bluuebunny/crossref_metadata_2025 huggingface dataset:
Bleeding From Band Ligation–induced Ulcers Following the Treatment of Esophageal Varices
Authors: Hu Zixuan , Liu Shaojun , Liu Tao , Zhu Wei , Li Jiake
Published: October 2021

Goal:

Our study aimed to explore the incidence of bleeding from ulcers due to premature band slippage and to identify possible associated factors.

Background:

Band ligation (BL) plays a vital role in treating esophageal varices; however, the procedure carries a considerable risk of band slippage, variceal site ulcer formation, and posttreatment bleeding.

Materials and Methods:

We retrospectively reviewed the records of patients with esophageal varices who underwent endoscopic hemostasis by BL at our institution between 2015 and 2020. We statistically compared the patients with post-BL ulcer bleeding and those without (controls). The outcome variable was the development of BL-induced ulcer bleeding. The patients’ demographics, clinical, and laboratory parameters, and BL procedure parameters were independent variables. Univariate followed by a multivariate logistic regression were performed to identify possible associated factors from the odds ratio (OR).

Results:

Of the 4579 eligible patients, 388 (8.5%) presented with post-BL ulcer bleeding. The presence of high-risk stigmata indicated a 1.271 times higher risk of bleeding [95% confidence interval (CI):1.018-1.587], and a greater number of varices was associated with an increased risk of post-BL ulcer bleeding [OR=1.184 (95% CI: 1.073-1.307)]. Conversely, the use of fewer bands per variceal site was associated with fewer bleeding incidents [OR=1.308 (95% CI: 1.090-1.569)]. Univariate analysis identified proton pump inhibitor as protective [OR=0.770 (95% CI: 0.603-0.983)]; however, the difference was not significant after multivariate analysis [OR=1.283 (95% CI: 1.003-1.640)].

Conclusions:

The overall incidence of post-BL ulcer bleeding was 8.5%. The presence of high-risk stigmata, higher number of varices, and bands per variceal site were associated with an increased risk of post-BL bleeding. The effect of adjuvant proton pump inhibitors was not statistically significant.
The Pandemic Within the Pandemic
Authors: Sohal Aalam , Khalid Sameeha , Green Victoria , Gulati Alakh , Roytman Marina
Published: October 2021

Background and Aim:

The third leading preventable cause of death in the United States is excessive alcohol consumption. Our study sought to assess the impact of the coronavirus disease 2019 (COVID-19) on hospitalizations for alcohol-related hepatitis at a community hospital system. We hypothesized an increase in cases of alcohol-related hepatitis requiring inpatient management, mirroring the strain on economic and societal norms imposed by the COVID-19 pandemic.

Approach/Results:

We performed a retrospective chart review to study the incidence of alcohol-related hepatitis in patients presenting to 3 community hospitals in Fresno, California, before and during the COVID-19. Data including patient demographics, markers of disease severity, and clinical course were extracted from electronic medical records for 329 patients included in the study. There was a 51% increase in the overall incidence of alcohol-related hepatitis requiring hospitalization between 2019 and 2020 (P=0.003) and 69% increase (P<0.001) after implementation of the stay-at-home orders. In addition, 94% (P=0.028) increase in rehospitalizations was noted in 2020 (P=0.028), a 100% increase in patients under the age of 40 (P=0.0028), as well as a trend towards a 125% increase (P=0.06) of female patients admitted with this diagnosis during the COVID-19 pandemic.

Conclusions:

Our study revealed drastic increases in severe alcohol-related hepatitis requiring inpatient management, specifically in patients under the age of 40 and in women during the COVID-19 pandemic. Given the high morbidity and mortality associated with severe alcohol-related hepatitis, these findings have far-reaching and lasting implications for our already strained health care system extending beyond the COVID-19 pandemic timeframe. Urgent public health interventions are needed to combat the rising misuse of alcohol and its consequences.
Quality and Safety in Healthcare, Part XCI
Authors: Harolds Jay A.
Published: October 2021

Lean thinking refers to the thought processes utilizing the main characteristics of Lean to improve processes, reduce waste, and increase value to the customer. Lean thinking can be used to improve health care organizations using such tools as the A3 form, root-cause analysis, value stream maps, Gemba walks, kaizen events, and defining standard work. Examples are given about how Lean thinking improved scheduling and productivity, as well as better compliance regarding core measures and adherence to best practices. Lean thinking examples are also given which resulted in less need for space, inventory, and personnel, and a decrease in hospital-acquired infections.
Presacral Benign Schwannoma Mimics Malignancy on 18F-FDG and 68Ga-FAPI PET/CT
Authors: Zhu Yahua , Wu Junhao , Wang Yingwei , Geng Jun , Zhang Chunyin
Published: October 2021

We present findings of FDG PET/CT and FAPI PET/CT in a 55-year-old woman with a history of black stools and low-back pain. Pelvic CT detected a giant presacral mass that was suspected to be malignant. 18F-FDG and 68Ga-FAPI PET/CT showed that the mass had intense activity. Pathological examination confirmed the mass as a benign schwannoma.
Characterization of microbial communities from rumen and large intestine of lactating creole goats grazing in arid plant communities
Authors: Barraza Aarón , Montes-Sánchez Juan J. , Caamal-Chan M. Goretty , Loera-Muro Abraham
Published: October 2021

