bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical activity is the default DNA state in eukaryotes
Authors: Luthra Ishika , Chen Xinyi E. , Jensen Cassandra , Rafi Abdul Muntakim , Salaudeen Asfar Lathif , de Boer Carl G.
Published: December 2022

Genomes encode for genes and the regulatory signals that enable those genes to be transcribed, and are continually shaped by evolution. Genomes, including those of human and yeast, encode for numerous regulatory elements and transcripts that have limited evidence of conservation or function. Here, we sought to create a genomic null hypothesis by quantifying the gene regulatory activity of evolutionarily naïve DNA, using RNA-seq of evolutionarily distant DNA expressed in yeast and computational predictions of random DNA activity in human cells and tissues. In yeast, we found that >99% of bases in naïve DNA expressed as part of one or more transcripts. Naïve transcripts are sometimes spliced, and are similar to evolved transcripts in length and expression distribution, indicating that stable expression and/or splicing are insufficient to indicate adaptation. However, naïve transcripts do not achieve the extreme high expression levels as achieved by evolved genes, and frequently overlap with antisense transcription, suggesting that selection has shaped the yeast transcriptome to achieve high expression and coherent gene structures. In humans, we found that, while random DNA is predicted to have minimal activity, dinucleotide content-matched randomized DNA is predicted to have much of the regulatory activity of evolved sequences, including active chromatin marks at between half (DNase I and H3K4me3) and 1/16th (H3K27ac and H3K4me1) the rate of evolved DNA, and the repression-associated H3K27me3 at about twice the rate of evolved DNA. Naïve human DNA is predicted to be more cell type-specific than evolved DNA and is predicted to generate co-occurring chromatin marks, indicating that these are not reliable indicators of selection. However, extreme high activity is rarely achieved by naïve DNA, consistent with these arising via selection. Our results indicate that evolving regulatory activity from naïve DNA is comparatively easy in both yeast and humans, and we expect to see many biochemically active and cell type-specific DNA sequences in the absence of selection. Such naïve biochemically active sequences have the potential to evolve a function or, if sufficiently detrimental, selection may act to repress them.
SnapFISH: a computational pipeline to identify chromatin loops from multiplexed DNA FISH data
Authors: Lee Lindsay , Yu Hongyu , Jia Bojing Blair , Jussila Adam , Zhu Chenxu , Chen Jiawen , Xie Liangqi , Hafner Antonina , Strambio-De-Castillia Caterina , Boettiger Alistair , Ren Bing , Li Yun , Hu Ming
Published: December 2022

Multiplexed DNA fluorescence in situ hybridization (FISH) imaging technologies have been developed to map the folding of chromatin fibers at tens of nanometer and tens of kilobase resolution in single cells. However, computational methods to reliably identify chromatin loops from such imaging datasets are still lacking. Here we present a Single-Nucleus Analysis Pipeline for multiplexed DNA FISH (SnapFISH), to process the multiplexed DNA FISH data and identify chromatin loops. SnapFISH can identify known chromatin loops from mouse embryonic stem cells with high sensitivity and accuracy. In addition, SnapFISH obtained comparable results of chromatin loops across datasets generated from diverse imaging technologies.
Indolent primary cutaneous B-cell lymphomas resemble persistent antigen reactions without signs of dedifferentiation
Authors: Griss Johannes , Gansberger Sabina , Oyarzun Inigo , Drach Mathias C. , Nguyen Vy , Shaw Lisa E. , Mann Ulrike , Porkert Stefanie , Farlik Matthias , Weninger Wolfgang , Dolak Werner , Aschenbrenner Bertram , Lichtenberger Beate M. , Wagner Christine , Simonitsch-Klupp Ingrid , Wagner Stephan N. , Jonak Constanze , Brunner Patrick M.
Published: December 2022

Primary cutaneous B-cell lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas. While primary cutaneous diffuse large B-cell lymphoma leg type (pcDLBCL-LT) is highly aggressive, the two other subtypes, primary cutaneous follicle centre lymphoma (pcFCL) and primary cutaneous marginal zone lymphoma (pcMZL), usually follow an indolent course.

To better understand the molecular landscape of these entities, we performed single-cell RNA sequencing of pcFCL, pcMZL, and pcDLBCL-LT skin lesions and compared them to B-cell rich lymphoid proliferation (rB-LP) lesions, gastric MALT lymphoma, nodal FCL, and nodal DLBCL.

Our data show that these lymphomas can be clearly distinguished from each other on a transcriptomic level based on scRNA-seq. pcMZL, pcFCL, and rB-LP all exhibited a persistent germinal centre reaction as evidenced by the presence of required support cells and continuous somatic hypermutation within the expanded clone. By contrast, malignant clones of pcDLBCL-LT and gastric MALT lymphoma lesions lacked these features. Further, pcMZL top expanded clones were developing within lesions from naïve and not post-germinal centre B cells as currently presumed. Therefore, pcMZL may represent a non-malignant reaction against a yet to be determined antigen. Conversely, in pcFCL, B cells showed a larger amount of clonal expansion. The lack of further differentiation of these B cells may explain its indolent clinical course. In contrast to pcDLCBL-LT, our data thus indicate that pcMZL and pcFCL, similar to rB-LP are characterised by a functional germinal centre reaction likely driven by (a yet unknown) antigen recognition, which supports the classification of pcMZL as a lymphoproliferative disease.

