bluuebunny/crossref_metadata_2025 huggingface dataset:
PROMOTING AT-HOME DISEASE MANAGEMENT OF IBD WITH A MULTIDISCIPLINARY DIGITAL THERAPY APP: SHORT-TERM RESULTS
Authors: Pater Roeland , Zentveld Dandyano , Booth Lisa
Published: January 2022

BACKGROUND

Although current concepts of disease management of Crohn’s Disease and ulcerative colitis (IBD) provide evidence of active engagement of patients, such a strategy is difficult to comply with unless multidisciplinary therapy is practiced.

In the past years mobile and/or digital health solutions have proven to be competent tools to promote and retain self management for patients across many disease areas.

The Nori Health mobile application was developed as multi-faceted digital therapy for IBD based on existing evidence in at-home management and treatment with the aim to accommodate multidisciplinary therapy remotely.

OBJECTIVE

The objective of this paper was to report on the retrospective short-term results of a multidisciplinary digital therapy app for the treatment and self-management of IBD; Nori Health.

METHODS

Nori Health is a mobile application that digitalizes multidisciplinary therapy, such as education, behavioral intervention and cognitive behavioral therapy (CBT), and is in the market as a CE class I medical device.

For the current study, the internal data of anonymized Nori Health users was retrospectively analyzed. User data was evaluated for 8 weeks regarding duration of use (Figures 1, 2) and effect on in-app user reported disease management levels, using the short IBD Control questionnaire (IBD-CONTROL).

RESULTS

Data of 273 users were available, of which 29 users completed the IBD-CONTROL questionnaire both prior and after the duration of the analysis period. The gender of the users was 61% female and 39% male.

Disease management levels increased 34% from baseline 50 to 67 for all users at the end of the observation period.

CONCLUSION

This retrospective study showed that in a randomized population of app users, an app digitalizing multidisciplinary interventions for the self-management of IBD improved user-reported disease management levels significantly.

Additional RCTs will be needed to adjust for selection effects, potential bias, and to further improve clinical relevance of these short-term results.
REDEFINING HEALTHCARE: A NOVEL, SCIENCE-BASED, EXPERIENTIAL FRAMEWORK FOR IMPROVING PATIENT OUTCOMES IN INFLAMMATORY BOWEL DISEASE
Authors: Puckett Amanda , Loftus Amy , Kornfeld Andrew
Published: January 2022

IBD affects 3 million individuals in the US alone but the prevalence is expanding globally. The economic burden of IBD in the US is high, with estimates indicating the combined IBD population in the US is expected to incur a lifetime total cost of over $800 billion. Many current IBD treatments lose effectiveness over time and up to 80% of patients with Crohn’s disease and 20% of patients with Ulcerative Colitis require at least one surgical intervention in their lifetime. Scientific evidence suggests diet, lifestyle factors, and mental health are emerging as key contributors to IBD’s pathogenesis but are often outside of the scope of frontline treatment interventions. Further, patient education is associated with improving outcomes but is not addressed by current treatment strategies. New innovative approaches are needed to improve the efficacy of existing treatments, ease the economic and personal burdens of living with IBD, and address the gaps in existing strategies.

The human-centered framework by IBDCoach is a newly developed and strategic patient-driven system, based on immersive science education and represents a reconceptualization of the IBD healthcare experience (Figures 1 and 2). This framework aims to facilitate seamless patient-doctor interaction, improve compliance to prescribed treatment strategies, empower patients to understand their condition and to develop an effective, well-rounded treatment protocol under the close supervision of their healthcare team, and promote successful behavioral change. The IBDCoach framework combines principles of systems-thinking, experiential scientific education, ancestral health, neuroplasticity and behavioral change, and compassion for the unique human experience of chronic illness to fill the gaps in existing IBD treatment strategies. We report on initial successes observed in the first 100 enrollees of this novel framework, the theory behind the program, and the broader implications for redefining the IBD healthcare landscape with creative solutions.

Figure 1. IBDCoach’s three mechanisms of IBD pathogenesis.

Figure 2. IBDCoach’s key framework steps.
REAL-WORLD UTILIZATION OF ADALIMUMAB BIOSIMILAR (ABP 501) IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN EUROPE
Authors: Jin Ran , Nduka Chidozie , Courmier Delphine , Knight Hannah , Meadows Rachael , Piercy James , Radziszewski Waldemar
Published: January 2022

OBJECTIVE

ABP 501 (AMGEVITA®) was the first approved biosimilar to adalimumab reference product (RP) by the European Medicines Agency and has been marketed in the European Union since 2018. Additional real-world data on its efficacy and safety, particularly for treating patients with inflammatory bowel disease (IBD), an indication approved on the basis of extrapolation, has the possibility of addressing barriers to utilization.

METHODS

This was a retrospective analysis of data collected between April and June 2021 from the Adelphi IBD Disease Specific Programme (DSP) covering ulcerative colitis (UC) and Crohn’s disease (CD) in Germany, France, Spain, Italy, and United Kingdom. Gastroenterologists provided data on demographics, clinical characteristics, treatment history, and treatment satisfaction. Patients had the option to complete the short IBD questionnaire (SIBDQ) aimed at measuring the burden of disease, work productivity and activity impairment (WPAI) questionnaire, and to indicate their assessment of treatment satisfaction. Descriptive analyses were conducted; continuous variables were reported as means or medians, categorical variables as number of patients and percentages.

