bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial plasmid-associated and chromosomal proteins have fundamentally different properties in protein interaction networks
Authors: Downing Tim , Rahm Alexander
Published: May 2022

Plasmids facilitate horizontal gene transfer, which enables the diversification of pathogens into new anatomical and environmental niches, implying that plasmid-encoded genes can cooperate well with chromosomal genes. We hypothesise that such mobile genes are functionally different to chromosomal ones due to this ability to encode non-essential functions like antimicrobial resistance and traverse distinct host cells. The effect of plasmid-driven gene gain on protein-protein interaction network topology is an important question in this area. Moreover, the extent to which these chromosomally- and plasmid-encoded proteins interact with proteins from their own groups compared to the levels with the other group remains unclear. Here, we examined the incidence and protein-protein interactions of all known plasmid-encoded genes across representative specimens from most bacteria using all available plasmids. We found that such plasmid-encoded genes constitute ∼0.7% of the total number of genes per bacterial sample, and that plasmid genes are preferentially associated with different species but had limited taxonomical power beyond this. Surprisingly, plasmid-encoded proteins had both more protein-protein interactions compared to chromosomal proteins, countering the hypothesis that genes with higher mobility rates should have fewer protein-level interactions. Nonetheless, topological analysis and investigation of the protein-protein interaction networks’ connectivity and change in the number of independent components demonstrated that the plasmid-encoded proteins had limited overall impact in >96% of samples. This paper assembled extensive data on plasmid-encoded proteins, their interactions and associations with diverse bacterial specimens that is available for the community to investigate in more detail.

Significance statement

It is well-established that plasmids drive new traits in their bacterial hosts, but the extent to which host-plasmid co-evolution is evident at the level of protein-protein interactions remains unclear. To address this, we compiled and analysed all available valid bacterial plasmids and associated proteins to explore the compositional differences between chromosomal and plasmid-encoded proteins and their interaction levels. We found that plasmid-encoded genes were highly correlated across the bacterial samples such that they had a high association with taxonomic context. Contrasting with the complexity hypothesis, plasmid-encoded proteins had far more interactions on average than chromosomal ones, though they had minimal effects on protein-protein interaction network structure. This demonstrated that host-plasmid co-evolution is evident and detectable at the level of protein interactions.
Evaluating deep learning for predicting epigenomic profiles
Authors: Toneyan Shushan , Tang Ziqi , Koo Peter K.
Published: May 2022

Deep learning has been successful at predicting epigenomic profiles from DNA sequences. Most approaches frame this task as a binary classification relying on peak callers to define functional activity. Recently, quantitative models have emerged to directly predict the experimental coverage values as a regression. As new models continue to emerge with different architectures and training configurations, a major bottleneck is forming due to the lack of ability to fairly assess the novelty of proposed models and their utility for downstream biological discovery. Here we introduce a unified evaluation framework and use it to compare various binary and quantitative models trained to predict chromatin accessibility data. We highlight various modeling choices that affect generalization performance, including a downstream application of predicting variant effects. In addition, we introduce a robustness metric that can be used to enhance model selection and improve variant effect predictions. Our empirical study largely supports that quantitative modeling of epigenomic profiles leads to better generalizability and interpretability.
Succinate mediates inflammation-induced adrenocortical dysfunction
Authors: Mateska Ivona , Witt Anke , Hagag Eman , Sinha Anupam , Yilmaz Canelif , Thanou Evangelia , Sun Na , Kolliniati Ourania , Patschin Maria , Abdelmegeed Heba , Henneicke Holger , Kanczkowski Waldemar , Wielockx Ben , Tsatsanis Christos , Dahl Andreas , Walch Axel , Li Ka Wan , Peitzsch Mirko , Chavakis Triantafyllos , Alexaki Vasileia Ismini
Published: May 2022

The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH) although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH) leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1β reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the SDHB promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1β-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for the adrenal dysfunction in severe inflammation but also a potential target for therapeutic intervention.
A pipeline for assessing the quality of images and metadata from crowd-sourced databases
Authors: Billotte Jackie
Published: May 2022

Abstract

Crowd-sourced biodiversity databases provide easy access to data and images for ecological education and research. One concern with using publicly sourced databases; however, is the quality of their images, taxonomic descriptions, and geographical metadata. The method presented in this paper attempts to address this concern using a suite of pipelines to evaluate taxonomic consistency, how well geo-tagging fits known distributions, and the image quality of crowd-sourced data acquired from iNaturalist, a crowd-sourced biodiversity database. Additionally, it provides researchers that use these datasets to report a quantifiable assessment of the taxonomic consistency. The pipeline allows users to analyze multiple images from iNaturalist and their associated metadata; to determine the level of taxonomic identification (family, genera, species) for each occurrence; whether the taxonomy label for an image matches accepted nesting of families, genera, and species; and whether geo-tags match the distribution of the taxon described using occurrence data from the Global Biodiversity Infrastructure Facility (GBIF) as a reference. Additionally, image quality is assessed using BRISQUE, an algorithm that allows for image quality evaluation without a reference photo. Entries from the order Araneae (spiders) are used as a case study. Overall, the results suggest that iNaturalist can provide large metadata and image sets for research. Given the inevitability of some low-quality observations, this pipeline provides a valuable resource for researchers and educators to evaluate the quality of iNaturalist and other crowd-sourced data.
Dopamine D1agonist effects in late-stage Parkinson’s disease
Authors: Lewis Mechelle M. , Van Scoy Lauren Jodi , Mailman Richard B. , De Jesus Sol , Hakun Jonathan , Kong Lan , Yang Yang , Snyder Bethany , Duvvuri Sridhar , Gray David L. , Huang Xuemei
Published: May 2022