Arid plant communities provide variable diets that can affect digestive microbial communities of free-foraging ruminants. Thus, we used next-generation sequencing of 16S and 18S rDNA to characterize microbial communities in the rumen (regurgitated digesta) and large intestine (faeces) and diet composition of lactating creole goats from five flocks grazing in native plant communities in the Sonoran Desert in the rainy season. The bacterial communities in the rumen and large intestine of the five flocks had similar alpha diversity (Chao1, Shannon, and Simpson indices). However, bacterial community compositions were different: a bacterial community dominated by

Proteobacteria

in the rumen transitioned to a community dominated by

Firmicutes

in the large intestine. Bacterial communities of rumen were similar across flocks; similarly occurred with large-intestine communities. Archaea had a minimum presence in the goat digestive tract. We detected phylum Basidiomycota, Ascomycota, and Apicomplexa as the main fungi and protozoa. Analyses suggested different diet compositions; forbs and grasses composed the bulk of plants in the rumen and forbs and shrubs in faeces. Therefore, lactating goats consuming different diets in the Sonoran Desert in the rainy season share a similar core bacterial community in the rumen and another in the large intestine and present low archaeal communities.
Incidence of SARS-CoV-2 infection in a cohort of workers from the University of Porto
Authors: Costa Joana Pinto , Meireles Paula , Rodrigues Pedro N. S. , Barros Henrique
Published: October 2021

Background

Repeated serosurveys in the same population provide more accurate estimates of the frequency of SARS-CoV-2 infection and more comparable data than notified cases. We aimed to estimate the incidence of SARS-CoV-2 infection, identify associated risk factors, and assess time trends in the ratio of serological/molecular diagnosis in a cohort of university workers.

Methods

Participants had a serological rapid test for SARS-CoV-2 Immunoglobulins M and G, and completed a questionnaire, in May-July 2020 (n=3628) and November 2020–January 2021 (n=2661); 1960 participated in both evaluations and provided data to compute the incidence proportion and the incident rate. Crude and adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) were computed using generalised linear models with Poisson regression.

Results

The incidence rate was 1.8/100 person-month (95%CI 1.6-2.1), and the 6 months’ cumulative incidence was 10.7%. The serological/molecular diagnosis ratio was 10:1 in the first evaluation and 3:1 in the second. Considering newly identified seropositive cases at the first (n=69) and second evaluation (n=202), 29.0% and 9.4% never reported symptoms, respectively, 14.5% and 33.3% reported contact with a confirmed case and 82.6%, and 46.0% never had a molecular test. Males (aIRR: 0.59; 95%CI: 0.42-0.83) and “high-skilled white-collar” workers (aIRR: 0.73, 95%CI: 0.52-1.02) had lower incidence of infection.

Conclusion

University workers presented a high SARS-CoV-2 incidence while restrictive measures were in place. The time decrease in the proportion of undiagnosed cases reflected the increased access to testing, but opportunities continued to be missed, even in the presence of COVID-19 like symptoms.

What is already known on this subject

The median ratio of seroprevalence to the corresponding cumulative incidence is 18, however, there is great variability between studies.

Seroprevalence studies are essential to estimate the true burden of the infection.

Few cohort studies focused on essential non-healthcare workers, such as university workers.

What this study adds

This longitudinal seroprevalence study among university workers found a SARS-CoV-2-specific IgM or IgG incidence rate of 1.8/100 person-month, and a 6 months’ cumulative incidence of 10.7%.

The undiagnosed fraction was 3:1 in the second evaluation, representing a decrease from a 10:1 in the first evaluation in the same population showing that a gap to test-trace-isolate remained in this highly educated working population.

Seropositive participants were mostly pauci- or symptomatic with no known contact with a COVID-19 confirmed case; “high-skilled white-collar” workers were at lower risk of being an incident seropositive case.
Estimating COVID-19 Hospitalizations in the United States with surveillance data using a Bayesian Hierarchical model
Authors: Couture A , Iuliano AD , Chang HH , Patel NN , Gilmer M , Steele M , Havers FP , Whitaker M , Reed C
Published: October 2021

Introduction

In the United States, COVID-19 is a nationally notifiable disease, cases and hospitalizations are reported to the CDC by states. Identifying and reporting every case from every facility in the United States may not be feasible in the long term. Creating sustainable methods for estimating burden of COVID-19 from established sentinel surveillance systems is becoming more important. We aimed to provide a method leveraging surveillance data to create a long-term solution to estimate monthly rates of hospitalizations for COVID-19.

Methods

We estimated monthly hospitalization rates for COVID-19 from May 2020 through April 2021 for the 50 states using surveillance data from COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) and a Bayesian hierarchical model for extrapolation. We created a model for six age groups (0-17, 18-49, 50-64, 65-74, 75-84, and ≥85 years), separately. We identified covariates from multiple data sources that varied by age, state, and/or month, and performed covariate selection for each age group based on two methods, Least Absolute Shrinkage and Selection Operator (LASSO) and Spike and Slab selection methods. We validated our method by checking sensitivity of model estimates to covariate selection and model extrapolation as well as comparing our results to external data.