RESULTS

82 physicians reported data on 396 patients (189 UC and 207 CD): 239 initiated ABP 501 as first advanced therapy (AT) (initiators), 157 switched to ABP 501 from RP with no prior use of other AT (switchers) (Table). Median time from IBD diagnosis to initiation of ABP 501 was 13.9 months for initiators with median time on ABP 501 being 7.5 months at the time of data collection. Switchers previously received RP for a median of 14.1 months and had been on ABP 501 for a median time of 7.7 months since switching. The main reasons for switching from RP to ABP 501 were related to the potential to lower healthcare cost. At the time of reporting, more than two-thirds (67% initiators, 83% switchers) had mild disease, more than three-quarters were in clinical remission (74% initiators, 88% switchers), and a majority were in improving or stable disease status (96% initiators, 98% switchers). Mean SIBDQ scores (56 vs. 59) and overall work impairment (4.7% vs. 3.2%) were similar across initiators and switchers, respectively. Physicians and patients (>90% each of initiators and switchers) reported being satisfied with current treatment with ABP 501.

CONCLUSION

ABP 501 was used as initial or continuing adalimumab therapy in the real-world setting to treat patients with IBD. At least three-fourths of patients currently on ABP 501 were in clinical remission, with a higher proportion in the switching group. Both physicians and patients reported very high levels of satisfaction with treatment.
VEDOLIZUMAB FOR REFRACTORY MICROSCOPIC COLITIS: A CASE SERIES
Authors: Dawoud Nabila , Fein Aaron , Elkammar Mahmoud , Eltaher Mohamed , Barrett Terrence , Perry Courtney
Published: January 2022

INTRODUCTION

Microscopic colitis (MC) is a chronic inflammatory disease of the colon that causes non-bloody, watery diarrhea occurs up to 15 times daily in the presence of normal-appearing mucosa in the colon. There are two main subtypes of MC based on histopathologic features, collagenous colitis (CC) and lymphocytic colitis (LC)1. Treatment of each subtype is similar and should be determined by the severity of symptoms. Some patients suffer severe symptoms despite maximum dosage of budesonide, in these cases biologic therapies should be considered. Vedolizumab, a monoclonal antibody that targets α4β7-integrin, is a gut-specific biologic with an exceptional safety profile. Here, we report our experience with vedolizumab for severe, refractory MC.

METHODS

Eleven patients presenting to the University of Kentucky with severe microscopic colitis refractory to maximum budesonide and Imodium therapy were treated with vedolizumab. Vedolizumab was given at standard induction dosing (300mg IV at week 0, 2 and 6, and then every 8 weeks).

RESULTS

Of the eleven patients included in this study, seven reported subjective symptomatic improvement on vedolizumab monotherapy, with four patients attaining less than 3 stools per day. Of the remaining four patients, one continues to do well on vedolizumab and budesonide combination therapy while another developed a rash after vedolizumab induction and treatment was stopped. The third patient was transitioned from vedolizumab to adalimumab and is now well controlled symptomatically and the final patient has not reached symptomatic remission of her disease. Interestingly, of the seven patients who displayed symptomatic improvement with vedolizumab monotherapy, 5/7 patients also showed improvement in albumin levels.

DISCUSSION

Vedolizumab use in refractory microscopic colitis is increasingly recognized as a conceivable therapy for symptomatic improvement and disease remission. Our case series corroborates these findings, as the majority of our patients reported overall improved quality of life. Vedolizumab binds to the α4β7-integrin and prevent adhesion to its ligand, MAdCAM-1, which causes downstream prevention of T-cell adhesion. Although the exact pathophysiology of microscopic colitis remains largely unidentified, it has been postulated that exposure to a luminal antigen may trigger an inflammatory cascade, leading to activation of CD8 T suppressor cells that attack and cause luminal damage to enterocytes2. This hypothesis is supported by vedolizumab’s mechanism of action and proposed efficacy in MC. Due to low volume studies, the data supporting vedolizumab use in refractory microscopic colitis remains limited, and further studies are needed to elucidate the its potential as a first-line therapy. However, based on our experience, we recommend considering vedolizumab for patients suffering from refractory MC.
The Impact of Frequent SARS-CoV-2 Testing on Weekly Case Rates Among Long-Term Care Facilities in Florida
Authors: Allan-Blitz Lao-Tzu , Aboabdo Belal , Turner Isaac , Klausner Jeffrey D.
Published: January 2022

SARS-CoV-2 testing frequency may be as important as test performance for disease control. We analyzed 1,292,165 SARS-CoV-2 test results among 361 long-term care facilities across Florida after implementing twice monthly testing (June 2020-April 2021). Our findings demonstrate that an increase in testing frequency reduced weekly case rates.
Regulation of balanced root fungal community of Vanda falcata (Orchidaceae) by partitioning its mycorrhizal fungi and ascomycetous fungi across growth and development
Authors: Pujasatria Galih Chersy , Nishiguchi Ikuo , Miura Chihiro , Yamato Masahide , Kaminaka Hironori
Published: January 2022