Key points

Indolent B cell neoplasms are uniquely characterised by ongoing, antigen-driven germinal centre reactions.

Primary cutaneous B cell lymphomas are distinct entities compared to their systemic counterparts.
Genomic insights intoPlasmodium vivaxpopulation structure and diversity in central Africa
Authors: Gartner Valerie , Redelings Benjamin D. , Gaither Claudia , Parr Jonathan B. , Kalonji Albert , Phanzu Fernandine , Brazeau Nicholas F. , Juliano Jonathan J. , Wray Gregory A.
Published: December 2022

Plasmodium vivaxmalaria has not traditionally been a major concern in central Africa given the high prevalence of the human Duffy-negative phenotype that is believed to prevent infection. Increasing reports of asymptomatic and symptomatic infections in Duffy-negative individuals throughout Africa raise the possibility thatP. vivaxis evolving to evade host resistance, but there are few parasite samples with genomic data available from this part of the world. In this study, we perform whole genome sequencing of a newP. vivaxisolate from the Democratic Republic of the Congo (DRC) and assess how this central African isolate fits into the global context of this species. We use population genomics methods to show thatP. vivaxfrom DRC is similar to other African parasite populations and is not closely related to the non-human primate parasiteP. vivax-like.

Significance

The second most common malaria species to infect humans,Plasmodium vivax, is not considered a major threat to human health in central Africa because people in this region frequently have a genetic variant that prevents theP. vivaxspecies from being able to cause illness. Recent research shows thatP. vivaxcan be found in individuals who should be immune, but there is insufficient data to understand why. Our study investigates the genome of oneP. vivaxsample collected from central Africa to show that the DRC population is closely related to otherP.vivaxpopulations in Africa.
Tumor Segmentation using temporal Independent Component Analysis for DCE-MRI
Authors: Lee Joonsang , Zhao Qun , Kent Marc , Platt Simon
Published: December 2022

In this study, we developed the temporal independent component analysis (tICA) to solve the partial volume effect (PVE) in canine brain tumor segmentation. The performance of the tICA is compared to that of spatial ICA (sICA) and an expert manual delineation of tumors based on three criteria: percent volume overlap or Dice coefficient, and percent volume difference. Seven in vivo DCE-MRI datasets of spontaneously occurring canine brain tumors were acquired on a 3 Tesla MRI system. The mean value of percent volume overlap (76.00%) between sICA and manual segmentation is lower than that between tICA and manual segmentation, which is 81.11%. In conclusion, the performance of the two ICA methods for segmenting tumors is very close to that of the expert delineation method. However, the tICA has the advantage over the sICA method in its ability to separate independent tissue signals in a voxel containing different types of tissues.
“Crochet … a little hook to improve attention?”
Authors: Sebastiano Davide Rossi , Muscio Cristina , Duran Dunja , Bonfoco Deborah , Dotta Sara , Anversa Paola , Tiraboschi Pietro , Visani Elisa
Published: December 2022

In this work we compared the short-term effects of crochet on the performance in the well-known Attention Network Test and on the global cortical functioning networks revealed by magnetoencephalography between a group of crocheters and a sex and age-matched control group.

Our data revealed that crochet is associated with an increase of the alerting and the orienting networks even after a brief, single work session and that this behavioural effect seems to have a counterpart in the modification seen in the global functional connectivity of the brain, where an increased speed of the information exchange between different brain areas have been seen. Moreover, we discuss the hypothesis that these effects on attentional networks are dissimilar from those determined by meditation, where an improvement in the executive control was previously demonstrated as the main effect.

Our results provided for the first time that crochet is associated with an increase in the attentional networks, and namely in alerting and orienting networks, paving the way for the use of textile-related arts in the neurorehabilitation, possibly in combination with meditation, considering that the two practices promote complementary effects on the attentional networks.

Highlights

Crocheting positively affects attention, improving alerting and orienting

Crocheting speeds up the information exchange between different brain areas

Crocheting and meditation promote different effects on the attentional networks
Perilous coexistence:Chilli Leaf Curl VirusandCandidatus Phytoplasma trifoliiinfectingCapsicum annuum, India
Authors: Pandey Vineeta , Srivastava Aarshi , Mall Smriti , Al-Sadi Abdullah M. , Shahid Muhammad Shafiq , Gaur R. K.
Published: December 2022

Molecular computing was used to investigate the possible causal agents of chilli crop samples showing mixed symptoms of yellow leaf curl and little leaf type diseases in the Uttar Pradesh province, India. Total genomic DNA was extracted from twenty-five samples and amplified by PCR using a universal primer pair for begomovirus and phytoplasma. Mixed infection samples show positive amplified products for begomovirus (DNA-A and betasatellite) and phytoplasma (16S rRNA and Sec A). The identified begomovirus from chilli samples was identified as a strain isolate of the previously described Chilli Leaf Curl Virus (94.2% nucleotide sequence identity), which is known to infectSolanum lycopersicon, in Oman, whereas the 16S rRNA was identified from the sourceCandidatus Phytoplasma trifolii(99.04% nucleotide sequence identity), which is known to infect Helichrysum flowering plants in India. Subsequently, molecular computing research based on phylogenetic interweaves, putative recombination, amino acid selection, and genetic diversity were investigated, revealing divergent evolutionary patterns with significant variation and recombination events. The majority of the sequence variations observed in begomovirus and phytoplasma were caused via inter- and intra-specific recombination. These findings could be the firstin silicocombined infection analysis of ChiLCV andCa.P.trifoliiin a chilli crop in India, revealing the potential adaption and evolution of begomovirus and phytoplasma to a new geographic range and crop.
Functional characterization of a small gene family coding for putrescine hydroxycinnamoyltransferases in tomato
Authors: Roumani Marwa , Besseau Sébastien , Hehn Alain , Larbat Romain
Published: December 2022

