bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of the Y Chromosome in Newfoundland and Labrador: Evidence of a Founder Effect
Authors: Zurel Heather , Bhérer Claude , Batten Ryan , MacMillan Margaret E. , Demiriz Sedat , Mirhendi Sadra , Gilbert Edmund , Cavalleri Gianpiero L. , Leach Richard A. , Scott Roderick E. M. , Mugford Gerald , Randhawa Ranjit , Symington Alison L. , Stephens J. Claiborne , Phillips Michael S.
Published: August 2022

The population of Newfoundland and Labrador (NL) is largely derived from settlers who migrated primarily from England and Ireland in the 1700-1800s. Previously described as an isolated founder population, based on historical and demographic studies, data on the genetic ancestry of this population remains fragmentary. Here we describe the largest investigation of patrilineal ancestry in NL. To determine the paternal genetic structure of the population, 1,110 Y chromosomes from an NL based cohort were analyzed using 5,761 Y-specific markers. We identified 160 distinct paternal haplotypes, the majority of which (71.4%) belong to the R1b haplogroup. When NL is compared with global reference populations, the haplotype composition and frequencies of the NL paternal lineages primarily resemble the English and Irish ancestral source populations. There is also evidence for genetic contributions from Basque, French, Portuguese, and Spanish fishermen and early settlers that frequented NL. The population structure shows geographical and religious clustering that can be associated with the settlement of ancestral source populations from England and Ireland. For example, the R1b-M222 haplotype, seen in people of Irish descent, is found clustered in the Irish-settled Southeast region of NL. The clustering and expansion of Y haplotypes in conjunction with the geographical and religious clusters illustrate that limited subsequent in-migration, geographic isolation and societal factors have contributed to the genetic substructure of the NL population and its designation as a founder population.
A Topological Study of a Surface Signaling Network and Possible Implications for Neural Dynamics
Authors: Sen Siddhartha , Ryan Tomás J. , Muldowney David , Stamenov Plamen S. , Pezzoli Maurizio
Published: August 2022

Theoretical neuroscience is progressing strongly with novel representations of the brain, enhanced by the constant increase of computational power now available. New models suggest new ways to understand how complex brain events are emerging and explore the mechanisms of storing memory. However, there are major conceptual theoretical problems that remain unaddressed. Current theoretical methods are very capable reacting to experimental results and modeling both neural signaling and structure. Yet they still fall short to throw light on how the brain creates its own information code, or relate the variety of brain signals observed, or explain where and how memories are stored. We present here with topology as our main tool, a mathematical structure that demonstrates that circuit architecture and signal can correlate, while preserving information. This concept would imply a possible substrate for memory recording, that despite so far not been observed in biological organisms, has been already demonstrated on solid state physics and is consistent with conventional understandings of neurobiology.
Warming undermines emergence success in a threatened alpine stonefly: a multi-trait perspective on vulnerability to climate change
Authors: Shah Alisha A. , Hotaling Scott , Lapsansky Anthony , Malison Rachel L. , Birrell Jackson H. , Keeley Tylor , Giersch J. Joseph , Tronstad Lusha M. , Woods H. Arthur
Published: August 2022

Species vulnerability to global warming is often assessed using short-term metrics such as the critical thermal maximum (CTmax), which represents an organism’s ability to survive extreme heat. However, an understanding of the long-term effects of sub-lethal warming is an essential link to fitness in the wild, and these effects are not adequately captured by metrics like CTmax. The meltwater stonefly,Lednia tumana, is endemic to high-elevation streams of Glacier National Park, MT, USA, and has long been considered acutely vulnerable to climate change-associated stream warming. In 2019, it was listed as Threatened under the U.S. Endangered Species Act. This presumed vulnerability to warming was challenged by a recent study showing that nymphs can withstand short-term exposure to temperatures as high as ~27 °C. But how this short-term tolerance relates to chronic, long-term warming has remained unclear. By measuring fitness-related traits at several ecologically relevant temperatures over several weeks, we show thatL. tumanacannot complete its life-cycle at temperatures well below the CTmax values measured for its nymphs. Although warmer temperatures maximized growth rates, they appear to have a detrimental impact on other key traits (survival, emergence success, and wing development), thus extending our understanding ofL. tumana’svulnerability to climate change. Our results call into question the use of CTmax as a measure of thermal sensitivity, while highlighting the power and complexity of multi-trait approaches to assessing climate vulnerability.
Plantar flexor deficits following Achilles tendon rupture: a novel small animal dynamometer and detailed instructions
Authors: Tang My M. , Nuss Courtney A. , Fogarty Natalie , Baxter Josh R.
Published: August 2022

Plantar flexor functional deficits measured using joint dynamometry are associated with poor outcomes in patients following Achilles tendon rupture. In this study, we developed a small animal dynamometer to quantify functional deficits in a rat Achilles tendon rupture model. Like our reported plantar flexor deficits in patients recovering from Achilles tendon ruptures, we found in our small animal model functional deficits across the ankle range of motion, resulting in an average 34% less positive work being done compared to the uninjured contralateral limb. These functional deficits are similar to 38% less plantar flexor work done by patients who were treated non-surgically in our prior research. Further, these deficits were greater in plantar flexion than dorsiflexion, which agree with clinical complaints of limited function during tasks like jumping and hiking. These findings highlight the impact of muscle-tendon loading during early tendon healing on long-term plantar flexor function and serve as compelling evidence that our Sprague Dawley rat model of an Achilles tendon rupture recapitulates the human disease. We provide thorough documentation for other groups to build their own dynamometers, which can be modified to meet unique experimental criteria.