Epiphytic orchids are commonly found in exposed environments, which plausibly lead to different root fungal community structures from terrestrial orchids. Until recently, no studies have been conducted to show the fungal community structure during the growth of a photosynthetic and epiphytic orchid in its natural growing state. In this study, the Vanda falcata (commonly known as Neofinetia falcata), one of Japan’s ornamental orchids, was used to characterize the fungal community structure at different developmental stages. Amplicon sequencing analysis showed that all development stages contain a similar fungal community: Ascomycota dominates half of the community while one-third of the community is Basidiomycota. Rhizoctonia-like fungi, a term to group the most common basidiomycetous fungi that form orchid mycorrhiza, exist even in a smaller portion (around a quarter) compared to other Basidiomycota members. While ascomycetous fungi exhibit pathogenicity, two Ceratobasidium strains isolated from young and adult plants could initiate seed germination in vitro. It was also found that the colonization of mycorrhizal fungi was concentrated in the lower part of the root where it directly attaches to the phorophyte bark, while ascomycetous fungi were distributed in the velamen but never colonized cortical cells. Additionally, lower root parts attached to the bark have denser exodermal passage cells, and these cells were colonized only by mycorrhizal fungi that further infiltrated the cortical area. Therefore, we propose that physical regulation of fungal entry to partition the ascomycetes and mycorrhizal fungi results in the balanced mycorrhizal symbiosis in this orchid.
Hummingbird blood traits track oxygen availability across space and time
Authors: Williamson Jessie L. , Linck Ethan B. , Bautista Emil , Smiley Ashley , McGuire Jimmy A. , Dudley Robert , Witt Christopher C.
Published: January 2022

Predictable trait variation across environmental gradients suggests that adaptive evolution repeatedly finds the same solution to a challenge. Trait-environment associations can reflect long-term, genetic evolution across phylogenies, or short-term, plastic responses of individuals. When phylogenetic and population-level patterns match, it implies consistency between the long timescale of adaptation and the short timescale of acclimatization. Alternatively, genetic adaptation can find solutions that ‘break the rules’ of trait-environment covariation. For example, blood-hemoglobin concentration ([Hb]) increases at high elevations in animals, but genetic adaptations in some populations have been shown to augment tissue oxygenation while curtailing hemoglobin production, altering this predictable [Hb]-elevation association. Here, we tested whether species adaptation to elevation generally alters trait-environment relationships for blood. To do this, we measured blood traits of 1,217 individuals representing 77 species of Andean hummingbirds, across a 4,600 m elevational gradient. We used hierarchical Bayesian modeling to estimate blood trait responses to elevation, environmental temperature, precipitation, individual and species characteristics, and phylogeny. Strikingly, the effects of elevation on [Hb] and hematocrit (Hct) were nearly identical for individuals and species, implying that rules of elevational blood variation are set by physics of gas exchange in the hummingbird respiratory system and are unchanged by species adaptation. However, when we looked at mechanisms of [Hb] adjustment—by changes in red blood cell size or number—we did find a signal of species adaptation: To adjust [Hb], species at low and high elevations, respectively, tended to adjust cell size, whereas species at mid-elevations tended to adjust cell number. Despite scale-independent elevational variation in [Hb] and Hct, the species-specific balance of red blood cell size versus number appears to have been affected by adaptations that distinguish hummingbird species living at moderate versus high elevations.
Urban population structure and dispersal of an Australian mosquito (Aedes notoscriptus) involved in disease transmission
Authors: Paris Véronique , Rane Rahul , Mee Peter , Lynch Stacey , Hoffmann Ary A , Schmidt Thomas L
Published: January 2022

Dispersal is a critical factor in designing successful pest control measures as it determines the rate of movement across target control areas and influences the risk of human exposure to the species and its pathogens. Here we used a fine scale spatial population genomic approach to investigate the dispersal ecology and population structure ofAedes notoscriptus, an important disease transmitting mosquito, on the Mornington Peninsula near Melbourne, Australia. The species is suspected to be involved in the transmission ofMycobacterium ulcerans, the bacterium that causes Buruli ulcer, in this area. We sampled and rearedAe. notoscriptuseggs at two time points from 170 traps up to 5 km apart and generated genomic data from 240 individuals. We also produced a draft genome assembly from a laboratory colony established from mosquitoes sampled near the study area. We found low genetic structure (Fst) and high coancestry throughout the study region. Using genetic data to identify close kin dyads, we found that mosquitoes had moved distances of >1km within a generation, which is further than previously described for this species. A spatial autocorrelation analysis of genetic distances indicated genetic dissimilarity at >4 km separation, a fourfold higher distance than for a comparable population of the dengue mosquito,Ae. aegypti, from Cairns, Australia. These findings point to high mobility ofAe. notoscriptus, highlighting the challenges of localized intervention strategies targeting this species. Further sampling within the same area at two time points 6 and 12 months after initial sampling showed that egg counts were relatively consistent across time, and that spatial variation in egg counts covaried with spatial variation in Wright’s neighbourhood size (NS). As NS increases linearly with population density, egg counts may be useful for estimating relative density inAe. notoscriptus. The results highlight the importance of acquiring species-specific data when planning control measures.
Temporal trends in legionellosis national notification data and the effect of COVID-19, Switzerland, 2000- 2020
Authors: Fischer Fabienne B. , Mäusezahl Daniel , Wymann Monica N.
Published: January 2022

