, and congenital kidney diseases was 1.0%, 3.0%, and 0.2%, respectively, with corresponding odds ratio for females versus males of 1.4 (95% confidence interval: 1.0, 2.0), 8.7 (6.2, 12.3), and 0.7 (0.3, 1.6), respectively. CKD prevalence was 8.6% when based on KDIGO criteria and 0.7% when self-reported, indicating that 95.3% of affected individuals were unaware of having CKD, with a similar figure of 92.9% in those reporting diabetes or hypertension. Overall, 15.8% of the population was affected by a kidney disease of any kind.

Conclusion

In this Alpine population, CKD prevalence aligned with Western European estimates. Kidney health questionnaire implementation in population studies is feasible and valuable to assess CKD awareness, which we found to be dramatically low.
Evaluating soluble Axl as a biomarker for glioblastoma: a pilot study
Authors: Raymond Daniel , Fukui Melanie B. , Zwernik Samuel , Kassam Amin , Rovin Richard A. , Akhtar Parvez
Published: March 2024

With current imaging, discriminating tumor progression from treatment effect following immunotherapy or oncolytic virotherapy of glioblastoma (GBM) is challenging. A blood based diagnostic biomarker would therefore be helpful. Axl is a receptor tyrosine kinase that is highly expressed by many cancers including GBM. Axl expression is regulated through enzymatic cleavage of its extracellular domain. The resulting fragment can be detected in serum as soluble Axl (sAxl). sAxl levels can distinguish patients with melanoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma from healthy controls. This is a pilot study to determine if sAxl is a candidate biomarker for GBM. The sAxl levels in the serum of 40 healthy volunteers and 20 GBM patients were determined using an enzyme-linked immunosorbent assay (ELISA). Pre- and post-operative sAxl levels were obtained. Volumetric MRI evaluation provided GBM tumor volume metrics. There was no significant difference in the sAxl levels of the volunteers (30.16±1.88 ng/ml) and GBM patients (30.74±1.96 ng/ml) p=0.27. The postoperative sAxl levels were significantly higher than preoperative levels (32.32±2.26 ng/ml vs 30.74±1.96 ng/ml, p=0.03). We found no correlation between tumor volume and sAxl levels. Axl expression was low or absent in 6 of 11 (55%) patient derived GBM cell lines. Given the wide range of Axl expression by GBM tumors, sAxl may not be a reliable indicator of GBM. However, given the small sample size in this study, a larger study may be considered.
Machine Learning Prediction of Autism Spectrum Disorder Through Linking Mothers’ and Children’s Electronic Health Record Data
Authors: Li Yongqiu , Huang Yu , Yang Shuang , Shychuk Elahe M. , Shenkman Elizabeth A. , Bian Jiang , Angell Amber M. , Guo Yi
Published: March 2024

Autism spectrum disorder (ASD) is a neurodevelopmental disorder typically diagnosed in children. Early detection of ASD, particularly in girls who are often diagnosed late, can aid long-term development for children. We aimed to develop machine learning models for predicting ASD diagnosis in children, both boys and girls, using child-mother linked electronic health records (EHRs) data from a large clinical research network. Model features were children and mothers’ risk factors in EHRs, including maternal health factors. We tested XGBoost and logistic regression with Random Oversampling (ROS) and Random Undersampling (RUS) to address imbalanced data. Logistic regression with RUS considering a three-year observation window for children’s risk factors achieved the best performance for predicting ASD among the overall study population (AUROC = 0.798), boys (AUROC = 0.786), and girls (AUROC = 0.791). We calculated SHAP values to quantify the impacts of important clinical and sociodemographic risk factors.
Changes in quantity and timing of foliar and reproductive phenology of tropical dry-forest trees under a warming and drying climate
Authors: Lai Hao Ran , Hill Timothy , Stivanello Silvio , Chapman Hazel M
Published: March 2024

Plant phenology drives population dynamics and forest productivity; it is also impacted by shifting environmental cues under climate change such as more prevalent drought. It is imperative to better understand how species and community phenology respond to climate change in leaf turnover and reproduction, both of which are required to integrate phenology into full life-cycle assessments.

However, relatively few studies to-date examined the quantity and timing of phenology simultaneously. We demonstrate that the simultaneous assessment of phenological quantity and timing across multiple organs reveals more nuanced and holistic insights into the consequences of climate change.

Extending a regression approach based on Fourier series, we decomposed the long-term (2004–2020) monthly leaf shedding, leaf flush, flowering and fruiting of 617 trees across 94 taxa at a Nigerian seasonally dry tropical forest into three periodic components—mean intensity, amplitude and phase—which respectively represents the total quantity, pulse concentration and peak timing of phenology. We then related each periodic component to warming minimum temperature and drying wet-season rainfall.

We found that climate explained more variation in phenological amplitudes (14–66%) compared to mean intensity and timing (6–49%). In drier years, more species (18%) shed leaves earlier (changing timing) or in more concentrated pulses (changing amplitude), while only a few (2%) shed leaves in greater total amounts (changing mean intensity). This combined with the decreased mean intensity of leaf flush imply a lower primary productivity as trees deployed fewer leaves for a shorter period. Some species (30%) produced fewer fruits despite no change or even increase in flowering; in a few species this could be explained by a shortened flowering period that limited pollination. At the community level, reproduction became more synchronous, potentially creating periods of scarcity for consumers.