SIGNIFIGANCE

Preclinical models are critical tools for translating knowledge discovery to clinical decision making. We developed a low-cost and flexible joint dynamometer that quantifies joint function in small animals. Here, we used a rat model to test the implications of Achilles tendon ruptures not surgically repaired on plantar flexor function. We found that Achilles tendon ruptures in a rodent model closely resemble the functional deficits our group has observed in patients.
Temporal Regulation of Cold Transcriptional Response in Switchgrass
Authors: Ranaweera Thilanka , Brown Brianna N.I. , Wang Peipei , Shiu Shin-Han
Published: August 2022

Switchgrass low-land ecotypes have significantly higher biomass but lower cold tolerance compared to up-land ecotypes. Understanding the molecular mechanisms underlying cold response, including the ones at transcriptional level, can contribute to improving tolerance of high-yield switchgrass under chilling and freezing environmental conditions. Here, by analyzing an existing switchgrass transcriptome dataset, the temporalcis-regulatory basis of switchgrass transcriptional response to cold is dissected computationally. We found that the number of cold-responsive genes and enriched Gene Ontology terms increased as duration of cold treatment increased from 30 min to 24 hours, suggesting an amplified response/cascading effect in cold-responsive gene expression. To identify genomic sequences likely important for regulating cold response, machine learning models predictive of cold response were established usingk-mer sequences enriched in the genic and flanking regions of cold-responsive genes but not non-responsive genes. Thesek-mers, referred to as putativecis-regulatory elements (pCREs) are likely regulatory sequences of cold response in switchgrass. There are in total 655 pCREs where 54 are important in all cold treatment time points. Consistent with this, eight of 35 known cold-responsive CREs were similar to top-ranked pCREs in the models and only these eight were important for predicting temporal cold response. More importantly, most of the top-ranked pCREs were novel sequences in cold regulation. Our findings suggest additional sequence elements important for cold-responsive regulation previously not known that warrant further studies.
Uncertain Precision: Neurobiological and Physiological Correlates of Conservative Confidence Bias
Authors: Allen Micah , Hauser Tobias U. , Schwarzkopf Dietrich Samuel , Dolan Raymond J. , Rees Geraint
Published: August 2022

Correctly estimating the influence of uncertainty on our decisions is a critical metacognitive faculty. However, the relationship between sensory uncertainty (or its inverse, precision), decision accuracy, and subjective confidence is currently unclear. Although some findings indicate that healthy adults exhibit an illusion of over-confidence, under-confidence in response to sensory uncertainty has also been reported. One reason for this ambiguity is that stimulus intensity and precision are typically confounded with one another, limiting the ability to assess their independent contribution to metacognitive biases. Here we report four psychophysical experiments controlling these factors, finding that healthy human participants are systematically under-confident when discriminating low-precision stimuli. This bias remains even when decision accuracy and reaction time are accounted for, indicating that a performance-independent computation partially underpins the influence of sensory precision on confidence. We further show that this influence is linked to fluctuations in arousal and individual differences in the neuroanatomy of the left superior parietal lobe and middle insula. These results illuminate the neural and physiological correlates of precision misperception in metacognition.

Significance Statement

The ability to recognize the influence of sensory uncertainty on our decisions underpins the veracity of self-monitoring, or metacognition. In the extreme, a systematic confidence bias can undermine decision accuracy and potentially underpin disordered self-insight in neuropsychiatric illness. Previously it was unclear if metacognition accurately reflects changes in sensory precision, in part due to confounding effects of stimulus intensity and precision. Here we overcome these limitations to repeatedly demonstrate a robust precision-related confidence bias. Further, we reveal novel neuroanatomical and physiological markers underlying this metacognitive bias. These results suggest a unique state-based computational mechanism may drive subjective confidence biases and further provide new avenues for investigating maladaptive awareness of uncertainty in neuropsychiatric disorders.
Genome-wide Profiling of Histone Modifications inPlasmodium falciparumusing CUT&RUN
Authors: Morillo Riward Campelo , Harris Chantal T. , Kennedy Kit , Kafsack Björn F.C.
Published: August 2022

We recently adapted a CUT&RUN protocol for genome-wide profiling of chromatin modifications in the human malaria parasitePlasmodium. Using the step-by-step protocol described below, we were able to generate high quality profiles of multiple histone modifications using only a small fraction of the cells required for ChIPseq. Using antibodies against two commonly profiled histone modifications, H3K4me3 and H3K9me3, we show here that CUT&RUN profiling is highly reproducible and closely recapitulates previously published ChIPseq-based abundance profiles of histone marks. Finally, we show that CUT&RUN requires substantially lower sequencing coverage for accurate profiling compared to ChIPseq.
Formulation excipients and their role in insulin stability and association state in formulation
Authors: Maikawa Caitlin L. , Nguyen Leslee T. , Mann Joseph L. , Appel Eric A.
Published: August 2022