Results

We estimated 3,569,500 (90% Credible Interval:3,238,000 – 3,934,700) hospitalizations for a cumulative incidence of 1,089.8 (988.6 – 1,201.3) hospitalizations per 100,000 population with COVID-19 in the United States from May 2020 through April 2021. Cumulative incidence varied from 352 – 1,821per 100,000 between states. The age group with the highest cumulative incidence was aged ≥85 years (5,583.1; 5,061.0 – 6,157.5). The monthly hospitalization rate was highest in December (183.8; 154.5 – 218.0). Our monthly estimates by state showed variations in magnitudes of peak rates, number of peaks and timing of peaks between states.

Conclusions

Our novel approach to estimate COVID-19 hospitalizations has potential to provide sustainable estimates for monitoring COVID-19 burden, as well as a flexible framework leveraging surveillance data.
Predicting sensitivity and resilience to modifiable risk factors for cardiometabolic morbidity and mortality
Authors: Pomares-Millan Hugo , Atabaki-Pasdar Naemieh , Johansson Ingegerd , Poveda Alaitz , Franks Paul W.
Published: October 2021

Background

Lifestyle exposures play a major role in the development of disease, yet people vary in their susceptibility. A critical step towards precision medicine is identifying individuals who are resilient or sensitive to the environment, and, assess whether the allocation to these predicted groups are more or less likely to develop cardiometabolic disease.

Methods

We have used repeated data from the VHU study (n=35440) to identify sensitive and resilient individuals using prediction intervals at the 5thand 95thquantile. Three exposure susceptibility groups were derived per cardiometabolic score using quantile regression forests in the training dataset; next, in the validation dataset, we assessed the different risks of the groups using Cox proportional hazard models for CVD and diabetes.

Results

The results of our study suggest that, after ∼10 y of follow-up, individuals with sensitivity to the environmental exposures associated with systolic and diastolic blood pressure, blood lipids, and glucose were at higher risk of developing cardiometabolic disease. Moreover, when hazards were pooled with the replication cohort, for those individuals sensitive to the exposures associated with blood pressure traits, the hazards remained significant.

Conclusions

Identifying individuals who are predicted to be sensitive are at higher risk of developing disease, this population may be a clinical target for prevention or early intervention and public health strategies.
Refining the Analysis of Multidimensional Psychometric Data: A Geometric Distance Approach
Authors: Joyce Dan W. , Meyer Nicholas
Published: October 2021

Validated instruments such as questionnaires, patient-reported outcome measures and clinician-rated psychopathology scales, are indispensable for measuring symptom burden and mental state, and for defining outcomes in both psychiatric practice and clinical trials. Most often, the values on the instrument’s multiple items (dimensions) are added to derive a single, univariate (scalar) sum-score. Although this approach simplifies interpretation, there are always many possible combinations of individual items that can yield the same sum-score. Two patients can therefore obtain identical scores on a given instrument, despite having very different combinations of underlying item scores corresponding to different patterns of clinical symptoms. The same is also true when a single patient is measured at two different time points, where the resulting sum-scores can obscure changes that may be clinically meaningful.

We present an alternative analytic framework, which leverages geometric concepts to represent measurements as points in a vector space. Using this framework, we show why sum-scores obscure information present in measurements of clinical state, and also provide a straightforward algorithm to mitigate against this problem. Clinically-relevant outcomes, such as remission or patient-centered treatment goals, can be represented intuitively, as reference points or ‘anchors’ within this space. Using real-world data, we then demonstrate how measuring the relative distance between points and anchors preserves more information, allowing outcomes such as proximity to remission, to be defined and measured.
Modeling the influence of vaccine administration on COVID-19 testing strategies
Authors: Forde Jonathan E. , Ciupe Stanca M.
Published: October 2021

Vaccination is considered the best strategy for limiting and eliminating the COVID-19 pandemic. The success of this strategy relies on the rate of vaccine deployment and acceptance across the globe. As these efforts are being conducted, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is continuously mutating, which leads to the emergence of variants with increased transmissibility, virulence, and lower response the vaccines. One important question is whether surveillance testing is still needed in order to limit SARS-CoV-2 transmission in an increasingly vaccinated population. In this study, we developed a multi-scale mathematical model of SARS-CoV-2 transmission in a vaccinated population and used it to predict the role of testing in an outbreak with alpha and delta variants. We found that, when the alpha variant is dominant, testing is effective when vaccination levels are low to moderate and its impact is diminished when vaccination levels are high. When the delta variant is dominant, widespread vaccination is necessary in order to prevent significant outbreaks. When only moderate vaccination can be achieved, frequent testing can significantly reduce the cumulative size of delta variant outbreak, with the impact of testing having maximum effects when focused on the non-vaccinated population.
Comparison of dipsogenic responses of adult offspring as a function of different perinatal programming models
Authors: Dadam FM , Amigone JL , Vivas L , Macchione AF
Published: October 2021