Abstract

Background

Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson’s disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients.

Objective

Explore if a D1/5dopamine agonist will have efficacy in LsPD that will be detected most sensitively by caregivers in a phase I study.

Methods

A double-blind controlled phase Ia/b study compared the D1/5agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Throughout the study, caregivers were with the patients. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2 and 3). Clinicians and caregivers completed clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings.

Results

Neither traditional scales, nor clinician impression of change, detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and engagement.

Conclusion

D1/5agonists may offer potential benefit for LsPD patients. Caregiver perspectives with mixed method analyses may overcome limitations in standard rater/clinician-based evaluations. Further studies are warranted and need to integrate caregiver input as an essential component of outcome evaluations.

Trial Registration#

ClinicalTrials.gov:NCT03665454
Comparative analysis of the outcomes of COVID-19 between patients infected with SARS-CoV-2 Omicron and Delta variants: a retrospective cohort study
Authors: Gunadi  , Hakim Mohamad Saifudin , Wibawa Hendra , Vujira Khanza Adzkia , Puspitarani Dyah Ayu , Supriyati Endah , Trisnawati Ika , Iskandar Kristy , Khair Riat El , Afiahayati  , Siswanto  , Puspadewi Yunika , Irene  , Irianingsih Sri Handayani , Daniwijaya Edwin Widyanto , Agung Nugrahaningsih Dwi Aris , Gabriela Gita Christy , Geometri Esensi Tarian , Eryvinka Laudria Stella , Trie Utami Fadila Dyah , Devana Edita Mayda , Aditama Lanang , Putri Kinasih Nathania Christi , Amadeus Verrell Christopher , Hediningsih Yekti , Ananda Nur Rahmi , Arguni Eggi , Nuryastuti Titik , Wibawa Tri
Published: May 2022

Background

The SARS-CoV-2 Omicron variant has replaced the previously dominant Delta variant because of high transmissibility. It is responsible for the current increase in the COVID-19 infectivity rate worldwide. However, studies on the impact of the Omicron variant on the severity of COVID-19 are still limited in developing countries. Here, we compared the outcomes of patients infected with SARS-CoV-2 Omicron and Delta variants and associated with prognostic factors, including age, sex, comorbidities, and smoking.

Methods

We involved 352 patients, 139 with the Omicron variant and 213 with the Delta variant. The whole-genome sequences of SARS-CoV-2 were conducted using the Illumina MiSeq next-generation sequencer.

Results

Ct value and mean age of COVID-19 patients were not significantly different between both groups (Delta: 20.35 ± 4.07 vs. Omicron: 20.62 ± 3.75; p=0.540; and Delta: 36.52 ± 21.24 vs. Omicron: 39.10 ± 21.24; p=0.266, respectively). Patients infected with Omicron and Delta variants showed similar hospitalization (p=0.433) and mortality rates (p=0.565). Multivariate analysis showed that older age (≥65 years) had higher risk for hospitalization (OR=3.67 [95% CI=1.22-10.94]; p=0.019) and fatalities (OR=3.93 [95% CI=1.35-11.42]; p=0.012). In addition, patients with cardiovascular disease had higher risk for hospitalization (OR=5.27 [95% CI=1.07-25.97]; p=0.041), whereas patients with diabetes revealed higher risk for fatalities (OR=9.39 [95% CI=3.30-26.72]; p=<0.001).

Conclusions

Our study shows that patients infected with Omicron and Delta variants reveal similar clinical outcomes, including hospitalization and mortality. In addition, our findings further confirm that older age, cardiovascular disease, and diabetes are strong prognostic factors for the outcomes of COVID-19 patients.
BRCA1 Hypermethylation In Sporadic Breast Cancers: Discovering A Novel Pathway To Tumorigenesis Via Coordinate NBR2 Deregulation And TNBC Transformation
Authors: Patra Dipyaman , Varghese Geetu Rose , Jaikumar Vishnu Sunil , Rajan Arathi , Krishnan Neethu , Kuppuswamy Krithiga , Thankappan Rateeshkumar , Srinivas Priya
Published: May 2022

Women with a family history of mutations in the Breast cancer susceptibility gene, BRCA1 will have an increased risk of developing breast neoplasms. However, majority of the breast cancers are sporadic where BRCA1 mutations are very rare. Instead, 5-65% of sporadic cases manifest BRCA1 promoter hypermethylation and 30-40% of such cases develop into Triple Negative Breast Cancers. Even then, the molecular mechanism of BRCA1 hypermethylation mediated breast tumorigenesis has remained an enigma till date. Here, we present a novel tumorigenesis pathway for breast cancers that engenders from BRCA1 hypermethylation by generating site-specific methylations in the BRCA1 promoter using a modified version of CRISPR technology.

