bluuebunny/crossref_metadata_2025 huggingface dataset:
Photoacoustic monitoring of angiogenesis predicts response to therapy in healing wounds
Authors: Mantri Yash , Tsujimoto Jason , Donovan Brian , Fernandes Christopher C. , Garimella Pranav S. , Penny William F. , Anderson Caesar A. , Jokerst Jesse V.
Published: October 2021

Chronic wounds are a major health problem that cause the medical infrastructure billions of dollars every year. Chronic wounds are often difficult to heal and cause significant discomfort. Although wound specialists have numerous therapeutic modalities at their disposal, tools that could 3D-map wound bed physiology and guide therapy do not exist. Visual cues are the current standard but are limited to surface assessment; clinicians rely on experience to predict response to therapy. Photoacoustic (PA) ultrasound (US) is a non-invasive, hybrid imaging modality that can solve these major limitations. PA relies on the contrast generated by hemoglobin in blood which allows it to map local angiogenesis, tissue perfusion and oxygen saturation—all critical parameters for wound healing. This work evaluates the use of PA-US to monitor angiogenesis and stratify patients respondingvs. not-responding to therapy. We imaged 19 patients with 22 wounds once a week for at least three weeks. Our findings suggest that PA imaging directly visualizes angiogenesis. Patients responding to therapy showed clear signs of angiogenesis and an increased rate of PA increase (p = 0.002). These responders had a significant and negative correlation between PA intensity and wound size. Hypertension was correlated to impaired angiogenesis in non-responsive patients. The rate of PA increase and hence the rate of angiogenesis was able to predict healing times within 30 days from the start of monitoring (power = 88%, alpha = 0.05) This early response detection system could help inform management and treatment strategies while improving outcomes and reducing costs.
Memory B cell and humoral responses elicited by Sputnik V in naïve and COVID-19-recovered vaccine recipients
Authors: Byazrova Maria G , Kulemzin Sergey V , Astakhova Ekaterina A , Belovezhets Tatyana N , Efimov Grigory A , Chikaev Anton N , Kolotygin Ilya O , Gorchakov Andrey A , Taranin Alexander V , Filatov Alexander V
Published: October 2021

The development of effective vaccines against SARS-CoV-2 remains a global health priority. Despite extensive use, the effects of Sputnik V on B cell immunity need to be explored in detail. We show that B memory cell (MBC) and antibody responses to Sputnik V were heavily dependent on whether the vaccinee had a history of SARS-CoV-2 infection or not. In vitro stimulated MBCs from previously infected recipients of Sputnik V secreted a significant amount of anti-RBD IgG both on days 28 and 85 from the beginning of vaccination. These antibodies demonstrated robust neutralization of the Wuhan Spike-pseudotyped lentivirus. In the naïve group of vaccinees, the level of anti-RBD IgG secretion was five- to six-fold reduced compared to that of the recovered group, and maximum virus neutralization (Wuhan spike) was achieved only on day 85. Sera from all the recovered and most naïve Sputnik V recipients were neutralizing against the ancestral Wuhan and mutant B.1.351 viruses. Thus, our in-depth analysis of MBC responses in Sputnik V vaccinees complements traditional serological approaches and may provide important outlook into future B cell responses upon re-encounter with the emerging variants of SARS-CoV-2.
Duration of viral shedding and culture positivity with post-vaccination breakthrough delta variant infections
Authors: Siedner Mark J. , Boucau Julie , Gilbert Rebecca , Uddin Rockib , Luu Jonathan , Haneuse Sebastien , Vyas Tammy , Reynolds Zahra , Iyer Surabhi , Chamberlin Grace , Goldstein Robert H. , North Crystal M. , Sacks Chana A. , Regan James , Flynn James P. , Choudhary Manish C. , Vyas Jatin M. , Barczak Amy , Lemieux Jacob , Li Jonathan Z.
Published: October 2021