While excipients are often overlooked as the “inactive” ingredients in pharmaceutical formulations, they often play a critical role in protein stability and absorption kinetics. Recent work has identified an ultrafast absorbing insulin formulation that is the result of excipient modifications. Specifically, the insulin monomer can be isolated by replacing zinc and the phenolic preservative metacresol with phenoxyethanol as an antimicrobial agent and an amphiphilic acrylamide copolymer excipient for stability. A greater understanding is needed of the interplay between excipients, insulin association state, and stability in order to optimize this formulation. Here, we formulated insulin with different preservatives and stabilizing excipient concentrations using both insulin lispro and regular human insulin and assessed the insulin association states using analytical ultracentrifugation as well as formulation stability. We determined that phenoxyethanol is required to eliminate hexamers and promote a high monomer content even in a zinc-free lispro formulation. There is also a concentration dependent relationship between the concentration of polyacrylamide-based copolymer excipient and insulin stability, where a concentration greater than 0.1 g/mL copolymer is required for a mostly monomeric zinc-free lispro formulation to achieve stability exceeding that of Humalog in a stressed aging assay. Further, we determined that under the formulation conditions tested zinc-free regular human insulin remains primarily hexameric and is not at this time a promising candidate for rapid-acting formulations.
Effects of fire regime on the bird community in an Amazonian savanna
Authors: Coelho Laís Araújo , Ritter Camila Duarte , Lima Albertina Pimentel , Cintra Renato , Magnusson William E. , Sanaiotti Tânia Margarete
Published: August 2022

Savanna ecosystems are maintained by fires with a fire-adapted biota, and savannas occur in Amazonia in patches surrounded by tropical forest. Different fire regimes can generate structurally diverse vegetation, and the composition of savanna bird assemblages is known to be closely related to vegetation structure. However, long-term approaches and interaction of fire with other environmental factors need to be explored for the better understanding of the effects of fire on birds. In an Amazonian landscape composed by savanna and forest, we investigated the effects of different fire regimes in a 12-ha area in three periods through 23 years. We also examined the effects of frequency and extent of fires, tree cover, and distance to forest on bird composition in twelve 3.7- ha savanna plots. Birds were surveyed with mist-nets and species were classified as to their habitat use by comparison of registers in forest and savanna plots through visual/acoustical surveys. After 13 years without fire, many forest species colonized the area and some savanna species were lost. Fire regime affected avifauna assemblages. The avifauna was sensitive to the occurrence of fires. After one fire event in a plot that had not burned for 12 years, some savanna species returned. These results highlight the effects of the fire regime on birds and indicate that many savanna bird species depend on the occurrence of regular fires.
Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity
Authors: Cheers Samuel R. , O’Connor Anne E. , Johnson Travis K. , Merriner D. Jo , O’Bryan Moira K. , Dunleavy Jessica E. M.
Published: August 2022

The development and function of male gametes is critically dependent on a dynamic microtubule network, yet how this is regulated remains poorly understood. We have recently shown that microtubule severing, via the action of the meiotic AAA ATPase protein clade, plays a critical role in this process. Here, we sought to elucidate the roles of spastin, an as yet unexplored member of this clade in spermatogenesis. Using a SpastKO/KO mouse model, we reveal that spastin loss resulted in a complete loss of functional germ cells. Spastin plays a critical role in the assembly and function of the male meiotic spindle, and in its absence, apoptosis is significantly increased. Consistent with meiotic failure, round spermatid nuclei were enlarged, indicating aneuploidy, but were still able to enter spermiogenesis. During spermiogenesis, we observed extreme abnormalities in manchette structure, supernumerary acrosome formation, and commonly, a loss of nuclear integrity. This work defines a novel and essential role for spastin in regulating microtubule dynamics during spermatogenesis and is of potential relevance to patients carrying Spastin variants and to the medically assisted reproductive technology industry.

Summary statement

We identify an essential role for the microtubule severing enzyme spastin in the regulation of microtubule dynamics during spermatogenesis.
Indoleamine 2, 3-dioxygenase 1 mediated alterations in the functionality of immune cells, decipher the pregnancy outcomes in crossbred dairy cows
Authors: Mohapatra Sunil Kumar , Chaudhary Dheeraj , Panda Bibhudatta S. K. , Somagond Yallappa M. , Kamboj Aarti , Kapila Rajeev , Dang Ajay Kumar
Published: August 2022