We report that induction of site-specific methylation on BRCA1 promoter α effectuates a downregulation in BRCA1 expression via alteration in the balance between its alternate transcripts β and α. Induced BRCA1 hypermethylation is also responsible for the attenuation of a long noncoding RNA, NBR2 (Neighbour of BRCA1 gene 2), which is transcribed through the bidirectional BRCA1 promoter α in the reverse direction. Downregulation of NBR2 activates a feedback loop by leading to further downregulation of BRCA1 which is more evident under glucose starvation conditions and is associated with impaired DNA damage repair. BRCA1 hypermethylation also results in significant overexpression of β-hCG (human chorionic gonadotrophin), which was found to be associated with highly aggressive and drug-resistant forms of BRCA1 mutated breast cancersinvitro&in vivoin our previous study. Further, we report a change in the hormone receptor levels as the tumor progresses which demonstrates how BRCA1 deficient cells modulate their expression of ER-α and ER-β to promote their proliferation in early stages of tumor development and at later stages, transform to a basal tumor subtype by shedding down the expression of ER-α & PR. Interestingly, we also discovered that modulation of ER-α expression upon BRCA1 hypermethylation is responsible for the alteration in BRCA1 transcript ratio. Finally, inin vivomouse studies, BRCA1 hypermethylated tumors were found to be much larger, aggressive and invasive as compared to wildtype, BRCA1 and NBR2 knockdown tumors with downregulation of ER-α and PR; which explains the most probable reason behind high relapse rates in BRCA1 hypermethylated tumors.

GRAPHICAL ABSTRACT
Compressive stress drives adhesion-dependent unjamming transitions in breast cancer cell migration
Authors: Cai Grace , Nguyen Anh , Bashirzadeh Yashar , Lin Shan-Shan , Bi Dapeng , Liu Allen P.
Published: May 2022

Cellular unjamming is the collective fluidization of cell motion and has been linked to many biological processes, including development, wound repair, and tumor growth. In tumor growth, the uncontrolled proliferation of cancer cells in a confined space generates mechanical compressive stress. However, because multiple cellular and molecular mechanisms may be operating simultaneously, the role of compressive stress in unjamming transitions during cancer progression remains unknown. Here we investigate which mechanism dominates in a dense, mechanically stressed monolayer. We find that long-term mechanical compression triggers cell arrest in benign epithelial cells and enhances cancer cell migration in transitions correlated with cell shape, leading us to examine the contributions of cell-cell adhesion and substrate traction in shape-dependent unjamming transitions. We show that cadherin-mediated cell-cell adhesion regulates differential cellular responses to compressive stress and predominantly controls unjamming transitions in dense monolayers. Importantly, compressive stress does not induce the epithelial—mesenchymal transition in unjammed cells. Using traction force microscopy, traction forces are attenuated in compressed cells in the bulk of the monolayer regardless of cell type and motility. Intercellular adhesion thus is the dominant regulator of compression-induced unjamming transitions and may impact collective cell motion in tumor development and breast cancer progression.
Transcription-induced active forces suppress chromatin motion
Authors: Shin Sucheol , Shi Guang , Cho Hyun Woo , Thirumalai D.
Published: May 2022

The organization of interphase chromosomes in a number of species is starting to emerge thanks to advances in a variety of experimental techniques. However, much less is known about the dynamics, especially in the functional states of chromatin. Some experiments have shown that the mobility of individual loci in human interphase chromosome decreases during transcription, and increases upon inhibiting transcription. This is a counter-intuitive finding because it is thought that the active mechanical force (F) on the order of ten pico-newtons, generated by RNA polymerase II (RNAPII) that is pre-sumably transmitted to the gene-rich region of the chromatin, would render it more open, thus enhancing the mobility. Inspired by these observations, we developed a minimal active copolymer model for interphase chromosomes to investigate howFaffects the dynamical properties of chromatin. The movements of the loci in the gene-rich region are suppressed in an intermediate range ofF, and are enhanced at smallFvalues, which has also been observed in experiments. In the intermediateF, the bond length between consecutive loci increases, becoming commensurate with the distance at the minimum of the attractive interaction between non-bonded loci. This results in a transient disorder-to-order transition, leading to the decreased mobility during transcription. Strikingly, theF-dependent change in the locus dynamics preserves the organization of the chromosome atF= 0. Transient ordering of the loci, which is not found in the polymers with random epigenetic profiles, in the gene-rich region might be a plausible mechanism for nucleating a dynamic network involving transcription factors, RNAPII, and chromatin.