The perinatal environment interacts with the genotype of the developing organism resulting in a unique phenotype through a developmental or perinatal programming phenomenon. However, it remains unclear how this phenomenon differentially affects particular targets expressing specific drinking responses depending on the perinatal conditions. The main goal of the present study was to compare the dipsogenic responses induced by different thirst models as a function of two perinatal manipulation models, defined by the maternal free access to hypertonic sodium solution and a partial aortic ligation (PAL-W/Na) or a sham-ligation (Sham-W/Na). The programmed adult offspring of both perinatal manipulated models responded similarly when was challenged by overnight water dehydration or after a sodium depletion showing a reduced water intake in comparison to the non-programmed animals. However, when animals were evaluated after a body sodium overload, only adult Sham-W/Na offspring showed drinking differences compared to PAL and control offspring. By analyzing the central neurobiological substrates involved, a significant increase in the number of Fos + cells was found after sodium depletion in the subfornical organ of both programmed groups and an increase in the number of Fos + cells in the dorsal raphe nucleus was only observed in adult depleted PAL-W/Na. Our results suggest that perinatal programming is a phenomenon that differentially affects particular targets which induce specific dipsogenic responses depending on matching between perinatal programming conditions and the osmotic challenge in the latter environment. Probably, each programmed-drinking phenotype has a particular set point to elicit specific repertoires of mechanisms to reestablish fluid balance.
Re-emergence of Invasive Pneumococcal Disease in Germany during the Spring and Summer of 2021
Authors: Perniciaro Stephanie , van der Linden Mark , Weinberger Daniel M.
Published: October 2021

Background

The incidence of invasive pneumococcal disease (IPD) decreased worldwide in 2020 and the first quarter of 2021, concurrent with non-pharmaceutical interventions (NPIs) intended to stymie transmission of SARS-CoV-2. In 2021, stringency of these NPI strategies has varied. We investigated age- and serotype-specific variations in IPD case counts in Germany in 2020-2021.

Methods

IPD cases through July 31, 2021 were stratified by age group, serotype, or geographic location. IPD surveillance data in 2020-2021 were compared with: 1) IPD surveillance data from 2015-2019, 2) mobility data during 2020 and 2021, and 3) NPI stringency data in 2020 and 2021.

Results

IPD began to return towards baseline values among children 0 to 4 years old in April 2021 and exceeded baseline levels by June 2021 (a 9% increase over the average monthly values for 2015-2019). Children 5 to 14, adults aged 15-34 and adults 80 years and older showed increases in IPD cases which went over baseline values starting in July 2021, with increases also starting in Spring 2021. The age distribution and proportion of vaccine serotype IPD remained comparable to previous years despite lower overall case counts in 2020 and 2021. The percent change in IPD incidence compared to the previous five years correlated with changes in mobility and with NPI stringency.

Conclusions

IPD levels began to return to and exceed seasonal levels in Spring/Summer 2021 in Germany following sharp declines in 2020 that coincided with NPIs related to the COVID-19 pandemic. Proportions of vaccine serotypes remained largely consistent throughout 2020-2021.
Prenatal alcohol consumption and child IQ and cognition: a Mendelian randomization study
Authors: Labrecque JA , Cecil CAM , Swanson SA
Published: October 2021

Background

Previous studies using Mendelian randomization have found that fetal alcohol exposure may be associated with lower IQ and test scores in childhood.

Objectives

We aim to replicate and extend these findings in Generation R Study, a birth cohort based in Rotterdam, the Netherlands.

Methods

We used data from Generation R which recruited pregnant women between 2002 and 2006. Alcohol use was assessed via questionnaire during each trimester. IQ was measured in the children between ages 5 and 8 using the Snijders-Oomen Non-Verbal Intelligence Test. Scores from a national standardized test administered around age 12 were used as a measure of cognition. We estimated the associations between ten genetic variants in the mothers previously found to be related to alcohol consumption and metabolism and each of the outcomes. In the children, we also estimated the association between the same genetic variants as well as two polygenic scores for alcohol consumption and the outcomes.

Results

Maternal genetic variants were not found to be related to either outcome but wide confidence intervals did not preclude important effects. A few genetic variants in the children were suggestive of a decrease in IQ. Likewise, one genetic variant and the genetic score had estimates and confidence intervals consistent with increases in standardized test scores.

Conclusions

Our results provide slight support for associations between genetic variants in children related to maternal prenatal alcohol consumption and IQ and cognition outcomes. These findings are in line with two previous studies on this topic.
Temperature and Low-stakes Cognitive Performance
Authors: Zhang Xin , Chen Xi , Zhang Xiaobo
Published: October 2021

In this paper we offer among the first evidence in a developing country context that transitory exposure to heat waves may disrupt low-stakes cognitive activities across a wide range of age cohorts. Matching cognitive test scores from a nationally representative longitudinal survey in China with weather data according to the exact time and geographic location of assessment, we find that exposure to a temperature above 32 °C on the test date, relative to a day within 22–24 °C, leads to a sizable decline in math scores by 0.088 SDs (equivalent to 0.30 years of education). The negative effect is more pronounced for less educated older adults taking math tests. Test takers living in hotter regions or having air conditioning installed on site are less vulnerable to extreme high temperatures, indicating the role of adaptation.