Pregnancy establishment in bovines requires maternal immune cell modulation. Present study investigated possible role of immunosuppressive indolamine-2, 3-dioxygenase 1 (IDO1) enzyme in the alteration of neutrophil (NEUT) and peripheral blood mononuclear cells (PBMCs) functionality of crossbred cows. Blood was collected from non-pregnant (NP) and pregnant (P) cows, followed by isolation of NEUT and PBMCs. Plasma pro-inflammatory (IFNγ and TNFα) and anti-inflammatory cytokines (IL-4 and IL-10) were estimated by ELISA and analysis of IDO1 gene in NEUT and PBMCs by RT-qPCR. Neutrophil functionality was assessed by chemotaxis, measuring activity of myeloperoxidase and β-D glucuronidase enzyme and evaluating nitric oxide production. Changes in PBMCs functionality was determined by transcriptional expression of pro-inflammatory (IFNγ, TNFα) and anti-inflammatory cytokine (IL-4, IL-10, TGFβ1) genes. Significantly elevated (P < 0.05) anti-inflammatory cytokines, increased IDO1 expression, reduced NEUT velocity, MPO activity and NO production observed only in P cows. Significantly higher (P < 0.05) expression of anti-inflammatory cytokines and TNFα genes were observed in PBMCs. Study highlights possible role of IDO1 in modulating the immune cell and cytokine activity during early pregnancy and may be targeted as early pregnancy biomarkers.
Mercury exposure and health risks associated with use of skin-lightening products: A systematic review
Authors: Bastiansz Ashley , Ewald Jessica , Saldaña Verónica Rodríguez , Santa-Rios Andrea , Basu Niladri
Published: August 2022

Background

The Minamata Convention on Mercury (Article 4) prohibits the manufacture, import or export of skin-lightening products containing mercury concentrations above 1 μg/g. However, there is a lack of knowledge surrounding the global prevalence of mercury-added skin-lightening products.

Objective

The objective of this study was to increase our understanding of worldwide human mercury exposure and associated health risks from the use of skin-lightening products.

Methods

A systematic search of peer-reviewed scientific literature was performed in four databases (PubMed, Web of Science Core Collection, Scopus, and Toxline). The initial search in July of 2018 identified 1,711 unique scientific articles, of which 34 were ultimately deemed eligible for inclusion after iterative screens at the title, abstract, and whole text levels. A second search was performed in November of 2020 using the same methods, of which another 7 scientific articles were included. All papers were organized according to four data groups 1) “Mercury in products”, 2) “Usage of products”, 3) “Human biomarkers of exposure”; and 4) “Health impacts”, prior to data extraction and synthesis.

Results

This review was based on data contained within 41 peer-reviewed scientific papers from 22 countries worldwide published between 2000 and 2020. In total, we captured mercury concentration values from 787 skin-lightening product samples (overall pooled central median mercury level was 0.49 μg/g, IQR: 0.02 – 5.9) and 1,042 human biomarker measurements from 863 individuals. We also synthesized usage information from 3,898 individuals, and self-reported health impacts associated with using mercury-added products from 832 individuals.

Discussion

This review suggests that mercury widely exists as an active ingredient in many skin-lightening products worldwide, and that users are at risk of variable, and often high exposures. These synthesized findings help increase our understanding of the health risks associated with the use of these products.
Physician Responses to Apple Watch-Detected Irregular Rhythm Alerts: A Case-Based Survey
Authors: Demkowicz Patrick C. , Dhruva Sanket S. , Spatz Erica S. , Beatty Alexis L. , Ross Joseph S. , Khera Rohan
Published: August 2022

Background

While the US Food and Drug Administration (FDA) has cleared smart watch software for detecting atrial fibrillation (AF), there is lack of guidance on management by physicians.

Methods

We conducted a case-based survey of physicians in primary care, emergency medicine, and cardiology at Yale and University of California San Francisco from September to December 2021. Cases described asymptomatic patients receiving Apple Watch AF alerts; cases varied in sex, race, medical (diabetes and hypertension) history, and notification frequency. Physicians were asked to select from among prespecified diagnostic testing, referral, and treatment options.

Results

We emailed 636 physicians, of whom 95 (14.9%) filled out the survey, including 39 primary care, 25 emergency medicine, and 31 cardiology physicians. Among a total of 192 cases (16 unique scenarios), physicians selected at least one diagnostic test in 191 (99.5%) cases and medications in 48 (25.0%). Rates of patient referral (14%, 30%, and 16%, respectively; P=.048), rhythm monitoring (84%, 46%, and 94%, respectively; P<.001), measurement of BNP (8%, 20%, and 2%; P=.003), and use of antiarrhythmics (16%, 4%, and 23%; P=.023) varied among primary care, emergency medicine, and cardiology, respectively. Management was largely consistent across case characteristics (race, sex, medical history, and alert frequency).

Conclusion

In hypothetical cases of patients presenting without clinical symptoms, physicians opted for further diagnostic testing and often to medical intervention based on Apple Watch irregular rhythm notifications. There was also considerable variation across physician specialties, suggesting a need for uniform clinical practice guidelines.
Plasma cell-free DNA methylome profiling in pre- and post-surgery oral cavity squamous cell carcinoma
Authors: Patel Krupal B , Padhya Tapan A , Huang Jinyong , Wang Liang , Wang Xuefeng
Published: August 2022

Purpose

Head and neck squamous cell carcinoma cancer (HNSCC), a highly heterogeneous disease that involves multiple anatomic sites, is a leading cause of cancer-related mortality worldwide. Although the utility of noninvasive biomarkers based on circulating cell-free DNA (cfDNA) methylation profiling has been widely recognized, limited studies have been reported so far regarding the dynamics of cfDNA methylome in oral cavity squamous cell carcinoma (OCSCC). It is hypothesized in this study that comparison of methylation profiles in pre- and post-surgery plasma samples will reveal OCSCC-specific prognostic and diagnostic biomarkers.