Phenolamides are specialized metabolites widely distributed in the plant kingdom. Their structure is composed by the association of hydroxycinnamic acid derivatives to mono-/poly-amine. This association is catalyzed by N-hydroxycinnamoyltransferases enzymes. Tomato plants are accumulating putrescine-derived phenolamides in their vegetative parts. Recently, we identified two genes coding for putrescine-hydroxycinnamoyltransferase (PHT,Solyc11g071470 and Solyc11g071480), which control the accumulation of caffeoylputrescine in tomato leaf submitted to the infestation of leafminer. In this study, we prospected for additional genes implicated in the accumulation of putrescine-derived phenolamides in the tomato vegetative organs. We identified two genes (Solyc06g074710andSolyc11g066640) that we functionally characterized as new PHT. The substrate specificity and the expression patternin plantawas determined for the four tomato PHT. Taken together the results give a comprehensive view of the control of the putrescine-derived phenolamide accumulation in tomato plant through the biochemical specificity and the spatial expression of this small family of PHT.

Main conclusion

We identified and functionally characterized two new putrescine hydroxycinnamoyl transferases (PHT) in tomato. These enzymes complete a set a four PHT which control the distribution of putrescine-derived phenolamides in tomato plants.
Home range and dynamic space use reveals age-related differences in risk exposure for reintroduced parrots
Authors: Forrest S. W. , Rodríguez-Recio M. , Seddon P. J.
Published: December 2022

Individual-level differences in animal spatial behaviour can lead to differential exposure to risk. We assessed the risk-exposure of a reintroduced population of kākā (Nestor meridionalis) in a fenced reserve in New Zealand by GPS tracking 10 individuals and comparing the proportion of each individual’s home range beyond the reserve’s fence in relation to age, sex, and fledging origin. To estimate dynamic space use, we used a sweeping window framework to estimate occurrence distributions from temporally overlapping snapshots. For each occurrence distribution, we calculated the proportion outside the reserve’s fence to assess temporal risk exposure, and the area, centroid and overlap to represent the behavioural pattern of space use. Home range area declined significantly and consistently with age, and the space use of juvenile kākā was more dynamic, particularly in relation to positional changes of space use. The wider- ranging and more dynamic behaviour of younger kākā resulted in consistently more time spent outside the reserve, which aligned with a higher number of incidental mortality observations. Quantifying both home range and dynamic space use is an effective approach to assess risk exposure, which can provide guidance for management interventions. We also emphasise the dynamic space use approach, which is flexible and can provide numerous insights towards a species’ spatial ecology.
A prospective evaluation of three saliva qualitative antigen testing kits for the detection of SARS-CoV-2 in Japan
Authors: Terada Norihiko , Akashi Yusaku , Takeuchi Yuto , Ueda Atsuo , Notake Shigeyuki , Nakamura Koji , Suzuki Hiromichi
Published: December 2022

Introduction

Rapid qualitative antigen testing has been widely used for the laboratory diagnosis of COVID-19 with nasopharyngeal samples. Saliva samples have been used as alternative samples, but the analytical performance of those samples for qualitative antigen testing has not been sufficiently evaluated.

Methods

A prospective observational study evaluated the analytical performance of three In Vitro Diagnostics (IVD) approved COVID-19 rapid antigen detection kits for saliva between June 2022 and July 2022 in Japan using real-time reverse transcription polymerase chain reaction (RT-PCR) as a reference. A nasopharyngeal sample and a saliva sample were simultaneously obtained, and RT-PCR was performed.

Results

In total, saliva samples and nasopharyngeal samples were collected from 471 participants (140 RT-PCR-positive saliva samples and 143 RT-PCR-positive nasopharyngeal samples) for the analysis. The median Ct values were 25.5 (interquartile range [IQR]: 21.9-28.8) for saliva samples and 17.1 (IQR: 15.5-18.7) for nasopharyngeal samples (p<0.001). Compared with saliva samples of RT-PCR, the sensitivity and specificity were 46.4% and 99.7% for ImunoAce SARS-CoV-2 Saliva, 59.3% and 99.1% for Espline SARS-CoV-2 N, and 61.4% and 98.8% for QuickChaser Auto SARS-CoV-2, respectively. The sensitivity is >90% for saliva samples with a moderate-to-high viral load (Ct<25), whereas the sensitivity is <70% for high-viral-load nasopharyngeal samples (Ct<20).