JEL Codes

I24, Q54, Q51
Excess risk and clusters of symptoms after COVID-19 in a large Norwegian cohort
Authors: Caspersen Ida Henriette , Magnus Per , Trogstad Lill
Published: October 2021

Physical, psychological and cognitive symptoms have been reported as post-acute sequelae for COVID-19 patients but are also common in the general, uninfected population. We aimed to calculate the excess risk and identify patterns of 22 symptoms up to 12 months after COVID-19 infection. We followed more than 70,000 participants in an ongoing cohort study, the Norwegian Mother, Father and Child Cohort Study (MoBa) during the COVID-19 pandemic. Infected and non-infected cohort participants registered presence of 22 different symptoms in March 2021. One year after the initial infection, 13 of 22 symptoms were associated with SARS-CoV-2 infection, based on relative risks between infected and uninfected subjects. For instance, 17.4% of SARS-CoV-2 infected cohort participants reported fatigue that persist 12 months after infection, compared to new occurrence of fatigue that had lasted less than 12 months in 3.8% of non-infected subjects (excess risk 13.6%). The adjusted relative risk for fatigue was 4.8 (95 % CI 3.5 to 6.7). Two main underlying factors explained 50% of the variance in the 13 symptoms. Brain fog, poor memory, dizziness, heart palpitations, and fatigue had high loadings on the first factor, while shortness-of breath and cough had high loadings on the second factor. Lack of taste and smell showed low to moderate correlation to other symptoms. Anxiety, depression and mood swings were not strongly related to COVID-19. Our results suggest that there are clusters of symptoms after COVID-19 due to different mechanisms and question whether it is meaningful to describe long COVID as one syndrome.
CoWWAn: Model-based assessment of COVID-19 epidemic dynamics by wastewater analysis
Authors: Proverbio Daniele , Kemp Françoise , Magni Stefano , Ogorzaly Leslie , Cauchie Henry-Michel , Gonçalves Jorge , Skupin Alexander , Aalto Atte
Published: October 2021

We present COVID-19 Wastewater Analyser (CoWWAn) to reconstruct the epidemic dynamics from SARS-CoV-2 viral load in wastewater. As demonstrated for various regions and sampling protocols, this mechanistic model-based approach quantifies the case numbers, provides epidemic indicators and accurately infers future epidemic trends. In situations of reduced testing capacity, analysing wastewater data with CoWWAn is a robust and cost-effective alternative for real-time surveillance of local COVID-19 dynamics.
A hierarchical transcriptional network activates specific CDK inhibitors that regulate G2 to control cell size and number in Arabidopsis
Authors: Nomoto Yuji , Takatsuka Hirotomo , Yamada Kesuke , Suzuki Toshiya , Suzuki Takamasa , Huang Ying , Latrasse David , An Jing , Gombos Magdolna , Breuer Christian , Ishida Takashi , Maeo Kenichiro , Imamura Miyu , Yamashino Takafumi , Sugimoto Keiko , Magyar Zoltán , Bögre László , Raynaud Cécile , Benhamed Moussa , Ito Masaki
Published: October 2021

How cell size and number are determined during organ development remains a fundamental question in cell biology. Here, we identified a GRAS family transcription factor, called SCARECROW-LIKE28 (SCL28), with a critical role in determining cell size in Arabidopsis. SCL28 is part of a transcriptional regulatory network downstream of the central MYB3Rs that regulate G2 to M phase cell cycle transition. We show that SCL28 forms a dimer with the AP2-type transcription factor, AtSMOS1, which defines the specificity for promoter binding and directly activates transcription of a specific set of SIAMESE-RELATED (SMR) family genes, encoding plant-specific inhibitors of cyclin-dependent kinases and thus inhibiting cell cycle progression at G2 and promoting the onset of endoreplication. Through this dose-dependent regulation ofSMRtranscription, SCL28 quantitatively sets the balance between cell size and number without dramatically changing final organ size. We propose that this hierarchical transcriptional network constitutes a cell cycle regulatory mechanism that allows to adjust cell size and number to attain robust organ growth.
Identification of multi-omics molecular signature of acute radiation injury using nonhuman primate model
Authors: Cheema Amrita K , Li Yaoxiang , Moulton Joanna , Girgis Michael , Wise Stephen Y. , Carpenter Alana , Fatanmi Oluseyi O. , Singh Vijay K.
Published: October 2021

The availability of validated biomarkers to assess radiation exposure and to assist in developing medical countermeasures remains an unmet need. We used a cobalt-60 gamma-irradiated nonhuman primate (NHP) model to delineate a multi-omics-based serum probability index of radiation exposure. Both male and female NHPs were irradiated with different doses ranging from 6.0 to 8.5 Gy, with 0.5 Gy increments between doses. We leveraged high resolution mass spectrometry for analysis of metabolites, lipids, and proteins at 1,2, and 6 days post-irradiation in NHP serum. A logistic regression model was implemented to develop a 4-analyte panel to stratify irradiated NHPs from unirradiated with high accuracy that was agnostic for all doses of γ-rays tested in the study, up to six days after exposure. This panel was comprised of Serpin Family A9, acetylcarnitine, PC (16:0/22:6), and suberylglycine, which showed 2 – 4-fold elevation in serum abundance upon irradiation in NHPs, and can potentially be translated for human use following larger validation studies. Taken together, this study, for the first time, demonstrates the utility of a combinatorial molecular characterization approach using an NHP model for developing minimally invasive assays from small volumes of blood that can be effectively used for radiation exposure assessments.
Combining metabolomics and experimental evolution reveals key mechanisms underlying longevity differences in laboratory evolved Drosophila melanogaster populations
Authors: Phillips Mark A. , Arnold Kenneth R. , Vue Zer , Beasley Heather K. , Lopez Edgar Garza , Marshall Andrea G. , Morton Derrick J. , McReynolds Melanie R. , Barter Thomas T. , Hinton Antentor
Published: October 2021