Materials and methods

Matched plasma samples from eight patients with OCSCC were collected at Moffitt Cancer Center before and after surgical resection. Plasma-derived cfDNA was analyzed by cfMBD-seq, which is a high-sensitive methylation profiling assay. Differential methylation analysis was then performed based on the matched samples profiled. As a strategy to further prioritize tumor-specific targets, top differential methylated regions (DMRs) were called by reanalyzing methylation data from paired tumor and normal tissue collected in the TCGA head and neck cancer cohort.

Results

In the top 200 HNSCC-specific DMRs detected based on the TCGA dataset, a total of 23 regions reached significance in the plasma-based DMR test. The top five validated DMR regions (ranked by the significance in the plasma study) are located in the promoter regions of genes PENK, NXPH1, ZIK1, TBXT and CDO1, respectively. The genome-wide cfDNA DMR analysis further highlighted candidate biomarkers located in genes SFRP4, SOX1, IRF4 and PCDH17. The prognostic relevance of candidate genes was confirmed by survival analysis using the TCGA data.

Conclusion

This study supports the utility of cfDNA-based methylome profiling as a promising noninvasive biomarker source for OCSCC and HNSCC.
MULTI-OMICS TEMPORAL PROFILING OF AXIAL SPONDYLOARTHRITIS PATIENTS REVEALS AN ASSOCIATION OF THERAPEUTIC RESPONSE TO ADALIMUMAB WITH DISEASE ACTIVITY AND INNATE / ADAPTIVE IMMUNITY
Authors: Sobral Daniel , Fernandes Ana F , Sardoo Atlas , Bernardes Miguel , Pinto Patrícia , Santos Helena , Lagoas-Gomes João , Tavares-Costa José , AP Silva José , Dias João M , Bernardo Alexandra , Gaillard Jean-Charles , Armengaud Jean , Benes Vladimir , Domingues Lúcia , Gouveia Nélia , Maia Sara , Branco Jaime C , Coelho Ana V , Pimentel-Santos Fernando M
Published: August 2022

Background

Axial Spondyloarthritis can lead to significant disability and impairment in quality of life. TNF inhibitors are recommended to patients enduring active disease despite conventional treatment. Nonetheless, up to 40% of patients of patients fail to respond to TNF inhibitors. In this context, it is important to identify as early as possible patients highly likely to respond. This study aims at identifying, among axial spondyloarthritis patients undergoing treatment with the TNF inhibitor adalimumab, early molecular biomarkers differentiating good responders from non-responders after 14 weeks of treatment, as measured by ASAS20.

Methods

Peripheral blood RNA sequencing and serum proteins measured by mass spectrometry were evaluated in a cohort of biologic naïve axial spondyloarthritis patients (n = 35), before (baseline) and after (3-5 days, 2 weeks and 14 weeks) treatment with adalimumab. Results from differential expression analysis were used in combination with clinical data to build logistic regression models and random forest models to predict response to adalimumab at baseline.

Results

Responders to adalimumab presented higher levels of markers of innate immunity at baseline, mostly related with neutrophils, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP and AFF3, the top differentially expressed gene between responders and non-responders at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC=0.96), with random forest models suggesting 80% predictive accuracy. A treatment-associated signature suggests a reduction in inflammatory activity, with C-reactive protein and Haptoglobin showing strong and early decrease in the serum of axial spondyloarthritis patients, while a cluster of apolipoproteins showed increased expression at week 14.

Conclusions

Differences in disease activity and/or blood innate/adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axial spondyloarthritis, where a model including clinical and blood gene expression variables shows high predictive power. Our results suggest novel molecular biomarkers of response to adalimumab at baseline.

Trial registration

Axial spondyloarthritis patients were selected from participants of the Bioefficacy study - Biomarkers Identification of Anti-TNFα Agent’s Efficacy in Ankylosing Spondylitis Patients Using a Transcriptome Analysis and Mass Spectrometry (clinical trials.gov identifier NCT02492217).
Published registered reports are rare, limited to one journal group and inadequate for randomized controlled trials in the clinical field
Authors: Anthony Norah , Tisseaux Antoine , Naudet Florian
Published: August 2022

Objective

Registered reports relate to a new publication of a peer-review of the protocol before the start of the study, followed by an in-principle acceptance by the journal before the study starts. We aimed to describe randomized controlled trials (RCTs) in the clinical field published as registered reports.

Study design and setting

This cross-sectional study (registration:https://osf.io/zf53p/) included registered report results for RCTs, identified on PubMed/Medline and on a list compiled by the Center for Open Science. It explored the proportion of reports that received in-principle acceptance (and/or published a protocol before inclusion of the first patient) and changes in the primary outcome.

Results

A total of 93 RCT publications identified as registered reports were included. All but one were published in the same journal group. The date of the in-principle acceptance was never documented. For most of these reports (79/93, 84.9 %) a protocol was published after the date of inclusion of the first patient. A change in the primary outcome was noted in 40/93 (44%) of these publications. Three out of the 40 (33%) mentioned this change.

Conclusions

Randomized controlled trials in the clinical field identified as registered reports were rare, they originated from a single journal group and did not comply with the basic features of this format.