Conclusion

COVID-19 rapid antigen detection kits with saliva showed high specificities, but the sensitivities varied among kits, and the analytical performance of saliva qualitative antigen detection kits was much worse than that of kits using nasopharyngeal samples.
A hormone-activated mobile RNAi pathway defends plant stem cells from virus infection
Authors: Incarbone Marco , Bradamante Gabriele , Pruckner Florian , Wegscheider Tobias , Rozhon Wilfried , Nguyen Vu , Gutzat Ruben , Lendl Thomas , MacFarlane Stuart , Nodine Michael , Scheid Ortrun Mittelsten
Published: December 2022

Stem cells are essential for the development and organ regeneration of multicellular organisms, so their infection by pathogenic viruses must be prevented. Accordingly, mammalian stem cells are highly resistant to viral infection due to dedicated antiviral pathways including RNA interference (RNAi) (1, 2). In plants, a small group of stem cells harbored within the shoot apical meristem (SAM) generates all postembryonic above-ground tissues, including the germline cells. Many viruses do not proliferate in these cells, yet the molecular bases of this exclusion remain only partially understood (3, 4). Here we show that a plant-encoded RNA-dependent RNA polymerase, after activation by the plant hormone salicylic acid, amplifies antiviral RNAi in infected tissues. This provides stem cells with RNA-based virus sequence information, which prevents virus proliferation. Furthermore, we find RNAi to be necessary for stem cell exclusion of several unrelated RNA viruses, despite their ability to efficiently suppress RNAi in the rest of the plant. This work elucidates a molecular pathway of great biological and economic relevance and lays the foundations for our future understanding of the unique systems underlying stem cell immunity.
Unique role for caspase-8 in the release of IL-1β and active caspase-1 from viable human monocytes duringToxoplasma gondiiinfection
Authors: Pandori William J. , Matsuno Stephanie Y. , Kao Tiffany H. , Mallya Sharmila , Batarseh Sarah N. , Lodoen Melissa B.
Published: December 2022

Monocytes are among the first cells recruited to sites of infection and major producers of the potent proinflammatory cytokine IL-1β. We previously showed that IL-1β release duringToxoplasma gondiiinfection of primary human monocytes requires the NLRP3 inflammasome and caspase-1 activity but is independent of gasdermin D and pyroptosis. To investigate potential mechanisms of pyroptosis-independent release of IL-1β duringT. gondiiinfection, we constructed caspases-1, -4, -5, or -8 knockout THP-1 monocytic cells. Genetic ablation of caspase-1 or -8, but not caspase-4 or -5, decreased IL-1β release duringT. gondiiinfection without affecting cell death. In contrast, TNF-α and IL-6 secretion were unperturbed in caspase-8 knockout cells duringT. gondiiinfection. Dual pharmacological inhibition of caspase-8 and RIPK1 in primary monocytes also decreased IL-1β release without affecting cell viability or parasite infection efficiency. In addition, caspase-8 was required for the release of active caspase-1 fromT. gondii-infected cells and for IL-1β release during infection with the related apicomplexan parasiteNeospora caninum. Surprisingly, caspase-8 was dispensable for the synthesis and cleavage of IL-1β, but caspase-8 deficiency resulted in theretentionof mature IL-1β within cells. Our data indicate that duringT. gondiiinfection of human monocytes, caspase-8 functions in a novel gasdermin D-independent mechanism controlling IL-1β release from viable cells. This study expands on the known molecular pathways that promote IL-1β in human immune cells and provides the first evidence of a role for caspase-8 in the mechanism of IL-1β release during host defense against infection.
A Genetic and Immunohistochemical Analysis ofH. PyloriPhenotypes and p27 expression in Adenocarcinoma Patients in Jordan
Authors: Al-Sheboul Suhaila A. , Mohammad Ahmad Abdul-Razzak , Shboul Yasemin , Brown Brent , Matalka Ismail I.
Published: December 2022

Stomach (gastric) cancer is one of the most prevalent and deadly cancers worldwide and the vast majority of gastric cancers are adenocarcinomas. Based on prior research, there is an association betweenHelicobacter pylori (H. pylori)infection and the frequency of duodenal ulcer, distal gastric adenocarcinoma, mucosa-associated lymphoid tissue lymphoma, and antral gastritis.H. pylorivirulence and toxicity factors have been identified to significantly influence the clinical outcomes ofH. pyloriinfection and gastric adenocarcinoma. However, it is unclear exactly how different strains ofH. pyloriinfection affect gastric adenocarcinoma. Current research suggests this involves tumor suppressor genes, like p27, but alsoH. Pyloritoxic proteins. Therefore, we quantified knownH. Pylorigenotypes within adenocarcinoma patients to establish the prevalence of known toxins that include cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA) within patients of variable diagnosis. This analysis used gastrectomy samples which were validated for DNA viability. The incidence ofH. Pyloriin adenocarcinoma patients in Jordan was established to be 54.5% positive (ureA gene) with cagA genotype occurrence at 57.1% but also vacA gene ratios 24.7%:22.1%: 14.3%:14.3%. (vacAs1:vacAs2: vacAm1:vacAm2). We found statistically significant evidence that p27 was dysregulated and suppressed within nearly allH. PylorivacA genotypes but also that 24.6% ofH. Pylorisamples analyzed had a different bacterial genotype and curiously that p27 protein expression was retained in 12% of tested adenocarcinomaH. Pylorisamples. This is suggestive that p27 could be used as a prognostic indicator but also that an unknown genotype could be contributing to the regulatory effects of p27 protein within this bacterial and cellular environment.

Key Contribution

In Jordan, this is the first retrospective study to use validated viable gastrectomy tissue samples rather than tissue biopsies to characterize each of the currently definedH. pyloristrains in patients with variable gastric cancer diagnosis whilst also comparing results with p27 expression within 8 years using these laboratory techniques.