The notification rate of legionellosis in Switzerland and other European countries has markedly increased over the last 20 years. Here, we investigated the Swiss notification data on legionellosis from 2000-2020 in regards of overall time trend, content and data quality. We further explored the impact of the COVID-19 pandemic on the reported case numbers using an interrupted time series approach. Between 2000 and 2020, 5,980 cases were included in our analysis. The annual crude notification rate for legionellosis cases increased from 1.1/100,000 population (CI: 0.9 - 1.4) in 2000 to 5.6/100,000 population (CI: 5.1 - 6.1) in 2020. In recent years, the summer peaks have been more pronounced and some shifted earlier in the year. The highest notification rate was recorded in 2018 with 6.7/100,000 population (CI: 6.2 - 7.3). The hospitalisation rate for notified cases remained high across all study years (89.9%), while the case fatality rate slightly decreased (from 7.7% to 3.6%). COVID-19 containment measures, such as travel restrictions and/or related behavioural changes, are associated with a temporary decline in cases of 35%. Overall, the quality of the notification data was good. Clinical data were more susceptible to interferences than data from laboratory reporting, which could be observed most clearly in the decline of clinical reports by 4.3 percentage points in 2020. As the case classification for Legionnaires’ disease includes pneumonia symptoms, this decline could lead to an underestimation of Legionnaires’ disease cases, yet the continuous reporting though the diagnostic laboratories suggested a robust surveillance system for legionellosis in Switzerland.
Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery
Authors: Shekarian Tala , Zinner Carl P. , Bartoszek Ewelina M. , Duchemin Wandrille , Wachnowicz Anna T. , Hogan Sabrina , Etter Manina M. , Flammer Julia , Paganetti Chiara , Martins Tomás A. , Schmassmann Philip , Zanganeh Steven , Le Goff Francois , Muraro Manuele G. , Ritz Marie-Françoise , Phillips Darci , Bhate Salil S. , Barlow Graham L. , Nolan Garry P. , Schürch Christian M. , Hutter Gregor
Published: January 2022

Recent therapeutic strategies for glioblastoma (GBM) aim at targeting immune tumor microenvironment (iTME) components to induce antitumoral immunity. A patient-tailored, ex vivo drug testing and response analysis platform for GBM would facilitate personalized therapy planning, provide insights into treatment-induced immune mechanisms in the iTME, and enable the discovery of biomarkers of therapy response and resistance.

We cultured 47 GBM explants from tumor center and periphery from 7 patients in perfusion bioreactors to assess iTME responses to immunotherapy. Explants were exposed to antibodies blocking the immune checkpoints CD47, PD-1 or or their combination, and were analyzed by highly multiplexed microscopy (CODEX, co-detection by indexing) using an immune-focused 55-marker panel. Culture media were examined for changes of soluble factors including cytokines, chemokines and metabolites. CODEX enabled the spatially resolved identification and quantification of >850,000 single cells in explants, which were classified into 10 cell types by clustering. Explants from center and periphery differed significantly in their cell type composition, their levels of soluble factors, and their responses to immunotherapy. In a subset of explants, culture media displayed increased interferon-γ levels, which correlated with shifts in immune cell composition within specific tissue compartments, including the enrichment of CD4+ and CD8+ T cells within an adaptive immune compartment. Furthermore, significant differences in the expression levels of functional molecules in innate and adaptive immune cell types were found between explants responding or not to immunotherapy. In non-responder explants, T cells showed higher expression of PD-1, LAG-3, TIM-3 and VISTA, whereas in responders, macrophages and microglia showed higher cathepsin D levels. Our study demonstrates that ex vivo immunotherapy of GBM explants enables an active antitumoral immune response within the tumor center in a subset of patients, and provides a framework for multidimensional personalized assessment of tumor response to immunotherapy.
Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer
Authors: Velenosi Thomas J. , Krausz Kristopher W. , Hamada Keisuke , Dorsey Tiffany H. , Ambs Stefan , Takahashi Shogo , Gonzalez Frank J.
Published: January 2022

Triple-negative breast cancer (TNBC) patients receive chemotherapy treatment, including doxorubicin, due to the lack of targeted therapies. Drug resistance is a major cause of treatment failure in TNBC and therefore, there is a need to identify biomarkers that determine effective drug response. Here, a pharmacometabolomics study was performed using TNBC patient-derived xenograft models to detect urinary metabolic biomarkers of doxorubicin effectiveness. Diacetylspermine was identified as a urine metabolite that robustly changed in response to effective doxorubicin treatment, which persisted after the final dose. Diacetylspermine was directly traced back to the tumor and correlated with tumor volume. Ex vivo tumor slices revealed that doxorubicin directly increases diacetylspermine production by increasing tumor spermidine/spermine N1-acetyltransferase 1 expression and activity, which was corroborated by elevated polyamine flux. In breast cancer patients, tumor diacetylspermine was elevated compared to matched non-cancerous tissue and increased in HER2+ and TNBC compared to ER+ subtypes. In addition, 12-hour urine diacetylspermine was associated with breast cancer tumor volume and poor tumor grade. This study describes a pharmacometabolomics strategy for identifying cancer metabolic biomarkers that indicate drug response. Our findings characterize urine diacetylspermine as a non-invasive biomarker of doxorubicin effectiveness in TNBC.
Tree size drives diversity and community structure of microbial communities on the bark of beech (Fagus sylvatica)
Authors: Dreyling Lukas , Schmitt Imke , Grande Francesco Dal
Published: January 2022