Isolation guidelines for SARS-CoV-2 are largely derived from data collected prior to emergence of the delta variant. We followed a cohort of ambulatory patients with post-vaccination breakthrough SARS-CoV-2 infections with longitudinal collection of nasal swabs for SARS-CoV-2 viral load quantification, whole genome sequencing, and viral culture. All delta variant infections (8/8, 100%) in our cohort were symptomatic, compared with 64% (9/14) of non-delta variant infections. Delta variant breakthrough infections were characterized by higher initial viral load, longer duration of virologic shedding by PCR (median 13.5 vs 4 days, hazard ratio [HR] 0.45, 95%CI 0.17-1.17), greater likelihood of replication-competent virus at early stages of infection (6/8 [75%] vs 3/14 [23%], P=0.03), and longer duration of culturable virus (median 7 vs 3 days, HR 0.38, 95%CI 0.14-1.02) compared to non-delta variants. Nonetheless, no individuals with delta variant infections had replication-competent virus by day 10 after symptom onset or 24 hours after resolution of symptoms. These data support current US Center for Disease Control isolation guidelines and reinforce the importance of prompt testing and isolation among symptomatic individuals with delta variant breakthrough infections. Additional data are needed to evaluate these relationships among asymptomatic and more severe delta variant breakthrough infections.
Interactions among common non-SARS-CoV-2 respiratory viruses and influence of the COVID-19 pandemic on their circulation in New York City
Authors: Yuan Haokun , Yeung Alice , Yang Wan
Published: October 2021

Background

Non-pharmaceutical interventions (NPIs) and voluntary behavioral changes during the COVID-19 pandemic have influenced the circulation of non-SARS-CoV-2 respiratory infections. We aimed to examine interactions among common non-SARS-CoV-2 respiratory virus and further estimate the impact of the COVID-19 pandemic on these viruses.

Methods

We analyzed incidence data for seven groups of respiratory viruses in New York City (NYC) during Oct 2015 - May 2021 (i.e., before and during the COVID-19 pandemic). We first used elastic net regression to identify potential virus interactions and further examined the robustness of the found interactions by comparing the performance of Auto Regressive Integrated Moving Average (ARIMA) models with and without the interactions. We then used the models to compute counterfactual estimates of cumulative incidence and estimate the reduction during the COVID-19 pandemic period from March 2020 to May 2021, for each virus.

Results

We identified potential interactions for three endemic human coronaviruses (CoV-NL63, CoV-HKU, and CoV-OC43), parainfluenza (PIV)-1, rhinovirus, and respiratory syncytial virus (RSV). We found significant reductions (by ~70-90%) in cumulative incidence of CoV-OC43, CoV-229E, human metapneumovirus, PIV-2, PIV-4, RSV, and influenza virus during the COVID-19 pandemic. In contrast, the circulation of adenovirus and rhinovirus was less affected.

Conclusions

Circulation of several respiratory viruses has been low during the COVID-19 pandemic, which may lead to increased population susceptibility. It is thus important to enhance monitoring of these viruses and promptly enact measures to mitigate their health impacts (e.g., influenza vaccination campaign and hospital infection prevention) in the coming months.
Novel point-of-care ultrasound (POCUS) technique to modernize the JVP exam and rule out elevated right atrial pressures
Authors: Istrail Larry , Stepanova Maria
Published: October 2021

Accurate assessment of the jugular venous pressure (JVP) and right atrial pressure (RAP) has relied on the same bedside examination method since 1930. While this technique provides a rough estimate of right sided pressures, it is limited by poor sensitivity and overall diagnostic inaccuracy. The internal jugular vein (IJV) is difficult to visualize in many patients and relies on an incorrect assumption that the right atrium lies 5 centimeters below the sternum. Point-of-care ultrasound (POCUS) offers an alternative method for more precisely estimating JVP and RAP. We propose a novel method of measuring the right atrial depth (RAD) using a sonographic measurement of the depth of the posterior left ventricular outflow tract as a surrogate landmark to the center of the right atrium when viewed in the parasternal long axis view. This is combined with determination if JVD was present at the supraclavicular point. Sensitivity, specificity, PPV, NPV of JVD at the supraclavicular point was 70%, 76%, 59%, 91% respectively. These values were confounded by the lack of standardization of zero reference landmarks (ZRLs) used during the right heart catheterizations. When the RAD measurement was adjusted to account for measurement error the sensitivity of JVD at supraclavicular point for elevated RAP improved to 90% with negative predictive value of 96%. This may offer a rapid and reliable method for ruling out elevated RAP and increase objectivity in our volume status assessment.
Progression Free Survival Prediction for Head and Neck Cancer using Deep Learning based on Clinical and PET-CT Imaging Data
Authors: Naser Mohamed A. , Wahid Kareem A. , Mohamed Abdallah S.R. , Abdelaal Moamen Abobakr , He Renjie , Dede Cem , van Dijk Lisanne V. , Fuller Clifton D.
Published: October 2021