Conclusions

Based on these results, a reduction in p27 expression inH. pylori-infected men and women of all ages may be associated with the occurrence of gastric adenocarcinomas. Therefore, p27 may represent a key diagnostic marker and predictor of adenocarcinoma prognosis in such individuals and may find use for guiding subsequent treatment decisions.
Modulation of prey size reveals adaptability and robustness in the cell cycle of an intracellular predator
Authors: Santin Yoann G. , Lamot Thomas , Kaljević Jovana , van Raaphorst Renske , Laloux Géraldine
Published: December 2022

Despite the remarkable diversity of bacterial lifestyles, the sophisticated regulatory networks underlying bacterial replication have only been investigated in a limited number of model species so far. In bacteria that do not rely on canonical binary division for proliferation, the coordination of major cellular processes is still mysterious. Moreover, bacterial growth and division remain largely unexplored within spatially confined niches where nutrients are limited. This includes the lifecycle of the model endobiotic predatory bacteriumBdellovibrio bacteriovorus, which grows by filamentation within its host or prey cells and produces a variable number of daughter cells. Here, we examined how the size of the micro-compartment in which predators replicate (i.e., the prey bacterium) impacts their cell cycle progression at the single-cell level. UsingEscherichia coliwith genetically encoded size differences, we show that the duration of the predator cell cycle scales with prey size. As a result, the size of the prey determines the number of predator offspring, through a relationship that is maintained across prey species. Strikingly, the nutritional quality of the prey cell determined the specific growth rate of predators regardless of prey size, reminiscent of the effect of medium composition on the growth of other bacteria. Tuning the predatory cell cycle by modulating prey dimensions also allowed us to reveal invariable temporal connections between key cellular processes. Altogether, our data uncover adaptability and robustness shaping the enclosed replication ofB. bacteriovorus. Consequently, predators optimally exploit the finite prey resources and space while ensuring a strict cell cycle progression. This study opens the way to explore diverse cell cycle control strategies by extending their characterization to intracellular lifestyles, beyond canonical models and growth conditions.
Optimizing tuberculosis treatment efficacy: comparing the standard regimen with Moxifloxacin-containing regimens
Authors: Budak Maral , Cicchese Joseph M. , Maiello Pauline , Borish H. Jacob , White Alexander G. , Chishti Harris B. , Tomko Jaime , Frye L. James , Fillmore Daniel , Kracinovsky Kara , Sakal Jennifer , Scanga Charles A. , Lin Philana Ling , Dartois Véronique , Linderman Jennifer J. , Flynn JoAnne L. , Kirschner Denise E.
Published: December 2022

Tuberculosis (TB) continues to be one of the deadliest infectious diseases in the world, causing ~1.5 million deaths every year. The World Health Organization initiated anEnd TB Strategythat aims to reduce TB-related deaths in 2035 by 95%. Recent research goals have focused on discovering more effective and more patient-friendly antibiotic drug regimens to increase patient compliance and decrease emergence of resistant TB. Moxifloxacin is one promising antibiotic that may improve the current standard regimen by shortening treatment time. Clinical trials andin vivomouse studies suggest that regimens containing moxifloxacin have better bactericidal activity. However, testing every possible combination regimen with moxifloxacin eitherin vivoor clinically is not feasible due to experimental and clinical limitations. To identify better regimens more systematically, we simulated pharmacokinetics/pharmacodynamics of various regimens (with and without moxifloxacin) to evaluate efficacies, and then compared our predictions to both clinical trials and nonhuman primate studies performed herein. We usedGranSim, our well-established hybrid agent-based model that simulates granuloma formation and antibiotic treatment, for this task. In addition, we established a multiple-objective optimization pipeline usingGranSimto discover optimized regimens based on treatment objectives of interest, i.e., minimizing total drug dosage and lowering time needed to sterilize granulomas. Our approach can efficiently test many regimens and successfully identify optimal regimens to inform pre-clinical studies or clinical trials and ultimately accelerate the TB regimen discovery process.

Author summary

Tuberculosis (TB) is a top global health concern and treatment for TB requires multiple antibiotics taken for long periods of time, which is challenging for TB patients. Therefore, identifying regimens that are more effective and more patient-friendly than the standard treatment is urgently needed. It is also known that non-compliance leads to the development of drug resistant TB. In this work, we pair computational and experimental models to predict new regimens for the treatment of TB that optimize how fast bacteria are cleared using minimal dosage. We apply novel approaches to this goal and validate our predictions using a non-human primate model. Our findings suggest that systems pharmacological modeling should be employed as a method to narrow the design space for drug regimens for tuberculosis and other diseases as well.
Genome-wide association study of longitudinal urinary albumin excretion in patients with type 1 diabetes
Authors: Hutchinson Anna M , Chen Wei-Min , Onengut-Gumuscu Suna , Benitez-Aguirre Paul , Cameron Fergus J , Chiesa Scott T , Couper Jennifer J , Craig Maria E , Dalton Neil R. , Daneman Denis , Davis Elizabeth A , Deanfield John E , Donaghue Kim C , Jones Timothy W , Mahmud Farid H , Marshall Sally M , Neil Andrew , Rich Stephen S , Marcovecchio M. Loredana , Wallace Chris
Published: December 2022