Protocol registration

https://osf.io/zf53p/

What is new ?

The registered report format for clinical randomized controlled (RCTs) trials is still marginal and few journals make use of it.

The clinical RCTs identified as registered reports were from a single journal group and did not necessarily comply with the basic features of this format, and common biases may thus persist.

To improve research trustworthiness, more efforts need to be made by Journal publishers, trial funders, etc. for the implementation of this format for clinical RCTs.
identifying cancer patients from GC-patterned fragment ends of cell-free DNA
Authors: Curtis Samuel D. , Summers Mahmoud , Cohen Joshua D. , Wang Yuxuan , Nehme Nadine , Popoli Maria , Ptak Janine , Sillman Natalie , Dobbyn Lisa , Buchanan Adam , Tie Jeanne , Gibbs Peter , Ho-Pham Lan T. , Tran Bich N. H. , Zhou Shibin , Bettegowda Chetan , Lennon Anne Marie , Hruban Ralph H. , Kinzler Kenneth W. , Papadopoulos Nickolas , Vogelstein Bert , Douville Christopher
Published: August 2022

One of the most intriguing characteristics of cell-free DNA (cfDNA) from plasma is the sequence at the ends of the fragments. Previous studies have shown that these end-sequences are somewhat different in cancer patients than in healthy individuals. While investigating this characteristic, we noticed that the bases at the 5’-ends of a double-stranded fragment were highly correlated with the GC content of that particular fragment. This led us to develop a method, called MendSeqS (Modified End-based sequencing System), that incorporates the correlation between end-motifs and GC content into the analysis of shallow (0.5x) whole genome sequencing (WGS). When applied to plasma samples, MendSeqS was able to classify patients with a sensitivity of 96% at 98% specificity in a cohort comprised of 107 individuals evaluated in our laboratory (43 with cancer and 64 without). In cohorts evaluated in three other laboratories, comprising a total of 401 individuals (193 with cancer and 208 without), MendSeqS achieved a sensitivity of 87% at 98% specificity. MendSeqS could in principle be combined with other methods of cfDNA analysis to enhance cancer detection.
Functional Correlates of Cognitive Performance and Working Memory in Temporal Lobe Epilepsy: Insights from Task-based and Resting-state fMRI
Authors: Fajardo-Valdez Alfonso , Camacho-Téllez Vicente , Rodríguez-Cruces Raúl , García-Gomar María Luisa , Pasaye-Alcaraz Erick H. , Concha Luis
Published: August 2022

Temporal lobe epilepsy (TLE) is a common form of medically intractable partial epilepsy. Although seizures originate in mesial temporal structures, there are widespread abnormalities of gray and white matter beyond the temporal lobes that negatively impact on functional networks and cognition. Previous studies have focused either on the global impact on functional networks, or on the functional correlates of specific cognitive abilities. Here, we use a step-wise approach to evaluate the link between whole-brain functional connectivity (FC) anomalies to overall cognitive performance, and how such abnormal connectivity alters the fronto-parietal brain regions involved in working memory (WMem), a cognitive disability often reported by TLE patients. We evaluated 40 TLE patients and 36 healthy subjects through extensive cognitive testing, resting-state functional magnetic resonance imaging (rs-fMRI), and task-based fMRI using Sternberg’s task to evaluate WMem. As a group, TLE patients displayed cognitive abnormalities across different domains, although considerable within-group variability was identified. TLE patients showed disruptions of functional networks between and within the default mode network (DMN) and task-positive networks (TPN) resulting in associations with cognitive performance. Furthermore, during the WMem task, TLE patients showed abnormal activity of fronto-parietal regions that was associated with other forms of memory, and alterations of seed-based connectivity analyses. Our results show that different degrees of abnormal functional brain activity and connectivity are related to the severity of cognitive disabilities across cognitive spheres. Differential activity between patients and healthy subjects suggest potential compensatory mechanisms to preserve adequate cognitive performance.
Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis
Authors: Papadopoulou D. , Roumelioti F. , Tzaferis C. , Chouvardas P. , Pedersen A.K. , Charalampous F. , Christodoulou-Vafeiadou E. , Ntari L. , Karagianni N. , Denis M. , Olsen J.V. , Matralis A.N. , Kollias G.
Published: August 2022