Determining progression-free survival (PFS) for head and neck squamous cell carcinoma (HNSCC) patients is a challenging but pertinent task that could help stratify patients for improved overall outcomes. PET/CT images provide a rich source of anatomical and metabolic data for potential clinical biomarkers that would inform treatment decisions and could help improve PFS. In this study, we participate in the 2021 HECKTOR Challenge to predict PFS in a large dataset of HNSCC PET/CT images using deep learning approaches. We develop a series of deep learning models based on the DenseNet architecture using a negative log-likelihood loss function that utilizes PET/CT images and clinical data as separate input channels to predict PFS in days. Internal model validation based on 10-fold cross-validation using the training data (N=224) yielded C-index values up to 0.622 (without) and 0.842 (with) censoring status considered in C-index computation, respectively. We then implemented model ensembling approaches based on the training data cross-validation folds to predict the PFS of the test set patients (N=101). External validation on the test set for the best ensembling method yielded a C-index value of 0.694. Our results are a promising example of how deep learning approaches can effectively utilize imaging and clinical data for medical outcome prediction in HNSCC, but further work in optimizing these processes is needed.
A Systematic Review of the Methodological Quality of Economic Evaluations in Genetic Screening and Testing for Monogenic Disorders
Authors: Johnson Karl , Saylor Kate , Guynn Isabella , Hicklin Karen , Berg Jonathan S. , Lich Kristen Hassmiller
Published: October 2021

Purpose

Understanding the value of genetic screening and testing for monogenic disorders requires high-quality, methodologically robust economic evaluations. This systematic review sought to assess the methodological quality among such studies and examine opportunities for improvement.

Methods

We searched Pubmed, Cochrane, Embase, and Web of Science for economic evaluations of genetic screening/testing (2013-2019). Methodological rigor and adherence to best practices were systematically assessed using the BMJ checklist.

Results

Across 47 identified studies, there was substantial variation in modeling approaches, reporting detail, and sophistication. Models ranged from simple decision trees to individual-level microsimulation, comparing between two and >20 alternative interventions. Many studies failed to report sufficient detail to enable replication or did not justify modeling assumptions, especially for costing methods and utility values. Meta-analyses, systematic reviews, or calibration were rarely used to derive parameter estimates. Nearly all studies conducted some sensitivity analysis, and more sophisticated studies implemented probabilistic sensitivity/uncertainty analysis, threshold analysis, and value of information analysis.

Conclusion

We describe a heterogeneous body of work and present recommendations and exemplar studies across the methodological domains of (1) perspective, scope, and parameter selection, (2) use of uncertainty/sensitivity analyses, and (3) reporting transparency for improvement in the economic evaluation of genetic screening/testing.
Projecting the transition of COVID-19 burden towards the young population while vaccines are rolled out: a modelling study
Authors: Cai Jun , Yang Juan , Deng Xiaowei , Peng Cheng , Chen Xinhua , Wu Qianhui , Liu Hengcong , Zhang Juanjuan , Zheng Wen , Zou Junyi , Zhao Zeyao , Ajelli Marco , Yu Hongjie
Published: October 2021

Objectives

SARS-CoV-2 infection causes most cases of severe illness and fatality in older age groups. In China, over 99% of individuals aged ⩾12 years have been fully vaccinated against COVID-19 (albeit with vaccines developed against historical lineages), while 65.0% children aged 3–11 years have been vaccinated their first doses (as of November 12, 2021). Here, we aimed to assess whether, in this vaccination landscape, the importation of Delta variant infections could shift the COVID-19 burden from adults to children.

Methods

We developed an age-structured susceptible-infectious-removed model of SARS-CoV-2 transmission dynamics to simulate epidemics triggered by the importation of Delta variant infections and project the age-specific incidence of SARS-CoV-2 infections, cases, hospitalisations, intensive care unit (ICU) admissions, and deaths.

Results

In the context of the vaccination programme targeting individuals aged ≥12 years (as it was the case until mid-October 2021), and in the absence of non-pharmaceutical interventions, the importation of Delta variant infections could have led to widespread transmission and substantial disease burden in mainland China, even with vaccination coverage as high as 97% across the eligible age groups. Extending the vaccination roll-out to include children aged 3–11 years (as it was the case since the end of October 2021) is estimated to dramatically decrease the burden of symptomatic infections and hospitalisations within this age group (54% and 81%, respectively, when considering a vaccination coverage of 99%), but would have a low impact on protecting infants (aged 0–2 years).