Experimental evolution with Drosophila melanogaster has been used extensively for decades to study aging and longevity. In recent years, the addition of DNA and RNA sequencing to this framework has allowed researchers to leverage the statistical power inherent to experimental evolution study the genetic basis of longevity itself. Here we incorporated metabolomic data into to this framework to generate even deeper insights into the physiological and genetic mechanisms underlying longevity differences in three groups of experimentally evolved D. melanogaster populations with different aging and longevity patterns. Our metabolomic analysis found that aging alters mitochondrial metabolism through increased consumption of NAD+ and increased usage of the TCA cycle. Combining our genomic and metabolomic data produced a list of biologically relevant candidate genes. Among these candidates, we found significant enrichment for genes and pathways associated with neurological development and function, and carbohydrate metabolism. While we do not explicitly find enrichment for aging canonical genes, neurological dysregulation and carbohydrate metabolism are both known to be associated with accelerated aging and reduced longevity. Taken together, our results provide plausible genetic mechanisms for what might be driving longevity differences in this experimental system. More broadly, our findings demonstrate the value of combining multiple types of omic data with experimental evolution when attempting to dissect mechanisms underlying complex and highly polygenic traits like aging.
TRPV1-lineage somatosensory fibers communicate with taste neurons in the mouse parabrachial nucleus
Authors: Li Jinrong , Ali Md Sams Sazzad , Lemon Christian H.
Published: October 2021

Trigeminal neurons supply somatosensation to craniofacial tissues. In mouse brain, ascending projections from medullary trigeminal neurons arrive at taste neurons in the autonomic parabrachial nucleus, suggesting taste neurons participate in somatosensory processing. However, the genetic cell types that support this convergence were undefined. Using Cre-directed optogenetics and in vivo neurophysiology in anesthetized mice of both sexes, here we studied whether TRPV1-lineage nociceptive and thermosensory fibers are primary neurons that drive trigeminal circuits reaching parabrachial taste cells. We monitored spiking activity in individual parabrachial neurons during photoexcitation of the terminals of TRPV1-lineage fibers that arrived at the dorsal spinal trigeminal nucleus pars caudalis, which relays orofacial somatosensory messages to the parabrachial area. Parabrachial neural responses to oral delivery of taste, chemesthetic, and thermal stimuli were also recorded. We found that optical excitation of TRPV1-lineage fibers frequently stimulated traditionally defined taste neurons in lateral parabrachial nuclei. The tuning of neurons across diverse tastes associated with their sensitivity to excitation of TRPV1-lineage fibers, which only sparingly engaged neurons oriented to preferred tastes like sucrose. Moreover, neurons that responded to photostimulation of TRPV1-lineage afferents showed strong responses to temperature including noxious heat, which predominantly excited parabrachial bitter taste cells. Multivariate analyses revealed the parabrachial confluence of TRPV1-lineage signals with taste captured sensory valence information shared across aversive gustatory, nociceptive, and thermal stimuli. Our results reveal that trigeminal fibers with defined roles in thermosensation and pain communicate with parabrachial taste neurons.

This multisensory convergence supports dependencies between gustatory and somatosensory hedonic representations in the brain.
Type IV pilus shapes a ‘bubble-jet’ pattern opposing spatial intermixing of two interacting bacterial populations
Authors: Wang Miaoxiao , Chen Xiaoli , Ma Yinyin , Tang Yue-Qin , Johnson David R , Nie Yong , Wu Xiao-Lei
Published: October 2021

Microbes are social organisms that commonly live in sessile biofilms. Spatial patterns of populations within biofilms can be an important determinant of community-level properties. The best-studied characteristics of spatial patterns is spatial intermixing of different populations. The specific levels of spatial intermixing critically contribute to how the dynamics and functioning of such communities are governed. However, the precise factors that determine spatial patterns and intermixing remain unclear. Here, we investigated the spatial patterning and intermixing of an engineered synthetic consortium composed of two Pseudomonas stutzeri strains that degrade salicylate via metabolic cross-feeding. We found that the consortium self-organizes across space to form a previously unreported spatial pattern (referred to here as a ‘bubble-jet’ pattern) that exhibits a low level of intermixing. Interestingly, when the genes encoding for type IV pili were deleted from both strains, a highly intermixed spatial pattern developed and increased the productivity of the entire community. The intermixed pattern was maintained in a robust manner across a wide range of initial ratios between the two strains. Our findings show that the type IV pilus plays a role in mitigating spatial intermixing of different populations in surface-attached microbial communities, with consequences for governing community-level properties. These insights provide tangible clues for the engineering of synthetic microbial systems that perform highly in spatially structured environments.