Significance Statement

In order to explain a physically counter-intuitive experimental finding that chromatin mobility is reduced during transcription, we introduced a polymer model for interphase chromosome that accounts for RNA polymerase (RNAP) induced active force. The simulations show that, over a range of active forces, the mobility of the gene-rich loci is suppressed. Outside this range, chromosomes are compact and exhibit glass-like dynamics. Our study, which accounts for the experimental observations, leads to a novel and testable mechanism of how transcription could shape the coexistence of fluid- and solid-like properties within chromosomes.
Elevator mechanism dynamics in a sodium-coupled dicarboxylate transporter
Authors: Kinz-Thompson Colin D. , Lopez-Redondo Maria Louisa , Mulligan Christopher , Sauer David B. , Marden Jennifer J. , Song Jinmei , Tajkhorshid Emad , Hunt John F. , Stokes David L. , Mindell Joseph A. , Wang Da-Neng , Gonzalez Ruben L.
Published: May 2022

VcINDY, the sodium-dependent dicarboxylate transporter fromVibrio cholerae, is responsible for C4- and C5-carboxylate uptake into cells. The molecular mechanism of how VcINDY physically moves substrates across the membrane, and does so in an energetically efficient manner, is unclear. Here, we use single-molecule fluorescence resonance energy transfer experiments to directly observe the individual mechanistic steps that VcINDY takes to translocate substrates across a lipid bilayer, and then test key predictions of transport cycle mechanistic models. Our data provide the first direct evidence that VcINDY undergoes stochastic, elevator-type conformational motions that enable substrate translocation. Kinetic analysis suggests that the two protomers of the VcINDY homodimer undergo those motions in a non-cooperative manner, and thus catalyze two independent transport reactions. The relative substrate independence of those motions supports the notion that the VcINDY transport cycle maintains strict co-substrate coupling using a cooperative binding mechanism. Finally, thermodynamic modeling provides insight into how such a cooperative binding mechanism provides a generalized approach to optimizing transport for many secondary active transporters.

Significance Statement

Transporter proteins use energy to move molecular materials into and out of cells. To be efficient, the transporter motions responsible for moving the molecules must be tightly choreographed to avoid wasting energy without transporting anything. By measuring the motions and kinetics of a prototypical transporter (VcINDY) at the single-molecule level, this study finds the first evidence that transporters like VcINDY achieve efficient transport by coordinating constantly dynamic, “elevator-type” motions while sitting in the cellular membrane. The efficiency of these surprisingly dynamic transporters is then revealed by thermodynamic modeling, which explains the molecular basis behind how highly cooperative, substrate binding reactions may have evolved as the optimal strategy for maximizing transporter efficiency.
How to Best Represent Proteins in Machine Learning-based Prediction of Drug/Compound-Target Interactions
Authors: Atas Heval , Doğan Tunca
Published: May 2022

The identification of drug/compound-target interactions (DTIs) constitutes the basis of drug discovery, for which computational predictive approaches have been applied. As a relatively new data-driven paradigm, proteochemometric (PCM) modeling utilizes both protein and compound properties as a pair at the input level and processes them via statistical/machine learning. The representation of input samples (i.e., proteins and their ligands) in the form of quantitative feature vectors is crucial for the extraction of interaction-related properties during the artificial learning and subsequent prediction of DTIs. Lately, the representation learning approach, in which input samples are automatically featurized via training and applying a machine/deep learning model, has been utilized in biomedical sciences. In this study, we performed a comprehensive investigation of different computational approaches/techniques for data preparation and protein featurization, including both conventional approaches and the novel learned embeddings, with the aim of achieving better data representations and more successful learning in PCM-based DTI prediction. For this, we first constructed realistic and challenging benchmark datasets on small, medium, and large scales to be used as reliable gold standards for specific DTI modeling tasks. We developed and applied a network analysis-based splitting strategy to divide datasets into structurally different training and test folds. Using these datasets together with various featurization methods, we trained and tested DTI prediction models and evaluated their performance from different angles. Our main findings can be summarized under 3 items: (i) random splitting of the dataset into train and test folds leads to near-complete data memorization and produce highly over-optimistic results, as a result, it should be avoided; (ii) learned protein sequence embeddings works well in DTI prediction, even though no information related to protein structures, interactions or biochemical properties is utilized during the training of these models; and (iii) PCM models tends to learn from compound features and leave out protein features, mostly due to the natural bias in DTI data. We hope this study will aid researchers in designing robust and high-performing data-driven DTI prediction systems that have real-world translational value in drug discovery.
Microbial metabolite butyrate-prodrug polymeric micelles demonstrate therapeutic efficacy in pre-clinical models of food allergy and colitis
Authors: Wang Ruyi , Cao Shijie , Bashir Mohamed Elfatih H. , Hesser Lauren A. , Su Yanlin , Hong Sung Min Choi , Thompson Andrew , Culleen Elliot , Sabados Matthew , Dylla Nicholas P. , Campbell Evelyn , Bao Riyue , Nonnecke Eric B. , Bevins Charles L. , Wilson D. Scott , Hubbell Jeffrey A. , Nagler Cathryn R.
Published: May 2022