Conclusions

Our findings highlight the importance of including children among the target population and the need to strengthen vaccination efforts by increasing vaccine effectiveness.
Escape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable
Authors: Zito A. , Roberts A.L. , Visconti A. , Rossi N. , Andres-Ejarque R. , Nardone S. , Moustafa J.E.S. , Falchi M. , Small K.S.
Published: October 2021

X-chromosome inactivation (XCI) silences one X-chromosome in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it varies across tissues and in a population is as yet unclear. In order to characterize the incidence and variability of escape across individuals and tissues, we conducted a large scale transcriptomic study of XCI escape in adipose, skin, lymphoblastoid cell lines (LCLs) and immune cells in 248 twins drawn from a healthy population cohort. We identify 159 X-linked genes with detectable escape, of which 54 genes, including 19 lncRNAs, were not previously known to escape XCI. Across tissues we find a range of tissue-specificity, with 11% of genes escaping XCI constitutively across tissues and 24% demonstrating tissue-restricted escape, including genes with cell-type specific escape between immune cell types (B, T-CD4+, T-CD8+ and NK cells) of the same individual. Escape genes interact with autosomal-encoded proteins and are involved in varied biological processes such as gene regulation. We find substantial variability in escape between individuals. 49% of genes show inter-individual variability in escape, indicating escape from XCI is an under-appreciated source of gene expression differences. We utilized twin models to investigate the role of genetics in variable escape. Overall, monozygotic (MZ) twin pairs share more similar escape than dizygotic twin pairs, indicating that genetic factors underlie differences in escape across individuals. However, we also identify instances of discordant XCI within MZ co-twin pairs, suggesting that environmental factors also influence escape. Thus, XCI escape may be shaped by an interplay of genetic factors with tissue- and cell type-specificity, and environment. These results illuminate an intricate phenotype whose characterization aids understanding the basis of variable trait expressivity in females.
Long-term imaging of the ventral nerve cord in behaving adultDrosophila
Authors: Hermans Laura , Kaynak Murat , Braun Jonas , Lobato Ríos Victor , Chen Chin-Lin , Günel Semih , Aymanns Florian , Sakar Mahmut Selman , Ramdya Pavan
Published: October 2021

The dynamics and connectivity of neural circuits continuously change during an animal’s lifetime on timescales ranging from milliseconds to days. Therefore, to investigate how biological networks accomplish remarkable cognitive and behavioral tasks, minimally invasive methods are needed to perform repeated measurements, or perturbations of neural circuits in behaving animals across time. Such tools have been developed to investigate the brain but similar approaches are lacking for comprehensively and repeatedly recording motor circuits in behaving animals. Here we describe a suite of microfabricated technologies that enable long-term, minimally invasive optical recordings of the adultDrosophila melanogasterventral nerve cord (VNC)—neural tissues that are functionally equivalent to the vertebrate spinal cord. These tools consist of (i) a manipulator arm that permits the insertion of (ii) a compliant implant into the thorax to expose the imaging region of interest; (iii) a numbered, transparent polymer window that encloses and provides optical access to the inside of the thorax, and (iv) a hinged remounting stage that allows gentle and repeated tethering of an implanted animal for two-photon imaging. We validate and illustrate the utility of our toolkit in several ways. First, we show that the thoracic implant and window have minimal impact on animal behavior and survival while also enabling neural recordings from individual animals across at least one month. Second, we follow the degradation of chordotonal organ mechanosensory nerve terminals in the VNC over weeks after leg amputation. Third, because our tools allow recordings of the VNC with the gut intact, we discover waves of neural population activity following ingestion of a high-concentration caffeine solution. In summary, our microfabricated toolkit makes it possible to longitudinally monitor anatomical and functional changes in premotor and motor neural circuits, and more generally opens up the long-term investigation of thoracic tissues.
Sex Differences in Pubertal Circadian and Ultradian Rhythmic Development Under Naturalistic Conditions
Authors: Grant Azure D. , Wilbrecht Linda , Kriegsfeld Lance J.
Published: October 2021