Tree bark constitutes ideal habitat for microbial communities, because it is a stable substrate, rich in micro-niches. Bacteria, fungi, and terrestrial microalgae together form microbial communities, which in turn support more bark-associated organisms, such as mosses, lichens, and invertebrates, thus contributing to forest biodiversity. We have a limited understanding of the diversity and biotic interactions of the bark-associated microbiome, as investigations have mainly focussed on agriculturally relevant systems and on single taxonomic groups. Here we implemented a multi-kingdom metabarcoding approach to analyse diversity and community structure of the green algal, bacterial, and fungal components of the bark-associated microbial communities of beech, the most common broadleaved tree of Central European forests. We identified the most abundant taxa, hub taxa, and co-occurring taxa. We found that tree size (as a proxy for age) is an important driver of community assembly, suggesting that environmental filtering leads to less diverse fungal and algal communities over time. Conversely, forest management intensity had negligible effects on microbial communities on bark. Our study suggests the presence of undescribed, yet ecologically meaningful taxa, especially in the fungi, and highlights the importance of bark surfaces as a reservoir of microbial diversity. Our results constitute a first, essential step towards an integrated framework for understanding microbial community assembly processes on bark surfaces, an understudied habitat and neglected component of terrestrial biodiversity. Finally, we propose a cost-effective sampling strategy to study bark-associated microbial communities across large spatial or environmental scales.
RaMP-DB 2.0: a renovated knowledgebase for deriving biological and chemical insight from genes, proteins, and metabolites
Authors: Braisted John , Patt Andrew , Tindall Cole , Eicher Tara , Sheils Timothy , Neyra Jorge , Spencer Kyle , Mathé Ewy A.
Published: January 2022

RaMP-DB 2.0 is a web interface, API, relational database and R package designed for straightforward and comprehensive functional interpretation of metabolomic and multi-omic data. Since its first release in 2018, RaMP-DB 2.0 has been upgraded with an expanded breadth and depth of functional and chemical annotation. Content from the source databases (Reactome, HMDB, and Wikipathways) has been updated, and new data types related to metabolite annotations have been incorporated. Structural information incorporated in RaMP-DB 2.0 includes SMILES strings, InChIs, InChIKeys. Chemical classes have been sourced from ClassyFire and LIPID MAPS. Accordingly, the RaMP-DB 2.0 R package has been updated and supports queries on pathways, common reactions, ontologies, chemical classes, and chemical structures. Additionally, RaMP-DB 2.0 now supports enrichment analyses on pathways and chemical classes. Our process for integrating annotations across resources has also been upgraded to lessen the burden of harmonization, thereby supporting more frequent updates. The code used to build all components of RaMP-DB 2.0 is freely available on GitHub athttps://github.com/ncats/ramp-dbandhttps://github.com/ncats/RaMP-Backend.
Reduced blood to brain glucose transport as the cause for hyperglycemia in a model resolves multiple anomalies in type 2 diabetes
Authors: Ojha Akanksha , Watve Milind
Published: January 2022

Classically type 2 diabetes is believed to be a result of insulin resistance and relative insulin deficiency. However, evidences have been accumulating against the insulin resistance centered models. Absence of fasting hyperglycemia by insulin receptor knockouts or insulin suppression, evidence for hyperinsulinemia preceding insulin resistance, the perplexing hyperinsulinemic normoglycemic state, reduced glucose transport to the brain preceding hyperglycemia, signs of vasculopathy preceding hyperglycemia, absent or poor correlation between fasting glucose and insulin, very strong positive correlation between indices of insulin resistance and β cell function in population data are some of the anomalous findings which glucose homeostasis models have not addressed so far. With increasing evidence for neuronal involvement in glucose regulation, we propose a refined model of glucose regulation that considers brain glucose and insulin levels as the ultimate target of homeostasis and combines central and peripheral mechanisms of regulation. A model considering reduced rate of blood to brain transportation of glucose and insulin as primary pathology explains most of the patterns, with or without insulin resistance. Apart from resolving multiple anomalies the model also accounts for the limited and inconsistent success of glucose normalization in effectively reducing diabetic complications and mortality.
Automated assessment reveals extinction risk of reptiles is widely underestimated across space and phylogeny
Authors: de Oliveira Caetano Gabriel Henrique , Chapple David G. , Grenyer Richard , Raz Tal , Rosenblatt Jonathan , Tingley Reid , Böhm Monika , Meiri Shai , Roll Uri
Published: January 2022