Identifying genetic determinants for longitudinal changes in albumin excretion in individuals with type 1 diabetes may help identify those that are predisposed to renal, retinal and cardiovascular complications. Most studies have focussed on genetic predisposition to diabetic kidney disease and used cross-sectional measurements of urinary albumin excretion, but with limited success. Here, we utilise the wealth of longitudinal data and bio-samples collected from cohorts of childhood-onset type 1 diabetes followed over the last 30 years to describe a novel trajectory phenotype quantifying urinary albumin excretion changes during childhood and adolescence. We conducted a genome-wide association study and fine-mapping analysis for albumin excretion in 1584 individuals, finding one signal for cross-sectional albumin excretion close toGALNTL6(rs150766792), which validated in a previous independent study, and a novel genome-wide significant signal for albumin excretion trajectory in theCDH18gene region (rs145715205). Our trajectory phenotype quantifies albumin progression and offers a complementary measure to an albumin excretion phenotype based on a single measurement (i.e. most recent data collection) or an average of repeated measurements in longitudinal studies. It can be used to identify genetic or other risk factors which predict better or worse prognosis, thus facilitating the development of new preventive and therapeutic approaches.
Training the next generation of physician-scientists: a cohort-based program for MD-only residents and fellows
Authors: Solvik Tina A. , Schnoes Alexandra M. , Nguyen Thi A. , Behrman Shannon L. , Maksoud Elie , Goodwin Sarah S. , Weiss Ethan J. , Padmanabhan Arun , Cornfield David N.
Published: December 2022

Importance

Despite the importance of clinician-scientists in propelling biomedical advances, the proportion of physicians engaged in both hypothesis-driven research and clinical care continues to decline. Recently, multiple institutions have developed programs that promote MD-only physicians pursuing careers in science, but few reports on the impact of these are available.

Objective

To assess if a cohort-based training program for MD-only physician-scientists that includes didactic and experiential curricula favorably informs participants’ scientific development.

Design

The Chan Zuckerberg Biohub (CZB) Physician-Scientist Fellowship Program (PSFP) conducted a study from July 2020 to August 2023.

Participants

24 inaugural program participants at UCSF and Stanford University (median postgraduate year at program start, 5.5; 17 clinical specialties represented; 10 [42%] identified as female; 7 [29%] identified as underrepresented in medicine).

Exposures

The CZB PSFP is a selective two-year career development program for MD-only physicians. Participants attended a two-week immersive training at the program outset, and subsequently, weekly curricular and scientific meetings throughout the program while conducting research.

Main Outcomes and Measures

Primary outcome measurements included pre-, 1-month, and 12-month assessments of confidence in research skills, career skills, and self-identification as scientists. Program satisfaction and feedback related to program curriculum and community were collected at 1 month, 6 months, and 12 months.

Results

After 12 months, 100% (N=16) reported satisfaction with the program and participants demonstrated increased confidence in research skills [median (IQR), 4.0 (2.5-5.0) pre-bootcamp to 5.5 (4.0-6.0) 12-mo], career skills significantly increased [median (IQR), 4.0 (4.0-5.0) pre-bootcamp to 5.5 (5.0-6.0) 12-mo], perceptions of belonging significantly increased [median (IQR), 4.0 (2.5-5.4) pre-bootcamp to 5.5 (5.1-7.0) 12-mo], and scientific identity significantly increased [median (IQR), 5.0 (4.0-5.5) pre-bootcamp to 6.0 (5.5-7.0) 12-mo].

Conclusion and Relevance

Participants demonstrated significant gains in confidence in core research and career skills as well as personal identification as scientists, demonstrating the efficacy of a longitudinal curriculum, peer support, and community building in fostering development as an investigator. The highly portable nature of this strategy may facilitate ready adoption and implementation at other institutions.
coronabambini.ch: Development and usage of an online decision support tool for pediatric COVID-testing in Switzerland: a cross-sectional analysis
Authors: Starvaggi C , Travaglini N , Aebi C , Romano F , Steiner I , Sauter T C , Keitel K
Published: December 2022

Objectives

To describe the development and usage of coronabambini.ch as an example of a pediatric electronic public health application and to explore its potential and limitations in providing information on disease epidemiology and public health policy implementation.

Design

We developed and maintained a non-commercial online decision support tool, coronabambini.ch, to translate the Swiss FOPH pediatric (age 0-18 years) COVID-19 guidelines around testing and school/daycare attendance for caregivers, teachers, and healthcare personnel. We analyzed the online decision tool as well as a voluntary follow-up survey from October 2020 to September 2021 to explore its potential as a surveillance tool for public health policy and epidemiology.

Participants

68’269 users accessed and 52’726 filled out the complete online decision tool. 3% (1’399/52’726) filled out a voluntary follow-up. 92% (18’797/20’330) of users were parents.

Results

Certain dynamics of the pandemic and changes in testing strategies were reflected in the data captured by coronabambini.ch: e.g. in terms of disease epidemiology, gastrointestinal symptoms were reported more frequently in younger age-groups (13% (3’308/26’180) in children 0-5 years versus 9% (3’934/42’089) in children ≥6 years, 𝒳2=184,P=<.001). As a reflection of public health policy, the proportion of users consulting the tool for a positive contact without symptoms in children 6-12 years increased from 4% (1’415/32’215) to 6% (636/9’872) after the FOPH loosened testing criteria in this age-group, 𝒳2=69,P=<.001. Adherence to the recommendation was generally high (84% (1’131/1’352)) but differed by the type of recommendation: 89% (344/385) for “stay at home and observe”, 75% (232/310) for “school attendance”.

Conclusions

Usage of coronabambini.ch was generally high in areas where it was developed and promoted. Certain patterns in epidemiology and adherence to public health policy could be depicted but selection bias was difficult to measure showing the potential and challenges of digital decision support as public health tools.