Biological rhythms in core body temperature (CBT) provide informative markers of adolescent development under controlled laboratory conditions. However, it is unknown if these markers are preserved under more variable naturalistic conditions, and if CBT may therefore prove useful in a real-world setting. To evaluate this possibility, we examined fecal steroid concentrations and CBT rhythms from pre-adolescence (p26) through early adulthood (p76) in intact male and female rats under natural light and climate at the University of California, Berkeley Field Station. Despite greater environmental variability, CBT markers of pubertal onset and its rhythmic progression were comparable to those previously reported in laboratory conditions in female rats and extend actigraphy-based findings in males. Specifically, sex differences emerged in circadian rhythm (CR) power and temperature amplitude prior to pubertal onset and persisted into early adulthood, with females exhibiting elevated CBT and decreased CR power compared to males. Within-day (ultradian rhythm; UR) patterns also exhibited a pronounced sex difference associated with estrous cyclicity. Pubertal onset, defined by vaginal opening, preputial separation, and sex steroid concentrations, occurred later than previously reported under lab conditions for both sexes. Vaginal opening and increased fecal estradiol concentrations were closely tied to the commencement of 4-day oscillations in CBT and UR power in female rats. By contrast, preputial separation and the first rise in testosterone concentration were not associated with adolescent changes to CBT rhythms in male rats. Together, males and females exhibited unique temporal patterning of CBT and sex steroids across pubertal development, with tractable associations between hormonal concentrations, external development, and temporal structure in females. The preservation of these features outside the laboratory supports CBT as a strong candidate for translational pubertal monitoring under naturalistic conditions in females.
Population-specific patterns of toxin sequestration in monarch butterflies from around the world
Authors: Freedman Micah G. , Choquette Sue-Ling , Ramírez Santiago R. , Strauss Sharon Y. , Hunter Mark D. , Vannette Rachel L.
Published: October 2021

Animals frequently defend themselves against predators using diet-derived toxins. Monarch butterflies are a preeminent example of toxin sequestration, gaining protection via cardenolides in their milkweed hosts. Few studies have considered genetic variation in sequestration ability, in monarchs or other species. Here, we use two approaches to study natural selection on cardenolide sequestration in monarchs. First, we conducted a reciprocal rearing experiment with six monarch populations and six associated host species from around the world to determine whether sequestration is higher in monarchs reared on sympatric host species. Second, we compared sequestered cardenolides in wild-caught monarchs from Guam—an island where bird predators have been functionally extirpated for >40 years—to a nearby island with intact birds. We found substantial genetic variation in sequestration ability, though no consistent sequestration advantage in sympatric combinations. One monarch population from Puerto Rico showed greatly reduced sequestration fromAsclepias syriaca, likely reflecting a lack of evolutionary association with this host. Monarchs from Guam showed reduced sequestration fromA. curassavica, both in a cross-island comparison and when reared under controlled conditions. Our results suggest that processes involved in toxin sequestration are subject to natural selection and may evolve in response to contemporary changes in species interactions.
Mapping enzyme catalysis with metabolomic biosensing
Authors: Xu Linfeng , Chang Kai-Chun , Payne Emory M. , Modavi Cyrus , Liu Leqian , Palmer Claire M. , Tao Nannan , Alper Hal S. , Kennedy Robert T. , Cornett Dale S. , Abate Adam R.
Published: October 2021

Enzymes are represented across a vast space of protein sequences and structural forms and have activities that far exceed the best chemical catalysts; however, engineering them to have novel or enhanced activity is limited by technologies for sensing product formation. Here, we describe a general and scalable approach for characterizing enzyme activity that uses the metabolism of the host cell as a biosensor by which to infer product formation. Since different products consume different molecules in their synthesis, they perturb host metabolism in unique ways that can be measured by mass spectrometry. This provides a general way by which to sense product formation, to discover unexpected products and map the effects of mutagenesis.
Cholinergic modulation of distinct inhibitory domains in granule cells of the olfactory bulb
Authors: Villar Pablo S. , Hu Ruilong , Teitz Batya , Araneda Ricardo C.
Published: October 2021