Importance

When growing on surfaces, multi-species microbial communities form biofilms that exhibit intriguing spatial patterns. These patterns can significantly affect the overall properties of the community, such as enabling otherwise impermissible metabolic functions to occur, as well as driving the evolutionary and ecological processes acting on communities. The development of these patterns is affected by several drivers, including cell-cell interactions, nutrient levels, density of founding cells and surface properties. The type IV pilus is commonly found to mediate surface-associated behaviors of microorganism, but its role on pattern formation within microbial communities is unclear. Here we report that in a cross-feeding consortium, the type IV pilus affects the spatial intermixing of interacting populations involved in pattern formation, and ultimately influences overall community productivity and robustness. This novel insight assists our understanding of the ecological processes of surface-attached microbial communities and suggests a potential strategy to engineer high-performance synthetic microbial communities.
Neurexins Regulate GABA Co-release by Dopamine Neurons
Authors: Ducrot Charles , de Carvalho Gregory , Delignat-Lavaud Benoît , Delmas Constantin V.L. , Giguère Nicolas , Mukherjee Sriparna , Burke-Nanni Samuel , Bourque Marie-Josée , Parent Martin , Chen Lulu Y. , Trudeau Louis-Éric
Published: October 2021

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which glutamate or GABA are released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. Here we tested the hypothesis that the trans-synaptic cell adhesion molecules neurexins (Nrxns) regulate DA neuron neurotransmission. Conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) showed that loss of Nrxns does not impair the basic development and ultrastructural characteristics of DA neuron terminals. However, loss of Nrxns caused an impairment of DA transmission revealed as a reduced rate of DA reuptake following activity-dependent DA release, decreased DA transporter levels, increased vesicular monoamine transporter expression, and impaired amphetamine-induced locomotor activity. Strikingly, electrophysiological recording revealed an increase of GABA co-release from DA neuron axons in the striatum of the KO mice. These findings suggest that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions.

Highlights

The study provides the first direct evidence of the role of neurexins in dopaminergic neurons.

The synaptic adhesion molecules, neurexins, are not required for maintaining the structure of dopamine neuron terminals.

Neurexins regulate dopaminergic neurotransmission through regulation of dopamine reuptake, impacting amphetamine-induced locomotion.

Deletion of Nrxns in DA neurons causes a region-specific increase of GABA release by DA neurons.
Transcriptional Regulation of Synthetic Polymer Networks
Authors: Graham Austin J. , Dundas Christopher M. , Partipilo Gina , Miniel Mahfoud Ismar E. , FitzSimons Thomas , Rinehart Rebecca , Chiu Darian , Tyndall Avery E. , Rosales Adrianne M. , Keitz Benjamin K.
Published: October 2021

Individual cells direct non-equilibrium processes through coordinated signal transduction and gene expression, allowing for dynamic control over multicellular, system-wide behavior. This behavior extends to remodeling the extracellular polymer matrix that encases biofilms and tissues, where constituent cells dictate spatiotemporal network properties including stiffness, pattern formation, and transport properties. The majority of synthetic polymer networks cannot recreate these phenomena due to their lack of autonomous centralized actuators (i.e., cells). In addition, non-living polymer networks that perform computation are generally restricted to a few inputs (e.g., light, pH, enzymes), limiting the logical complexity available to a single network chemistry. Toward synergizing the advantages of living and synthetic systems, engineered living materials leverage genetic and metabolic programming to establish control over material-wide properties. Here we demonstrate that a bacterial metal respiration mechanism, extracellular electron transfer (EET), can control metal-catalyzed radical cross-linking of polymer networks. Linking metabolic electron flux to a synthetic redox catalyst allows dynamic, tunable, and predictable control over material formation and bulk polymer network mechanics using genetic circuits. By programming key EET genes with transcriptional Boolean logic, we rationally design computational networks that sense-and-respond to multiple inputs in biological contexts. Finally, we capitalize on the wide reactivity of EET and redox catalyses to predictably control another class of living synthetic materials using copper(I) alkyne-azide cycloaddition click chemistry. Our results demonstrate the utility of EET as a bridge for controlling abiotic materials and how the design rules of synthetic biology can be applied to emulate physiological behavior in polymer networks.
In situ architecture of the ciliary base reveals the stepwise assembly of IFT trains
Authors: van den Hoek Hugo , Klena Nikolai , Jordan Mareike A. , Viar Gonzalo Alvarez , Schaffer Miroslava , Erdmann Philipp S. , Wan William , Plitzko Jürgen M. , Baumeister Wolfgang , Pigino Gaia , Hamel Virginie , Guichard Paul , Engel Benjamin D.
Published: October 2021

The cilium is an antenna-like organelle that performs numerous cellular functions, including motility, sensing, and signaling. The base of the cilium contains a selective barrier that regulates the entry of large intraflagellar transport (IFT) trains, which carry cargo proteins required for ciliary assembly and maintenance. However, the native architecture of the ciliary base and the process of IFT train assembly remain unresolved. Here, we use in situ cryo-electron tomography to reveal native structures of the transition zone region and assembling IFT trains at the ciliary base. We combine this direct cellular visualization with ultrastructure expansion microscopy to describe the front-to-back stepwise assembly of IFT trains: IFT-B forms the backbone, onto which IFT-A, then dynein-1b, and finally kinesin-2 sequentially bind before entry into the cilium.