The microbiome modulates host immunity and aids in maintenance of tolerance in the gut, where microbial and food-derived antigens are abundant. Modern lifestyle practices, including diet and antibiotic use, have depleted beneficial taxa, specifically butyrate-producing Clostridia. This depletion is associated with the rising incidence of food allergy, inflammatory bowel diseases, and other noncommunicable chronic diseases. Although butyrate is known to play important roles in regulating gut immunity and maintaining epithelial barrier function, its clinical translation is challenging due to its offensive odor and quick absorption in the upper gut. Here, we have developed two polymeric micelle systems, one with a neutral charge (NtL-ButM) and one with a negative charge (Neg-ButM) that release butyrate from their polymeric core in different regions of the gastrointestinal tract when administered intragastrically to mice. We show that these butyrate-containing micelles, used in combination, restore a barrier-protective response in mice treated with either dextran sodium sulfate or antibiotics. Moreover, butyrate micelle treatment protects peanut-allergic dysbiotic mice from an anaphylactic reaction to peanut challenge and rescues their antibiotic-induced dysbiosis by increasing the abundance ofClostridiumCluster XIVa. Butyrate micelle treatment also reduces the severity of colitis in a murine model. By restoring microbial and mucosal homeostasis, these butyrate-prodrug polymeric micelles may function as a new, antigen-agnostic approach for the treatment of allergic and inflammatory disease.
Decoding natural gait cycle in Parkinson’s disease from cortico-subthalamic field potentials
Authors: Louie Kenneth H. , Gilron Ro’ee , Yaroshinsky Maria S. , Morrison Melanie A. , Choi Julia , de Hemptinne Coralie , Little Simon , Starr Philip A. , Wang Doris D.
Published: May 2022

Human bipedal walking is a complex motor behavior that requires precisely timed alternating activity across multiple nodes of the supraspinal network. However, understanding the neural dynamics that underlie walking is limited. We investigated the cortical-subthalamic circuit dynamics of overground walking from three patients with Parkinson’s disease without major gait impairments. All patients were implanted with chronic bilateral deep brain stimulation leads in the subthalamic nucleus (STN) and electrocorticography paddles overlying the primary motor (M1) and sensory (S1) cortices. Local field potentials were wirelessly streamed through implanted bidirectional pulse generators during overground walking and synchronized to external gait kinematics sensors. We found that the STN displays increased low frequency (4-12 Hz) spectral power between ipsilateral heel strike to contralateral leg swing. Furthermore, the STN shows increased theta frequency (4-8 Hz) coherence with M1 through the initiation and early phase of contralateral leg swing. Our findings support the hypothesis that oscillations from the basal ganglia and cortex direct out-of-phase, between brain hemispheres in accordance with the gait cycle. In addition, we identified patient-specific, gait-related biomarkers in both STN and cortical areas at discrete frequency bands. These field potentials support classification of left and right gait events. These putative biomarkers of the gait cycle may eventually be used as control signals to drive adaptive DBS to further improve gait dysfunction in patients with Parkinson’s disease.
An Early Return-to-Work Program for COVID-19 Close Contacts in Healthcare During the Omicron Wave in Japan
Authors: Naruse Hiroyuki , Doi Yohei , Iwata Mitsunaga , Ishikawa Kiyohito
Published: May 2022

During the coronavirus disease 2019 (COVID-19) pandemic, maintaining adequate staffing in healthcare facilities is important to provide a safe work environment for healthcare workers (HCWs). Japan’s early return-to-work (RTW) program may be a rational strategy at a time when there is an increased demand for the services of HCWs. We assessed whether the early RTW program for HCWs who have been in close contact with a COVID-19 case in our hospital was justified. Close contacts were identified according to the guidance of the World Health Organization. Between January and March 2022, 256 HCWs were identified as close contacts (median age, 35 years; 192 female). Thirty-seven (14%) secondary attack cases of COVID-19 were detected. Among 141 HCWs who applied to the early RTW program, nurses and doctors comprised about three-quarters of participants, with a higher participation rate by doctors (78%) than nurses (59%). Eighteen HCWs tested positive for COVID-19 by the sixth day after starting the early RTW program. No COVID-19 infection clusters were reported during the observation period. These findings suggest that the early RTW program for COVID-19 close contacts was a reasonable strategy for HCWs during the Omicron wave.
Real-World Progression-Free Survival as an Endpoint in Advanced Non-Small-Cell Lung Cancer: Replicating Atezolizumab and Docetaxel Arms of the OAK Trial Using Data Derived From Electronic Health Records
Authors: Mhatre Shivani K. , Machado Robson J. M. , Ton Thanh G.N. , Trinh Huong , Mazieres Julien , Rittmeyer Achim , Bretscher Michael T.
Published: May 2022

Background

Evaluating cancer treatments in real-world data (RWD) requires informative endpoints. Due to non-standardized data collection in RWD, it is unclear if and when common oncology endpoints are approximately equivalent to their clinical trial analogues. This study used RWD to replicate both the atezolizumab and docetaxel arms of the OAK trial. Outcomes using progression-free survival (PFS) derived from abstracted physician’s notes in RWD (rwPFS) were then compared against PFS outcomes derived according to Response Evaluation Criteria in Solid Tumors (RECIST) from the clinical trial (ctPFS).