Early olfactory processing relies on a large population of inhibitory neurons in the olfactory bulb (OB), the granule cells (GCs). GCs inhibit the OB output neurons, the mitral and tufted cells (M/TCs), shaping their responses to odors both in the spatial and temporal domains, therefore, the activity of GCs is finely tuned by local and centrifugal excitatory and inhibitory inputs. While the circuit substrates underlying regulatory inputs onto GCs are well-established, how they are locally modulated remains unclear. Here, we examine the regulation of GABAergic inhibition onto GCs by acetylcholine, a main neuromodulatory transmitter released in the OB, by basal forebrain (BF) neurons. In acute brain slices from male and female mice, we show that activation of muscarinic acetylcholine receptors (mAChRs) produces opposing effects on local and centrifugal inhibition onto GCs. By using electrophysiology, laser uncaging and optogenetics we show that the kinetics of GABAergic currents in GCs could be correlated with distal and proximal spatial domains from where they originate, along the GC somatodendritic axis. Proximal inhibition from BF afferents, is suppressed by activation of M2/M4-mAChRs. In contrast, distal local inhibition from deep short axon cells (dSACs) is enhanced by activation of M3-mAChRs. Furthermore, we show that the cholinergic enhancement of distal inhibition in GCs reduces the extent of dendrodendritic inhibition in MCs. Interestingly, the excitatory cortical feedback, which also targets the proximal region of GCs, was not modulated by acetylcholine, suggesting that muscarinic activation shifts the synaptic balance towards excitation in GCs. Together, these results suggest that BF cholinergic inputs to the OB fine tune GC-mediated inhibition of M/TCs by differentially modulating the proximal and distal domains of inhibition in GCs.
Estimating global variation in the maximum growth rates of eukaryotic microbes from cultures and metagenomes via codon usage patterns
Authors: Weissman JL , Dimbo Edward-Robert O. , Krinos Arianna I. , Neely Christopher , Yagües Yuniba , Nolin Delaney , Hou Shengwei , Laperriere Sarah , Caron David A. , Tully Benjamin , Alexander Harriet , Fuhrman Jed A.
Published: October 2021

Microbial eukaryotes are ubiquitous in the environment and play important roles in key ecosystem processes, including accounting for a significant portion of global primary production. Yet, our tools for assessing the functional capabilities of eukaryotic microbes in the environment are quite limited because many microbes have yet to be grown in culture. Maximum growth rate is a fundamental parameter of microbial lifestyle that reveals important information about an organism’s functional role in a community. We developed and validated a genomic estimator of maximum growth rate for eukaryotic microbes, enabling the assessment of growth potential for organisms and communities directly in the environment. We produced a database of over 700 maximum growth rate predictions from genomes, transcriptomes, and metagenome-assembled genomes. By comparing the maximal growth rates of existing culture collections with environmentally-derived genomes we found that, unlike for prokaryotes, culture collections of microbial eukaryotes are only minimally biased in terms of growth potential. We then extended our tool to make community-wide estimates of growth potential from over 500 marine metagenomes, mapping growth potential across the global oceans. We found that prokaryotic and eukaryotic communities have highly correlated growth potentials near the ocean surface, but there is no correlation in their genomic potentials deeper in the water column. This suggests that fast growing eukaryotes and prokaryotes thrive under similar conditions at the ocean surface, but that there is a decoupling of these communities as resources become scarce deeper in the water column.
When are bacteria really gazelles? Comparing patchy ecologies with dimensionless numbers
Authors: Urmy Samuel S. , Cramer Alli N. , Rogers Tanya L. , Sullivan-Stack Jenna , Schmidt Marian , Stewart Simon D. , Symons Celia C.
Published: October 2021

From micro to planetary scales, spatial heterogeneity—patchiness—is ubiquitous in ecological systems, defining the environments in which organisms move and interact. While this fact has been recognized for decades, most large-scale ecosystem models still use spatially averaged “mean fields” to represent natural populations, while fine-scale, spatially explicit models are mostly restricted to particular organisms or systems. In a conceptual paper, Grünbaum (2012,Interface Focus2: 150-155) introduced a heuristic framework, based on three dimensionless ratios quantifying movement, reproduction, and resource consumption, to characterize patchy ecological interactions and identify when mean-field assumptions are justifiable. In this paper, we calculated Grünbaum’s dimensionless numbers for 33 real interactions between consumers and their resource patches in terrestrial, aquatic, and aerial environments. Consumers ranged in size from bacteria to blue whales, and patches lasted from minutes to millennia, spanning spatial scales of mm to hundreds of km. We found that none of the interactions could be accurately represented by a purely mean-field model, though 26 of them (79%) could be partially simplified by averaging out movement, reproductive, or consumption dynamics. Clustering consumer-resource pairs by their non-dimensional ratios revealed several unexpected dynamic similarities between disparate interactions. For example, bacterialPseudoalteromonasexploit nutrient plumes in a similar manner to Mongolian gazelles grazing on ephemeral patches of steppe vegetation. Our findings suggest that dimensional analysis is a valuable tool for characterizing ecological patchiness, and can link the dynamics of widely different systems into a single quantitative framework.
Kernel-based genetic association analysis for microbiome phenotypes identifies host genetic drivers of beta-diversity
Authors: Liu Hongjiao , Ling Wodan , Hua Xing , Moon Jee-Young , Williams-Nguyen Jessica S. , Zhan Xiang , Plantinga Anna M. , Zhao Ni , Zhang Angela , Knight Rob , Qi Qibin , Burk Robert D. , Kaplan Robert C. , Wu Michael C.
Published: October 2021