Strengths and limitations of this study

We developed and maintained a non-commercial online decision support tool, coronabambini.ch, based on the Swiss Federal Office of Public Health (FOPH) pediatric COVID-19 guidelines around testing and school/daycare attendance.

We performed a descriptive analysis of the usage data from the tool between October 2020 to September 2021 to explore its potential as a surveillance tool for public health policy and epidemiology.

A follow-up survey measured comprehensibility and adherence of the online decision tool.

The types of selection biases of the data were difficult to assess within this voluntary online survey system.

Response rate of the follow-up survey was low and participants with high education and high health literacy were overrepresented.
The Canadian Food Intake Screener for assessing alignment of adults’ dietary intake with the 2019 Canada’s Food Guide healthy food choices recommendations: Scoring system and construct validity
Authors: Hutchinson Joy M. , Dodd Kevin W. , Guenther Patricia M. , Lamarche Benoit , Haines Jess , Wallace Angela , Perreault Maude , Williams Tabitha E. , Costa Louzada Maria Laura da , Jessri Mahsa , Lemieux Simone , Olstad Dana Lee , Prowse Rachel , Simpson Janis Randall , Vena Jennifer E. , Szajbely Kathleen , Kirkpatrick Sharon I.
Published: December 2022

The Canadian Food Intake Screener/Questionnaire court canadien sur les apports alimentaires was developed to rapidly assess alignment of adults’ dietary intake over the past month with the 2019 Canada Food Guide’s healthy food choices recommendations. From July to December 2021, adults (n=154) aged 18-65 years completed the screener and up to two 24-hour dietary recalls. The screener scoring system was aligned with the Healthy Eating Food Index-2019 (HEFI-2019), to the extent possible. ANOVA compared screener scores among subgroups with known differences in diet quality. Using the recall data, the National Cancer Institute multivariate method was used to model HEFI-2019 components, with the screener score as a covariate, and the correlation coefficient between screener and total HEFI-2019 scores was estimated. The mean screener score was 35 points (SD=4.7; maximum, 65), ranging from 25 (1stpercentile) to 45 (99thpercentile). Differences in scores in hypothesized directions were evident by gender identity (p=0.06), perceived income adequacy (p=0.07), education (p=0.02), and smoking status (p=0.003). The correlation between screener and HEFI-2019 scores was 0.53 (SE=0.12). The screener’s moderate construct validity supports its use for rapid assessment of alignment of adults’ intake with the healthy food choices recommendations when comprehensive dietary assessment is not possible.

Novelty

The Canadian Food Intake Screener was developed to rapidly assess alignment of dietary intake with Canada’s Food Guide-2019 healthy food choices recommendations.

Scoring is aligned with the Healthy Eating Food Index-2019, to the extent possible.

Among a sample of adults, variation in screener scores was noted, mean screener scores differed between some subgroups with known differences in diet quality, and a moderate correlation between screener scores and total Healthy Eating Food Index-2019 scores based on repeat 24-hour dietary recalls was observed.

The Canadian Food Intake Screener has moderate construct validity for rapid assessment of overall alignment of adults’ dietary intake with the Canada’s Food Guide-2019 healthy food choices recommendations when comprehensive dietary assessment is not possible.
Performance of ChatGPT on USMLE: Potential for AI-Assisted Medical Education Using Large Language Models
Authors: Kung Tiffany H. , Cheatham Morgan ,   ChatGPT, Medenilla Arielle , Sillos Czarina , De Leon Lorie , Elepaño Camille , Madriaga Maria , Aggabao Rimel , Diaz-Candido Giezel , Maningo James , Tseng Victor
Published: December 2022

We evaluated the performance of a large language model called ChatGPT on the United States Medical Licensing Exam (USMLE), which consists of three exams: Step 1, Step 2CK, and Step 3. ChatGPT performed at or near the passing threshold for all three exams without any specialized training or reinforcement. Additionally, ChatGPT demonstrated a high level of concordance and insight in its explanations. These results suggest that large language models may have the potential to assist with medical education, and potentially, clinical decision-making.
Annotation and Information Extraction of a Consumer-Friendly Health Website for Enhancing Laboratory Test Reporting in Patient Portals
Authors: He Zhe , Tian Shubo , Erdengasileng Arslan , Hanna Karim , Gong Yang , Zhang Zhan , Luo Xiao , Lustria Mia Liza A.
Published: December 2022

Viewing laboratory test results is patients’ most frequent activity when accessing patient portals, but lab results can be very confusing for patients. Previous research has explored various ways to present lab results, but few have attempted to provide tailored information support based on individual patient’s medical context. In this study, we collected and annotated interpretations of textual lab result in 251 health articles about laboratory tests from AHealthyMe.com. Then we evaluated transformer-based language models including BioBERT, ClinicalBERT, RoBERTa, and PubMedBERT for recognizing key terms and their types. Using BioPortal’s term search API, we mapped the annotated terms to concepts in major controlled terminologies. Results showed that PubMedBERT achieved the best F1 on both strict and lenient matching criteria. SNOMED CT had the best coverage of the terms, followed by LOINC and ICD-10-CM. This work lays the foundation for enhancing the presentation of lab results in patient portals by providing patients with contextualized interpretations of their lab results and individualized question prompts that they can, in turn, refer to during physician consults.
Clinical prediction rule to guide diagnostic testing forShigellosisand improve antibiotic stewardship for pediatric diarrhea
Authors: Ahmed Sharia M. , Brintz Ben J. , Pavlinac Patricia B. , Hossain Md Iqbal , Khan Ashraful Islam , Platts-Mills James A. , Kotloff Karen L. , Leung Daniel T.
Published: December 2022

Background

Diarrheal diseases are a leading cause of death for children under-5.