Methods

Atezolizumab and docetaxel arms of the phase III OAK RCT (NCT02008227) were replicated in a US nationwide real-world database by applying selected OAK inclusion/exclusion criteria, followed by adjustment for baseline prognostic variables using propensity score-based methods. Multiple rwPFS definitions were characterized and a definition was chosen that was acceptable from both clinical and data analysis perspectives. Concordance of outcomes was assessed using Kaplan-Meier (KM) medians and hazard ratios (HRs).

Results

Overall, 133 patients receiving atezolizumab and 479 patients receiving docetaxel were selected for the RWD cohort. After adjustment, prognostic variables were balanced between RCT arms and corresponding RWD cohorts. Comparing rwPFS against ctPFS outcomes in terms of KM median and HR showed better concordance for docetaxel (2.99 vs 3.52 months; HR, 0.99, 95% CI, 0.85-1.15) than for atezolizumab (3.71 vs 2.76 months; HR, 0.8, 95% CI 0.61-1.02). The latter improved when events labelled “pseudo-progression” were excluded from the RWD (im-rwPFS) and immune-modified RECIST PFS (im-ctPFS) was used in the RCT Atezolizumab data (4.24 vs 4.14 months; HR, 0.95, 95% CI, 0.70-1.25). These findings were robust across several sensitivity analyses.

Conclusions

While rwPFS and ctPFS were similar under docetaxel treatment, this was only the case for atezolizumab when immune-modified progression criteria were used, suggesting that similarity of RWD endpoints to their clinical trial analogues depends on drug category and possibly other factors. Replication of RCTs using RWD and comparison of outcomes can be used as a tool for characterizing RWD endpoints. Additional studies are needed to verify these findings and to better understand the conditions for approximate numerical equivalence of rwPFS and ctPFS endpoints.
Victims of human trafficking and exploitation in the healthcare system: a retrospective study using a large multi-state dataset and ICD-10 codes
Authors: Gutfraind Alexander , Sokat Kezban Yagci , Muscioni Guido , Alahmadi Sami , Hudlow Jonathan , Hershow Ronald , Norgeot Beau
Published: May 2022

Background

Trafficking and exploitation for sex or labor affects millions of persons worldwide. To improve healthcare for these patients, in late 2018 new ICD-10 medical diagnosis codes were implemented in the US.

Methods

Here we report on a database search of a large US health insurer that contained approximately 47.1 million patients and 0.9 million provider organizations, not limited to large medical systems. We reported on any diagnosis with the new codes between 2018-09-01 and 2022-09-01.

Results

The dataset was found to contain 5,262 instances of the ICD-10 codes. Regression analysis of the codes found a 5.8% increase in the uptake of these codes per year, representing a decline relative to 6.7% annual increase in the data. The codes were used by 1,810 different providers (0.19% of total) for 2,793 patients. Of the patients, 1,248 were recently trafficked, while the remainder had a personal history of exploitation. Of the recent cases, 86% experienced sexual exploitation, 14% labor exploitation and 0.8% both types. These patients were predominantly female (83%) with a median age of 20 (interquartile range: 15-35). The patients were characterized by persistently high prevalence of mental health conditions (including anxiety - 21%, post-traumatic stress disorder - 20%, major depression - 18%), sexually-transmitted infections, and high utilization of the emergency department (ED). The first report of trafficking occurred most often outside of a hospital or emergency setting (55%), primarily during primary care and psychiatric visits.

Conclusions

Our study strengthens the case for expanding the use of the new ICD-10 codes and studying the barriers to their implementation.
Leishmania allelic selection during experimental sand fly infection correlates with mutational signatures of oxidative DNA damage
Authors: Bussotti Giovanni , Li Blaise , Pescher Pascale , Vojtkova Barbora , Louradour Isabelle , Pruzinova Katerina , Sadlova Jovana , Volf Petr , Späth Gerald F.
Published: May 2022