One Sentence Summary

Native molecular structure of the ciliary transition zone and hierarchical order of IFT assembly visualized within Chlamydomonas cells.
An optimized live bacterial delivery platform for the production and delivery of therapeutic nucleic acids and proteins
Authors: Mora Darcy S.O. , Cox Madeline , Magunda Forgivemore , Williams Ashley B. , Linke Lyndsey
Published: October 2021

There is an unmet need for delivery platforms that realize the full potential of next-generation therapeutic and vaccine technologies, especially those that require intracellular delivery of nucleic acids. The in vivo usefulness of the current state-of-the-art delivery systems is limited by numerous intrinsic weaknesses, including lack of targeting specificity, inefficient entry and endosomal escape into target cells, undesirable immune activation, off-target effects, a small therapeutic window, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we present our characterization of a delivery platform based on the use of engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli strain SVC1) for intracellular cargo delivery. The SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to escape the endosome upon intracellularization, and to have minimal immunogenicity. Here we report findings on key features of this system. First, we demonstrated that bacterial delivery of a short hairpin RNA (shRNA) can target and silence a gene in an in vitro mammalian respiratory cell model. Next, we used an in vivo mouse model to demonstrate that SVC1 bacteria are invasive to epithelial cells of various tissues and organs (eye, nose, mouth, stomach, vagina, skeletal muscle, and lungs) via local administration. We also showed that repeat dosing of SVC1 bacteria to the lungs is minimally immunogenic and that it does not have adverse effects on tissue homeostasis. Finally, to validate the potential of SVC1 bacteria in therapeutic applications, we demonstrated that bacterial delivery of influenza-targeting shRNAs to the respiratory tissues can mitigate viral replication in a mouse model of influenza infection. Our ongoing work is focused on further refining this platform for efficient delivery of nucleic acids, gene editing machinery, and therapeutic proteins, and we expect that this platform technology will enable a wide range of advanced therapeutic approaches.
Structure of the human ATM kinase and mechanism of Nbs1 binding
Authors: Warren C. , Pavletich N.P.
Published: October 2021

DNA double-strand breaks (DSBs) can lead to mutations, chromosomal rearrangements, genome instability, and ultimately cancer. Central to the sensing of DSBs are ATM (Ataxia-telangiectasia mutated) kinase, which belongs to the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family, and the MRN (Mre11-Rad50-Nbs1) protein complex that activates ATM. How the MRN complex recruits and activates ATM kinase is poorly understood. Previous studies indicate that the FxF/Y motif of Nbs1 directly binds to ATM kinase and is required to retain active ATM at sites of DNA damage. Here, we report the 2.5 Å resolution cryo-EM structures of human ATM and its complex with the Nbs1 FxF/Y motif. In keeping with previous structures of ATM and its yeast homolog Tel1, the dimeric human ATM kinase adopts a symmetric, butterfly-shaped autoinhibited structure. The conformation of the ATM kinase domain is most similar to the inactive states of other PIKKs, suggesting that activation may involve an analogous realigning the N and C lobes along with relieving the blockage of the substrate-binding site. We show that the Nbs1 FxF/Y motif binds to a conserved hydrophobic cleft within the Spiral domain of ATM, suggesting an allosteric mechanism of activation. We evaluate the importance of these interactions with mutagenesis and biochemical assays.
Synaptotagmin-7 enhances phasic dopamine release
Authors: Kissiwaa Sarah A. , Lebowitz Joseph J. , Engeln Kim A. , Bowman Anna M. , Williams John T. , Jackman Skyler L.
Published: October 2021

Dopamine released from substantia nigra pars compacta (SNc) neurons modulates movement, motivation, and reward. In addition to their tonic firing pattern, dopamine neurons also fire high-frequency bursts that cause superlinear increases in dopamine release. To study this poorly understood form of short-term plasticity, we used the fluorescent dopamine sensor dLight1.3b to examine the role of the calcium-binding protein synaptotagmin-7 (SYT7). We report that SYT7 mediates a hidden component of facilitation, which was unmasked by lowering initial release probability, or by low-frequency stimulation of nerve terminals. InSyt7KO neurons, there was profound synaptic depression that significantly reduced release during stimulations that mimicin vivofiring patterns of SNc neurons. D2-mediated inhibitory postsynaptic currents in the SNc revealed a similar role for SYT7 in somatodendritic release. Our results indicate that SYT7 drives short-term facilitation of release from dopamine neurons, which likely underlies frequency-dependence of dopamine signalingin vivo.
Cell type matching in single-cell RNA-sequencing data using FR-Match
Authors: Zhang Yun , Aevermann Brian , Gala Rohan , Scheuermann Richard H.
Published: October 2021

Reference cell type atlases powered by single cell transcriptomic profiling technologies have become available to study cellular diversity at a granular level. We present FR-Match for matching query datasets to reference atlases with robust and accurate performance for identifying common and novel cell types and suboptimally clustered cell types in the query data. FR-Match shows excellent performance for cross-platform, cross-sample type, and cross-tissue region cell type matching.