Identification of etiology helps guide pathogen-specific therapy, but availability of diagnostic testing is often limited in low resource settings. Our goal is to develop a clinical prediction rule (CPR) to guide clinicians in identifying when to use a point-of-care diagnostic forShigellain children presenting with acute diarrhea.

Methods

We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) study to build predictive models for diarrhea ofShigellaetiology in children ≤59 months presenting with moderate-to-severe diarrhea in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to externally validate our GEMS-derived CPR.

Results

Of the 5011 cases analyzed, 1332 (27%) had diarrhea ofShigellaetiology. Our CPR had high predictive ability (AUC=0.80 (95% CI: 0.79, 0.81) using the top two predictive variables, age and caregiver reported bloody diarrhea. We show that by using our CPR to triage who receives diagnostic testing, 3 times moreShigelladiarrhea cases would have been identified compared to current symptom-based guidelines, with only 27% of cases receiving a point-of-care diagnostic test.

Conclusions

We demonstrate how a clinical prediction rule can be used to guide use of a point-of-care diagnostic test for diarrhea management. Using our CPR, available diagnostic capacity can be optimized to improve appropriate antibiotic use.

Key points

Using an externally validated clinical prediction tool to triage who receives diagnostic testing, 3 times moreShigelladiarrhea cases would have been identified compared to current symptom-based guidelines, with only 27% of cases receiving a point-of-care diagnostic test.
The convergence and divergence of spontaneous brain activity of humans and marmosets
Authors: Zhang Jinbo
Published: December 2022

The brain at rest or during periods of relative inactivity, complex dynamical patterns of activity spontaneously form over the entire brain. In this study, we plan to clarify the convergence and divergence of spontaneous brain activity across humans and marmosets. We investigated the spontaneous brain dynamics of marmosets, and compared its convergence and divergence with human neuroimaging results. We identified seven representative FC patterns (FC states) in the resting-state activity of marmosets. The most prevalent two FC patterns (VC1 and VC2) corresponds to a state of BOLD coherence of primary visual and auditory processing regions. Our results suggested that the spontaneous activity does reflect the inherent properties of the brain of marmosets.
Multi-location trials and population-based genotyping reveal high diversity and adaptation to breeding environments in a large collection of red clover
Authors: Nay Michelle M. , Grieder Christoph , Frey Lea A. , Amdahl Helga , Radovic Jasmina , Jaluvka Libor , Palmé Anna , Skøt Leif , Ruttink Tom , Kölliker Roland
Published: December 2022

Red clover (Trifolium pratenseL.) is an outcrossing forage legume that has adapted to a wide range of climatic and growing conditions across Europe. Red clover is valued for its high yield potential and forage quality. The high amount of genetic diversity present in red clover provides an invaluable, but often poorly characterized resource to improve key traits such as yield, quality, and resistance to biotic and abiotic stresses. In this study, we examined the genetic and phenotypic diversity within a diverse set of 395 diploid red clover accessions via genome wide allele frequency fingerprinting and multi-location field trials across Europe. We found that the genetic structure of accessions mostly reflected their geographic origin and only few cases were detected, where breeders integrated foreign genetic resources into their local breeding pools. Phenotypic performance of accessions in the multi-location field trials revealed a very strong accession x location interaction. Notably, breeding material and cultivars generally performed well at the location where they were developed. Local adaptation was especially prominent in Nordic red clover accessions that showed a distinct adaptation to the growing conditions and cutting regime of the North. Our results confirmed that red clover cultivars were bred from regional ecotypes and show a narrow adaptation to regional conditions. Our study can serve as a valuable basis for identifying interesting material that express the desired characteristics and contribute to the adaptation of red clover to future climatic conditions.
Targeted Protein Degradation through E2 Recruitment
Authors: Forte Nafsika , Dovala Dustin , Hesse Matthew J. , McKenna Jeffrey M. , Tallarico John A. , Schirle Markus , Nomura Daniel K.
Published: December 2022

Targeted protein degradation (TPD) with Proteolysis Targeting Chimeras (PROTACs), heterobifunctional compounds consisting of protein targeting ligands linked to recruiters of E3 ubiquitin ligases, has arisen as a powerful therapeutic modality to induce the proximity of target proteins with E3 ligases to ubiquitinate and degrade specific proteins in cells. Thus far, PROTACs have primarily exploited the recruitment of E3 ubiquitin ligases or their substrate adapter proteins but have not exploited the recruitment of more core components of the ubiquitin-proteasome system (UPS). In this study, we used covalent chemoproteomic approaches to discover a covalent recruiter against the E2 ubiquitin conjugating enzyme UBE2D—EN67—that targets an allosteric cysteine, C111, without affecting the enzymatic activity of the protein. We demonstrated that this UBE2D recruiter could be used in heterobifunctional degraders to degrade neo-substrate targets in a UBE2D-dependent manner, including BRD4 and the androgen receptor. Overall, our data highlight the potential for the recruitment of core components of the UPS machinery, such as E2 ubiquitin conjugating enzymes, for TPD, and underscore the utility of covalent chemoproteomic strategies for identifying novel recruiters for additional components of the UPS.