The Red List of Threatened Species, published by the International Union for Conservation of Nature (IUCN), is a crucial tool for conservation decision making. However, despite substantial effort, numerous species remain unassessed, or have insufficient data available to be assigned a Red List threat category. Moreover, the Red Listing process is subject to various sources of uncertainty and bias. The development of robust automated assessment methods could serve as an efficient and highly useful tool to accelerate the assessment process and offer provisional assessments. Here we aimed to: 1) present a machine learning based automated threat assessment method that can be used on less known species; 2) offer provisional assessments for all reptiles - the only major tetrapod group without a comprehensive Red List assessment; and 3) evaluate potential effects of human decision biases on the outcome of assessments. We use the method presented here to assess 4,369 reptile species that are currently unassessed or classified as Data Deficient by the IUCN. Our models range in accuracy from 88% to 93% for classifying species as threatened/non-threatened, and from 82% to 87% for predicting specific threat categories. Unassessed and Data Deficient reptiles were more likely to be threatened than assessed species, adding to mounting evidence that they should be considered threatened by default. The overall proportion of threatened species greatly increased when we included our provisional assessments. Assessor identities strongly affected prediction outcomes, suggesting that assessor effects need to be carefully considered in extinction risk assessments. Regions and taxa we identified as likely to be more threatened should be given increased attention in new assessments and conservation planning. Lastly, the method we present here can be easily implemented to help bridge the assessment gap on other less known taxa.
PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19
Authors: Hong E. , Almond L.M. , Chung P.S. , Rao A.P. , Beringer P.M.
Published: January 2022

Background

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (pwCF) due to the potential for significant drug-drug interactions (DDI). However, pwCF are more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.

Methods

CYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A4 inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators.

Results

When ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor.

Conclusions

Coadministration of nirmatrelvir-ritonavir requires a significant reduction in the ETI dosing frequency with delayed resumption of full dose due to the mechanism-based inhibition with ritonavir.
Determinants of Late Initiation for Antenatal Care Follow up Among Pregnant Mothers Attending Public Health Centers at Jimma Town, South West Ethiopia, 2021: Unmatched Case–Control Study
Authors: Jihad Mohammed , Woldemichael Kifle , Gezehagn Yenealem
Published: January 2022

Background

World Health Organization recommends that, a woman without complications should have at least four antenatal care visits, the first of which should take place during the first trimester (not > 16 weeks). But, high proportion of pregnant women in most of developing countries attended first ANC at a late time. In Ethiopia, magnitude of late ANC follow up initiation is 64% and in study area 68.7% however determinants of the problem were not identified particularly in the study area.

Objective

To identify determinants of late antenatal care initiation among pregnant women attending antenatal care in public health centers of Jimma town, south west Ethiopia 2021.

Methods

Facility based unmatched case control study was conducted from May 1-30. The cases (n=177) were mothers who attended their first antenatal care visit at >= 16 weeks of gestational age and the controls (n=177) were mothers who attended their first antenatal care visit at <16 weeks of gestational age during the data collection period. Data was collected through face to face interview using pre tested structured questionnaire. Descriptive and summary statistics was done. Bivariable and multivariable logistic regression analysis was done using SPSS version 21.0 to identify candidate variables at P-value <0.25 and determinants of late ANC initiation at P-value <0.05 respectively.

Results

The current study identified that, being age > 25 years (AOR= 2.623, 95% CI 1.059 - 6.496), poor knowledge about ANC (AOR= 3.856, 95% CI 1.266-11.750), lack of history of abortion (AOR= 3.326, 95% CI 1.082-10.224), place of previous delivery (AOR=3.926, 95%CI 1.023-15.063), recognizing pregnancy through missed period(AOR= 3.631, 95% CI 1.520-8.674), pregnancy related pain(AOR= 3.499, 95% CI 1.423 - 8.603) and lack of family support (AOR=2.647, 95% CI 1.092-6.415) were determinants of late ANC initiation.

Conclusion

Being age > 25 years, poor knowledge about ANC, lack of history of abortion, place of previous delivery, recognizing pregnancy through missed period, pregnancy related pain, and lack of family support during ANC booking were determinants of late ANC initiation.Health facilities and respective health care providers should provide health education at facility level regularly with due attention to late ANC initiation.
A high-throughput approach measures cell type-specific telomere lengths in fixed archival tissues from patient cohorts for research on prognosis
Authors: Heaphy Christopher M. , Zarinshenas Reza , Barber John R. , Davis Christine , Brosnan-Cashman Jacqueline A. , De Marzo Angelo M. , Joshu Corinne E. , Platz Elizabeth A. , Meeker Alan K.
Published: January 2022