Synovial Fibroblasts (SFs) are key pathogenic drivers in arthritis and their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models. TNF blockade has been efficacious for a large percentage of Rheumatoid Arthritis (RA) patients, although characterized by a plethora of side effects. Novel therapeutic discoveries remain however challenging, especially in optimizing drug safety, side effects, longer-term responses, costs and administration routes. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, in order to identify compounds that could potentially reverse the pathogenic expression signature of arthritogenic SFs, derived from the human TNF transgenic mouse model (hTNFtg). We identified a neuroleptic drug, namely Amisulpride, which was validated to reduce SFs’ inflammatory potential while decreasing the clinical score of hTNFtg polyarthritis. Notably, we found that Amisulpride did not exert its biological activities through its known targets Dopamine receptors 2 and 3 and Serotonin Receptor 7, nor through TNF-TNFRI binding inhibition. By applying a click chemistry approach, novel potential targets of Amisulpride were identified, which were further validated to repress hTNFtg SFs’ inflammatory potential in vitro (Ascc3 and Sec62), while phosphoproteomics analysis revealed important fibroblast activation pathways, such as adhesion, to be altered upon treatment. Our data support that Amisulpride could provide an additive beneficial effect to patients suffering from RA and comorbid dysthymia, as it may reduce SFs pathogenicity in parallel with its anti-depressive activity. Importantly, Amisulpride may also serve as a “lead” compound for the development of novel, more potent therapeutics against chronic inflammatory diseases.
Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria
Authors: Opi D. Herbert , Ndila Carolyne M , Uyoga Sophie , Macharia Alex W , Fennell Clare , Nyutu Gideon , Ojal John , Shebe Mohammed , Awuondo Kennedy O , Mturi Neema , Peshu Norbert , Tsofa Benjamin , Band Gavin , Maitland Kathryn , Kwiatkowski Dominic P , Rockett Kirk A , Williams Thomas N. , Rowe J. Alexandra
Published: August 2022

Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA, BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that “double dose” non-O genotypes (AA, BB, AB) are associated with increased risk of severe malaria and larger rosettes than “single dose” heterozygotes (AO, BO). In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (P=0.02, Wald test). In vitro experiments with blood group A-preferring P. falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO, whereas AO genotype rosettes were indistinguishable from OO. Overall, the data show that ABO genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity.
Next-generation large-scale binary protein interaction network for Drosophila
Authors: Tang Hong-Wen , Spirohn Kerstin , Hu Yanhui , Hao Tong , Kovács István A. , Gao Yue , Binari Richard , Yang-Zhou Donghui , Wan Kenneth H. , Bader Joel S. , Balcha Dawit , Bian Wenting , Booth Benjamin W. , Cote Atina G. , De Rouck Steffi , Desbuleux Alice , Kim Dae-Kyum , Knapp Jennifer J. , Lee Wen Xing , Lemmens Irma , Li Cathleen , Li Mian , Li Roujia , Lim Hyobin Julianne , Luck Katja , Markey Dylan , Pollis Carl , Rangarajan Sudharshan , Rodiger Jonathan , Schlabach Sadie , Shen Yun , TeeKing Bridget , Roth Frederick P. , Tavernier Jan , Calderwood Michael A. , Hill David E. , Celniker Susan E. , Vidal Marc , Perrimon Norbert , Mohr Stephanie E.
Published: August 2022

Generating reference maps of the interactome networks underlying most cellular functions can greatly illuminate genetic studies by providing a protein-centric approach to finding new components of existing pathways, complexes, and processes. Here, we applied state-of-the-art experimental and bioinformatics methods to identify high-confidence binary protein-protein interactions (PPIs) for Drosophila melanogaster. We performed four all-by-all yeast two-hybrid (Y2H) screens of >10,000 Drosophila proteins, resulting in the ‘FlyBi’ dataset of 8,723 PPIs among 2,939 proteins. As part of this effort, we tested subsets of our data and data from previous PPI datasets using an orthogonal assay, which allowed us to normalize data quality across datasets. Next, we integrated our FlyBi data with previous PPI data, resulting in an expanded, high-confidence binary Drosophila reference interaction network, DroRI, comprising 17,232 interactions among 6,511 proteins. These data are accessible through the Molecular Interaction Search Tool (MIST) and other databases. To assess the utility of the PPI resource, we used novel interactions from the FlyBi dataset to generate an autophagy interaction network that we validated in vivo using two different autophagy-related assays. We found that deformed wings (dwg) encodes a protein that is both a regulator and a target of autophagy. Altogether, the resources generated in this project provide a strong foundation for building high-confidence new hypotheses regarding protein networks and function.
Adult and regenerating planarians respond differentially to chronic drug exposure
Authors: Bayingana Kevin , Ireland Danielle , Rosenthal Elizabeth , Rabeler Christina , Collins Eva-Maria S.
Published: August 2022

There is a lack of data on the effects of chronic exposure to common drugs and stimulants on the developing nervous system. Freshwater planarians have emerged as a useful invertebrate model amenable to high-throughput behavioral phenotyping to assay chemical safety in adult and developing brains. Here, we leverage the unique strength of the system to test in parallel for effects on the adult and developing nervous system, by screening ten common drugs and stimulants (forskolin, clenbuterol, LRE-1, MDL-12,330A, adenosine, caffeine, histamine, mianserin, fluoxetine and sertraline) using the asexual freshwater planarianDugesia japonica. The compounds were tested up to 100 µM nominal concentration for their effects on planarian morphology and behavior. Quantitative phenotypic assessments were performed on days 7 and 12 of exposure using an automated screening platform. The antidepressants sertraline and fluoxetine were the most potent to induce lethality, with significant lethality observed at 10 µM. All ten compounds caused sublethal morphological and/or behavioral effects, with the most effects, in terms of potency and breadth of endpoints affected, seen with mianserin and fluoxetine. Four of the compounds (forskolin, clenbuterol, mianserin, and fluoxetine) were developmentally selective, causing effects at lower concentrations in regenerating planarians. Of these, fluoxetine showed the greatest differences between the two developmental stages, inducing many behavioral endpoints in regenerating planarians but only a few in adult planarians. While some of these behavioral effects may be due to neuroefficacy, these results substantiate the need for better evaluation of the safety of these common drugs on the developing nervous system.
Microbial community-based production of single cell protein from soybean-processing wastewater of variable chemical composition
Authors: Vethathirri Ramanujam Srinivasan , Santillan Ezequiel , Thi Sara Swa , Hoon Hui Yi , Wuertz Stefan
Published: August 2022