Trypanosomatid pathogens are transmitted by blood-feeding insects, causing devastating human infections. Survival of these parasites in their vertebrate and invertebrate hosts relies on their capacity to differentiate into distinct stages that are the result of a co-evolutionary process. These stages show in addition important phenotypic shifts that often impacts infection, affecting for example parasite pathogenicity, tissue tropism, or drug susceptibility. Despite their clinical relevance, the evolutionary mechanisms that allow for the selection of such adaptive phenotypes remain only poorly investigated. Here we use Leishmania donovani as a trypanosomatid model pathogen to shed first light on parasite evolutionary adaptation during experimental sand fly infection. Applying a comparative genomics approach on hamster- isolated amastigotes and derived promastigotes before (input) and after (output) infection of Phlebotomus orientalis revealed a strong bottleneck effect on the parasite population as judged by principal component and phylogenetic analyses of input and output parasite DNA sequences. Despite random genetic drift caused by the bottleneck effect, our analyses revealed various genomic signals that seem under positive selection given their convergence between independent biological replicates. While no significant fluctuations in gene copy number were revealed between input and output parasites, convergent selection was observed for karyotype, haplotype and allelic changes during sand fly infection. Our analyses further uncovered signature mutations of oxidative DNA damage in the output parasite genomes, suggesting that Leishmania suffers from oxidative stress inside the insect digestive tract. Our results propose a new model of Leishmania genomic adaptation during sand fly infection, where oxidative DNA damage and DNA repair processes drive haplotype and allelic selection. The experimental and computational framework presented here provides a useful blueprint to assess evolutionary adaptation of other eukaryotic pathogens inside their insect vectors, such as Plasmodium spp, Trypanosoma brucei and Trypanosoma cruzi.
Axl contributes to efficient migration and invasion of melanoma cells
Authors: Shao Hanshuang , Teramae Diana , Wells Alan
Published: May 2022

Axl, a member of the TAM receptor family has been broadly suggested to play a key role in tumor metastasis. However, the function of Axl in the invasion and metastasis of melanoma, the most lethal skin cancer, remains largely unknown. In the present study, we found that melanoma cell lines present variable protein levels of Axl and Tyro3; interestingly, MerTK is not noted at detectable levels in any of tested MGP (metastatic growth phase) cell lines. Treatment with recombinant human Gas6 significantly activates Akt in the Axl-expressing WM852 and IgR3 lines but just slightly in WM1158. IgR3, WM852 and WM1158 demonstrate different autocrine signaling. Knockdown of Axl by siRNA or the treatment with Axl-specific inhibitor R428 dramatically inhibits the migration and invasion of both IgR3 and WM852 in vitro. These findings suggest that Axl enhances the invasion of melanoma cells.
Mechanically primed cells transfer memory to fibrous matrices for persistent invasion
Authors: Almeida José , Mathur Jairaj , Lee Ye Lim , Sarker Bapi , Pathak Amit
Published: May 2022

In disease and development, cells sense and migrate across mechanically dissimilar environments. We investigated whether mechanical memory of past environments empowers cells to navigate new, three-dimensional environments. Here, we show that cells primed by stiff matrices apply higher forces, compared to soft-primed cells, to accumulate and align collagen fibers towards sustained invasion. This priming advantage persists in dense or stiffened collagen. Through an energy-minimization model, we elucidate how memory-laden cells overcome mechanosensing of softer or challenging environments via a cell-matrix transfer of memory. Consistent with model predictions, depletion of α-catenin and YAP hamper coordinated forces and cellular memory required for collagen remodeling before invasion. We release tension in collagen fibers via laser ablation and disable fiber remodeling by lysyl-oxidase inhibition; both of which disrupt cell-to-matrix transfer of memory and reduce invasion. These results have implications for cancer, fibrosis, and aging, where potential matrix memory may generate prolonged cellular response.

One-Sentence Summary

Cell invasion across mechanically dissimilar environments is mediated by force-based storage and extraction of cell and matrix memory.
A Phytophthora nucleolar effector, Pi23226, targets to host ribosome biogenesis for necrotrophic cell death
Authors: Lee Soeui , Kim Jaehwan , Kim Myung-Shin , Min Cheol Woo , Kim Sun Tae , Choi Sang-Bong , Lee Joo Hyun , Choi Doil
Published: May 2022

Pathogen effectors target diverse subcellular organelles to manipulate the plant immune system. Although nucleolus has been emerged as a stress marker, and several effectors are localized in the nucleolus, the roles of nucleolar-targeted effectors remain elusive. In this study, we showed Phytophthora infestans infection of Nicotiana benthamiana results in nucleolar inflation during the transition from biotrophic to necrotrophic phase. Multiple P. infestans effectors were localized in the nucleolus: Pi23226 induced cell death in Nicotiana benthamiana and nucleolar inflation similar to that observed in the necrotrophic stage of infection, whereas its homolog Pi23015 and a deletion mutant (Pi23226ΔC) did not induce cell death or affect nucleolar size. RNA immunoprecipitation and iCLIP-seq analysis indicated that Pi23226 bound to the 3′-end of 25S rRNA precursors, resulting in the accumulation of unprocessed 27S pre-rRNAs. The nucleolar stress marker NAC082 was strongly upregulated under Pi23226-expressing conditions. Pi23226 subsequently inhibited global protein translation in host cells by interacting with ribosomes. Pi23226 enhanced P. infestans pathogenicity, indicating that Pi23226-induced ribosome malfunction and cell death was beneficial for pathogenesis in the host. Our results provide evidence for the molecular mechanism underlying RNA-binding effector activity in host ribosome biogenesis, and lead to new insights into the nucleolar action of effectors in pathogenesis.
Pleiotrophin drives a pro-metastatic immune niche within the breast tumor microenvironment
Authors: Ganguly Debolina , Schmidt Marcel O. , Coleman Morgan , Ngo Tuong-Vi , Sorrelle Noah , Dominguez Adrian TA. , Toombs Jason E. , Lewis Cheryl , Fang Yisheng , Mora Fatima Valdes , Gallego-Ortega David , Wellstein Anton , Brekken Rolf A.
Published: May 2022

Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-kB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor associated neutrophils and reverts local immune suppression resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade + chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a pro-metastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer.
Convergence on reduced aggression through shared behavioral traits in multiple populations of Astyanax mexicanus
Authors: Rodriguez-Morales Roberto , Gonzalez-Lerma Paola , Yuiska Anders , Han Ji Heon , Guerra Yolanda , Crisostomo Lina , Keene Alex C. , Duboue Erik R. , Kowalko Johanna
Published: May 2022

Aggression is a complex behavior that is observed across the animal kingdom, and plays roles in resource acquisition, defense, and reproductive success. While there are many individual differences in propensity to be aggressive within and between populations, the mechanisms underlying differences in aggression between individuals in natural populations are not well understood. We addressed this using the Mexican tetra, Astyanax mexicanus, a powerful model organism to understand behavioral evolution. A. mexicanus exists in two forms: a river-dwelling surface form and multiple populations of a blind cave form. We characterized aggression in surface fish and cavefish in a resident/intruder assay through quantifying multiple behaviors occurring during social interactions. Surface fish, which are aggressive, display multiple social behaviors in this context, which we characterized into two types of behaviors: aggression- associated and escape-associated behaviors. The majority of these behaviors were reduced or lost in Pachón cavefish. Further, both aggression-associated and escape-associated behaviors were not dependent on the presence of light, and both surface fish and cavefish remained aggressive or non-aggressive, respectively, when opposed to fish from a different population. Additionally, we found that within populations, levels of stress response were not correlated with aggression- or escape-associated behaviors. Finally, when we compared aggression- and escape- associated behaviors across four cavefish populations, we found that both types of behaviors are reduced in three cave populations, while still present in one. Together, these results reveal that multiple cavefish populations have repeatedly evolved reduced aggression through shared behavioral components, while other cavefish have retained aggression.

Summary Statement

Comparison of aggression between surface fish and cavefish demonstrates that multiple complex behaviors compose aggression in surface fish and reveals heterogeneity in loss of aggression in cave populations.
Discovery and structure of a widespread bacterial ABC transporter specific for ergothioneine
Authors: Zhang Yifan , Gonzalez-Gutierrez Giovanni , Legg Katherine A. , Edmonds Katherine A. , Giedroc David P.
Published: May 2022

Ergothioneine (ET) is the 2-thiourea derivative of trimethylhistidine that is biosynthesized only by select fungi and bacteria, notablyMycobacterium tuberculosis, and functions as a potent scavenger of reactive oxygen species. Although ET is obtained in the diet and accumulates in vertebrate cells via an ET-specific transporter, the extent to which ET broadly functions in bacterial cells unable to synthesize it is unknown. Here we show thatspd_1642-1643inStreptococcus pneumoniaeD39, a Gram-positive respiratory pathogen, encodes a novel ergothioneine uptake ATP-binding cassette (ABC) transporter, which we designate EgtUV. EgtU is a permease-solute binding domain (SBD) fusion protein, and the SBD binds ET with high affinity and exquisite specificity in the cleft between the two subdomains, with cation-π interactions engaging the betaine moiety and a water-mediated hydrogen bonding network surrounding the C2-sulfur-containing imidazole ring. Bioinformatics studies reveal that EgtUV is uniquely strongly conserved among known quaternary amine-specific transporters and widely distributed in firmicutes, including the human pathogensListeria monocytogenes, as BilEB,Enterococcus faecalisandStaphylococcus aureus. This discovery significantly diversifies the LMW thiol pool in Gram-positive human pathogens that may contribute to antioxidant defenses in the infected host.
Disrupting the ciliary gradient of active Arl3 affects rod photoreceptor nuclear migration
Authors: Travis Amanda M. , Manocha Samiya , Willer Jason R. , Wessler Timothy S. , Skiba Nikolai P. , Pearring Jillian N.
Published: May 2022

The small GTPase Arl3 is important for the enrichment of lipidated proteins to primary cilia, including the outer segment of photoreceptors. Human mutations in the small GTPase Arl3 cause both autosomal recessive and dominant inherited retinal dystrophies. We discovered that dominant mutations result in increased active G-protein—Arl3-D67V has constitutive activity and Arl3-Y90C is fast cycling—and their expression in mouse rods resulted in a displaced nuclear phenotype due to an aberrant Arl3-GTP gradient. Using multiple strategies, we go on to show that removing or restoring the Arl3-GTP gradient within the cilium is sufficient to rescue the nuclear migration defect. Together, our results reveal that a Arl3 ciliary gradient is involved in proper positioning of photoreceptor nuclei during retinal development.