Telomeres, the repetitive DNA elements at chromosome ends, are pivotal for maintenance of genome integrity. Previous studies from our group and others have highlighted the translational potential of tissue-based telomere length measurements to address the clinical challenge of improving diagnosis, individualized risk stratification, and accurate prognostication of different diseases. Here, we describe a high-throughput method that quantitates cell type-specific telomere lengths at a single cell level in archival tissues from patient cohorts for research on prognosis. This approach is based on telomere-specific fluorescence in situ hybridization (FISH) combined with multiplex immunostaining for cell type-specific antibodies, followed by semi-automated slide scanning and multi-channel acquisition of fluorescent images using the TissueFAXS Plus microscopy workstation and TissueQuest software (TissueGnostics). Here, we demonstrate that this method is sufficiently robust and reproducible to detect biologically significant differences in telomere lengths in archived tissues either on whole slides or sampled across tissue microarrays, which is essential when assessing prognosis in large patient cohorts.
Brainstem somatostatin-expressing cells control the emotional regulation of pain behavior
Authors: Winke Nanci , Aby Frank , Jercog Daniel , Zoé Grivet , Girard Delphine , Landry Marc , Castell Laia , Valjent Emmanuel , Valerio Stephane , Fossat Pascal , Herry Cyril
Published: January 2022

In mammals, threat-related behavior is typically induced by a noxious physical stressor and is associated with a broad range of behavioral responses such as freezing and avoidance. These behavioral responses are associated with the regulation of pain responses allowing individuals to cope with noxious stimuli. Whereas the structures and mechanisms involved in pain behavior are well documented, little is known about the precise neuronal circuits mediating the emotional regulation of pain behavior. Here we used a combination of behavioral, anatomical, optogenetic, and electrophysiological approaches to show that somatostatin-expressing neurons in the ventrolateral periaqueductal gray matter (vlPAG SST cells) promote antinociceptive responses during the presentation of conditioned stimuli (CS) predicting footshocks. Whereas the optogenetic inhibition of vlPAG SST cells during CS presentation promoted analgesia, their optogenetic activation reduced analgesia by potentiating pain responses in the spinal cord through a relay in the rostral ventromedial medulla (RVM). Together these results identify a brainstem circuit composed of vlPAG SST cells specifically projecting to the RVM and mediating fear conditioned analgesia (FCA) to regulate pain responses during threatful situations.
Recruitment of Corticotropin-releasing Hormone CRH Neurons in response to Categorically Distinct Stress Challenges in the Mouse Brain
Authors: Horváth Krisztina , Juhász Balázs , Kuti Dániel , Ferenczi Szilamér , Török Bibiána , Zelena Dóra , Kovács Krisztina J.
Published: January 2022

1.

Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (Pa) are in the position to integrate stress-related information and initiate adaptive neuroendocrine-, autonomic-, metabolic- and behavioral responses. In addition to hypophyseotropic cells, CRH is widely expressed in the CNS, however their involvement in organization of the stress response is not fully understood. In these experiments, we took the advantage of recently available Crh-IRES-Cre; Ai9 mouse line to study the recruitment of hypothalamic and extrahypothalamic CRH neurons in categorically distinct, acute stress reactions. Reporter mice were exposed to restraint, ether, high salt and lipopolisacharide stress. The induced activation of CRH neurons was detected by colocalization of immediate early gene c-Fos in Td tomato expressing cells. We found differential activation of CRH neurons in central amygdaloid nucleus (Ce), bed nucleus stria terminalis lateral division, ventral posterior (BSTLVP), medial preoptic nucleus (MPO), ventromedial hypothalamic nucleus (VMH), premammillary nucleus (PM) and prepositus hypoglossal nucleus (Pr) in response to physiological (ether, high salt and LPS) and psychological (restraint) stressors. CRH positive cells in Pa became activated, however in the Barrington’s nucleus and locus coeruleus no actiovation could be observed due to most tested stressors. Furthermore no CRH neuron activation occured in dorsal (BSTLD) and posterior (BSTLP) region of lateral division of bed nucleus stria terminalis after restraint stress. In the inferior olive only ether exposition resulted in CRH neuron activation. These results confirm activation of CRH neurons in the Pa, reveals new subset of stress-related CRH cells through the mouse brain and disprove the recruitment of CRH cells in the SOL and in the Barrington’s nucleus to acute psychological stress in mice.
Image-centric compression of protein structures improves space savings
Authors: Staniscia Luke , Yu Yun William
Published: January 2022

Background

Because of the rapid generation of data, the study of compression algorithms to reduce storage and transmission costs is important to bioinformaticians. Much of the focus has been on sequence data, including both genomes and protein amino acid sequences stored in FASTA files. Current standard practice is to use an ordinary lossless compressor such as gzip on a sequential list of atomic coordinates, but this approach expends bits on saving an arbitrary ordering of atoms, and it also prevents reordering the atoms for compressibility. The standard MMTF and BCIF file formats extend this approach with custom encoding of the coordinates. However, the brand new Foldcomp tool introduces a new paradigm of compressing local angles, to great effect. In this article, we explore a different paradigm, showing for the first time that image-based compression using global angles can also significantly improve compression ratios. To this end, we implement a prototype compressor ‘PIC’, specialized for point clouds of atom coordinates contained in PDB and mmCIF files. PIC maps the 3D data to a 2D 8-bit greyscale image and leverages the well developed PNG image compressor to minimize the size of the resulting image, forming the compressed file.

Results

PIC outperforms gzip in terms of compression ratio on proteins over 20,000 atoms in size, with a savings over gzip of up to 37.4% on the proteins compressed. In addition, PIC’s compression ratio increases with protein size.