The use of food-processing wastewaters to produce microbial biomass-derived single cell protein (SCP) is a sustainable way to meet the global food demand. Yet, despite the potential benefits of lower costs and greater resource recovery compared to pure cultures, bioconversion processes relying on microbial community-based approaches to SCP production have received scarce attention. Here, we evaluated SCP production from soybean-processing wastewaters under controlled reactor conditions using the existent microbial communities in these wastewaters. Six sequencing batch reactors of 4.5-L working volume were operated at 30 □ for 34 d in cycles consisting of 3-h anaerobic and 9-h aerobic phases. Four reactors received no microbial inoculum and the remaining two were amended with a 1.5 L of mixed culture from a prior microbial community-based SCP production. Microbial characterization was done via 16S rRNA gene metabarcoding. Influent wastewater batches had variable chemical characteristics but a similar microbial composition. Reactors produced more SCP when fed with wastewaters of higher soluble total Kjeldahl nitrogen (sTKN) content and a lower carbon-to-nitrogen ratio (sCOD:sTKN). The biomass protein yield ranged from 0.24 to 3.13 g protein/g sTKN, with a maximum protein content of 50%. An average of 92% of sCOD and 73% of sTN removal was achieved. Distinct microbial communities were enriched in all six bioreactors after 34 d, where the prevailing genera included Azospirillum, Rhodobacter, Lactococcus, Novosphingobium, and Acidipropionibacterium. In contrast, the microbial community of influent wastewaters was dominated by Lactococcus and Weissella. We showed that constituents in soybean wastewater can be converted to SCP through microbial community-based growth processes and demonstrated the effect of variable influent wastewater composition on SCP production.
Perceptual stability reflected in neuronal pattern similarities in human visual cortex
Authors: Broday-Dvir Rotem , Norman Yitzhak , Harel Michal , Mehta Ashesh D. , Malach Rafael
Published: August 2022

The magnitude of neuronal activation is commonly considered a critical factor for conscious perception of visual content. However, this dogma contrasts with the phenomenon of rapid adaptation, in which the magnitude of neuronal activation drops dramatically in a rapid manner, while the visual stimulus and the conscious experience it elicits remain stable. Here we report that the profiles of multi-site activation patterns and their relational geometry –i.e. the similarity distances between activation patterns, as revealed using iEEG recordings, are sustained during extended stimulation despite the major magnitude decrease. These results are compatible with the hypothesis that conscious perceptual content is associated with the neuronal pattern profiles and their similarity distances, rather than by the overall activation magnitude, in human visual cortex.
Prediction, scanning and designing of TNF-α inducing epitopes for human and mouse
Authors: Dhall Anjali , Patiyal Sumeet , Choudhury Shubham , Jain Shipra , Narang Kashish , Raghava Gajendra P. S.
Published: August 2022

Tumor Necrosis Factor alpha (TNF-α) is a pleiotropic pro-inflammatory cytokine that plays a crucial role in controlling signaling pathways within the immune cells. Recent studies reported that the higher expression levels of TNF-α is associated with the progression of several diseases including cancers, cytokine release syndrome in COVID-19 and autoimmune disorders. Thus, it is the need of the hour to develop immunotherapies or subunit vaccines to manage TNF-α progression in various disease conditions. In the pilot study, we have proposed a host-specific in-silico tool for the prediction, designing and scanning of TNF-α inducing epitopes. The prediction models were trained and validated on the experimentally validated TNF-α inducing/non-inducing for human and mouse hosts. Firstly, we developed alignment free (machine learning based models using composition of peptides) methods for predicting TNF-α inducing peptides and achieved maximum AUROC of 0.79 and 0.74 for human and mouse hosts, respectively. Secondly, alignment based (using BLAST) method has been used for predicting TNF-α inducing epitopes. Finally, a hybrid method (combination of alignment free and alignment-based method) has been developed for predicting epitopes. Our hybrid method achieved maximum AUROC of 0.83 and 0.77 on an independent dataset for human and mouse hosts, respectively. We have also identified the potential TNF-α inducing peptides in different proteins of HIV-1, HIV-2, SARS-CoV-2 and human insulin. Best models developed in this study has been incorporated in a webserver TNFepitope (https://webs.iiitd.edu.in/raghava/tnfepitope/), standalone package and GitLab (https://gitlab.com/raghavalab/tnfepitope).

Key Points

TNF-α is a multifunctional pleiotropic pro-inflammatory cytokine.

Anti-TNF-α therapy used as an effective treatment in several autoimmune disorders.

Composition-based features generated using Pfeature for each peptide sequence.

Alignment-based and alignment-free models developed.

Prediction and scanning of TNF-α inducing regions in antigens.

TNFepitope is available as a web-server, standalone package and GitLab.