Synthesis:Our findings highlight several contrasting yet complementary phenology– climate insights, indicating that assessments of forests’ climate resilience necessitate multiple aspects of phenology rather than a single performance indicator. The decline of leaf and fruit productions, as well as the temporal mismatches in leaf turnover and reproduction, will have cascading impacts on trophic interactions and nutrient cycling.
Dietary regulation of silent synapses in the dorsolateral striatum
Authors: Meyers Allison M. , Gnazzo Federico G. , Barrera Eddy D. , Nabatian Tikva , Chan Larry , Beeler Jeff A.
Published: March 2024

Obesity and drugs of abuse share overlapping neural circuits and behaviors. Silent synapses are transient synapses that are important for remodeling brain circuits. They are prevalent during early development but largely disappear by adulthood. Drugs of abuse increase silent synapses during adulthood and may facilitate reorganizing brain circuits around drug-related experience, facilitating addiction and contributing to relapse during treatment and abstinence. Whether obesity causes alterations in the expression of silent synapses in a manner similar to drugs of abuse has not been examined. Using a dietary-induced obesity paradigm, mice that chronically consumed high fat diet (HFD) exhibited increased silent synapses in both direct and indirect pathway medium spiny neurons in the dorsolateral striatum. Both the time of onset of increased silent synapses and their normalization upon discontinuation of HFD occurs on an extended time scale compared to drugs of abuse. These data demonstrate that chronic consumption of HFD, like drugs of abuse, can alter mechanisms of circuit plasticity likely facilitating neural reorganization analogous to drugs of abuse.
Optimisation of SARS-CoV-2 culture from clinical samples for clinical trial applications
Authors: Wooding Dominic , Buist Kate , Romero-Ramirez Alessandra , Savage Helen , Watkins Rachel , Bengey Daisy , Greenland-Bews Caitlin , Thompson Caitlin R , Kontogianni Nadia , Body Richard , Hayward Gail , Byrne Rachel L , Gould Susan , Group CONDOR Steering , Myerscough Christopher , Atkinson Barry , Shaw Victoria , Greenhalf Bill , Adams Emily , Cubas-Atienzar Ana , Khoo Saye , Fletcher Tom , Edwards Thomas
Published: March 2024

Clinical trials of SARS-CoV-2 therapeutics often include virological secondary endpoints to compare viral clearance and viral load reduction between treatment and placebo arms. This is typically achieved using RT-qPCR, which cannot differentiate replicant competent virus from non-viable virus or free RNA, limiting its utility as an endpoint. Culture based methods for SARS-CoV-2 exist; however, these are often insensitive and poorly standardised for use as clinical trial endpoints.

We report optimisation of a culture-based approach evaluating three cell lines, three detection methods, and key culture parameters. We show that Vero-ACE2-TMPRSS2 (VAT) cells in combination with RT-qPCR of culture supernatants from the first passage provides the greatest overall detection of Delta viral replication (22/32, 68.8%), being able to identify viable virus in 83.3% (20/24) of clinical samples with initial Ct values <30. Likewise, we demonstrate that RT-qPCR using culture supernatants from the first passage of Vero hSLAM cells provides the highest overall detection of Omicron viral replication (9/31, 29%), detecting live virus in 39.1% (9/23) of clinical samples with initial Ct values < 25. This assessment demonstrates that combining RT-qPCR with virological end point analysis has utility in clinical trials of therapeutics for SARS-CoV-2; however, techniques may require optimising based on dominant circulating strain.
Exploring the Diagnostic Potential of miRNA Signatures in the Fabry Disease Serum: A Comparative Study of Automated and Manual Sample Isolations
Authors: Fang Josephine Y. , Ayyadurai Saravanan , Pybus Alyssa F. , Sugimoto Hiroshi , Qian Mark G.
Published: March 2024

Fabry disease, an X-linked lysosomal storage disorder caused by galactosidase alpha (GLA) gene mutations, exhibits diverse clinical manifestations, and poses significant diagnostic challenges. Early diagnosis and treatment are crucial for improved patient outcomes, pressing the need for reliable biomarkers. In this study, we aimed to identify miRNA candidates as potential biomarkers for Fabry disease using the KingFisher™ automated isolation method and NanoString nCounter® miRNA detection assay.

Clinical serum samples were collected from both healthy subjects and Fabry disease patients. RNA extraction from the samples was performed using the KingFisher™ automated isolation method with the MagMAX mirVana™ kit or manually using the Qiagen miRNeasy kit. The subsequent NanoString nCounter® miRNA detection assay showed consistent performance and no correlation between RNA input concentration and raw count, ensuring reliable and reproducible results. Interestingly, the detection range and highly differential miRNA between the control and disease groups were found to be distinct depending on the isolation method employed. Nevertheless, enrichment analysis of miRNA-targeting genes consistently revealed significant associations with angiogenesis pathways in both isolation methods. Additionally, our investigation into the impact of enzyme replacement therapy on miRNA expression indicated that some differential miRNAs may be sensitive to treatment.

Our study provides valuable insights to identify miRNA biomarkers for Fabry disease. While different isolation methods yielded various detection ranges and highly differential miRNAs, the consistent association with angiogenesis pathways suggests their significance in disease progression. These findings lay the groundwork for further investigations and validation studies, ultimately leading to the development of non-invasive and reliable biomarkers to aid in early diagnosis and treatment monitoring for Fabry disease.