Conclusion

Image-centric compression as demonstrated by our prototype PIC provides a potential means of constructing 3D structure-aware protein compression software, though future work would be necessary to make this practical.
In Silico Analysis Of The Effects Of Omicron Spike Amino Acid Changes On The Interactions With Human ACE2 Receptor And Structurally Characterized Complexes With Human Antibodies
Authors: D’Arminio Nancy , Giordano Deborah , Scafuri Bernardina , Biancaniello Carmen , Petrillo Mauro , Facchiano Angelo , Marabotti Anna
Published: January 2022

The new SARS-CoV-2 variant Omicron is characterised, among others, by more than 30 amino acid changes (including 4 deletions and 1 insertion) occurring on the spike glycoprotein.

We report a comprehensive analysis of the effects of the Omicron spike amino acid changes in the interaction with human ACE2 receptor or with human antibodies, obtained by analysing the publicly available resolved 3D structures. Our analysis predicts that amino acid changes occurring on amino acids interacting with the ACE2 receptor may increase Omicron transmissibility. The interactions of Omicron spike with human antibodies can be both negatively and positively affected by amino acid changes, with a predicted total loss of interactions only in few complexes. We believe that such an approach can be used to better understand SARS-CoV-2 transmissibility, detectability, and epidemiology, especially when extended to other than spike proteins.
Engineered bacterial swarm patterns as spatial records of environmental inputs
Authors: Doshi Anjali , Shaw Marian , Tonea Ruxandra , Moon Soonhee , Doshi Anish , Laine Andrew , Guo Jia , Danino Tal
Published: January 2022

A diverse array of bacteria species naturally self-organize into durable macroscale patterns on solid surfaces via swarming motility—a highly coordinated, rapid movement of bacteria powered by flagella1–5. Engineering swarming behaviors is an untapped opportunity to increase the scale and robustness of coordinated synthetic microbial systems. Here we engineer Proteus mirabilis, which natively forms centimeter-scale bullseye patterns on solid agar through swarming, to “write” external inputs into a visible spatial record. Specifically, we engineer tunable expression of swarming-related genes that accordingly modify pattern features, and develop quantitative approaches to decode input conditions. Next, we develop a two-input system that modulates two swarming-related genes simultaneously, and show the resulting patterns can be interpreted using a deep learning classification model. Lastly, we show a growing colony can record dynamic environmental changes, which can be decoded from endpoint images using a segmentation model. This work creates an approach for building a macroscale bacterial recorder and expands the framework for engineering emergent microbial behaviors.
Broadly-recognized, cross-reactive SARS-CoV-2 CD4 T cell epitopes are highly conserved across human coronaviruses and presented by common HLA alleles
Authors: Becerra-Artiles Aniuska , Calvo-Calle J. Mauricio , Co Marydawn , Nanaware Padma P. , Cruz John , Weaver Grant C. , Lu Liying , Forconi Catherine , Finberg Robert W. , Moormann Ann M. , Stern Lawrence J.
Published: January 2022

Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can impact the T cell response in COVID-19. We studied T cells recognizing SARS-CoV-2 and HCoVs in convalescent COVID-19 donors, and identified a highly conserved SARS-CoV-2 sequence S811-831, with two overlapping epitopes presented by common MHC-II proteins HLA-DQ5 and HLA-DP4. These epitopes were recognized by CD4+T cells from convalescent COVID-19 donors, mRNA vaccine recipients, and by low-abundance CD4+T cells in uninfected donors. TCR sequencing revealed a diverse repertoire with public TCRs. CD4+T cell cross-reactivity was driven by the remarkably strong conservation of T cell contact residues in both HLA-DQ5 and HLA-DP4 binding frames, with distinct patterns of HCoV cross-reactivity explained by MHC-II binding preferences and substitutions at secondary TCR contact sites. These data highlight S811-831as a highly-conserved CD4+T cell epitope broadly recognized across human populations.
High efficiency multiplex biallelic heritable editing in Arabidopsis using an RNA virus
Authors: Nagalakshmi Ugrappa , Meier Nathan , Liu Jau-Yi , Voytas Daniel F. , Dinesh-Kumar Savithramma P
Published: January 2022

Delivery of gene editing components such as the Cas nuclease and single guide RNAs (sgRNAs) into plant cells is commonly accomplished by agrobacterium-mediated transformation. Although Arabidopsis is easy to transform, generation of biallelic edited plants requires screening a large number of plants in subsequent generations. Here, we describe optimization of the Tobacco rattle virus (TRV) for in planta delivery of sgRNAs fused to a tRNAIleu that induces efficient multiplex somatic and biallelic heritable editing in Arabidopsis. Inclusion of tRNAIleu enhances the systemic movement of TRV and the mutant phenotype is visible in the initial TRV::sgRNA-tRNAIleu infected Arabidopsis, which allows for the uncovering of lethal phenotypes. Mutant progeny are recovered in the next generation (M1) at frequencies ranging from 30-60%, with 100% mutant recovery in the following (M2) generation. TRV::tRNAIleu system described here allows generation of biallelic edited plants in a single generation and is amenable for large-scale high throughput CRISPR screens.