Understanding human genetic influences on the gut microbiota helps elucidate the mechanisms by which genetics affects health outcomes. We propose a novel approach, the covariate-adjusted kernel RV (KRV) framework, to map genetic variants associated with microbiome beta-diversity, which focuses on overall shifts in the microbiota. The proposed KRV framework improves statistical power by capturing intrinsic structure within the genetic and microbiome data while reducing the multiple-testing burden. We apply the covariate-adjusted KRV test to the Hispanic Community Health Study/Study of Latinos in a genome-wide association analysis (first gene-level, then variant-level) for microbiome beta-diversity. We have identified an immunity-related gene,IL23R, reported in previous association studies and discovered 3 other novel genes, 2 of which are involved in immune functions or autoimmune disorders. Our findings highlight the value of the KRV as a powerful microbiome GWAS approach and support an important role of immunity-related genes in shaping the gut microbiome composition.
Individual differences in visual search performance extend from artificial arrays to naturalistic environments
Authors: Botch Thomas L. , Garcia Brenda D. , Choi Yeo Bi , Robertson Caroline E.
Published: October 2021

Visual search is a universal human activity in naturalistic environments. Traditionally, visual search is investigated under tightly controlled conditions, where head-restricted participants locate a minimalistic target in a cluttered array presented on a computer screen. Do classic findings of visual search extend to naturalistic settings, where participants actively explore complex, real-world scenes? Here, we leverage advances in virtual reality (VR) technology to relate individual differences in classic visual search paradigms to naturalistic search behavior. In a naturalistic visual search task, participants looked for an object within their environment via a combination of head-turns and eye-movements using a head-mounted display. Then, in a classic visual search task, participants searched for a target within a simple array of colored letters using only eye-movements. We tested how set size, a property known to limit visual search within computer displays, predicts the efficiency of search behavior inside immersive, real-world scenes that vary in levels of visual clutter. We found that participants’ search performance was impacted by the level of visual clutter within real-world scenes. Critically, we also observed that individual differences in vi1–3sual search efficiency in classic search predicted efficiency in real-world search, but only when the comparison was limited to the forward-facing field of view for real-world search. These results demonstrate that set size is a reliable predictor of individual performance across computer-based and active, real-world visual search behavior.
The nitrogen phosphotransferase regulator PtsN (EIIANtr) regulates inorganic polyphosphate production inEscherichia coli
Authors: Bowlin Marvin Q. , Long Abagail R. , Huffines Joshua T. , Gray Michael J.
Published: October 2021

Inorganic polyphosphate (polyP) is synthesized by bacteria under stressful environmental conditions and acts by a variety of mechanisms to promote cell survival. While the kinase that synthesizes polyP (PPK, enocoded by theppkgene) is well known, little is understood about how environmental stress signals lead to activation of this enzyme. Previous work has shown that the transcriptional regulators DksA, RpoN (σ54), and RpoE (σ24) positively regulate polyP production, but notppktranscription, inEscherichia coli. In this work, we set out to examine the role of the alternative sigma factor RpoN and nitrogen starvation stress response pathways in controlling polyP synthesis in more detail. In the course of these experiments, we identified GlnG, GlrR, PhoP, PhoQ, RapZ, and GlmS as proteins that affect polyP production, and uncovered a central role for the nitrogen phosphotransferase regulator PtsN (EIIANtr) in a polyP regulatory pathway, acting upstream of DksA, downstream of RpoN, and apparently independently of RpoE. However, none of these regulators appears to act directly on PPK, and the mechanism(s) by which they modulate polyP production remain unclear. Unexpectedly, we also found that the pathways that regulate polyP production vary depending not only on the stress condition applied, but also on the composition of the media in which the cells were grown before exposure to polyP-inducing stress. These results constitute substantial progress towards deciphering the regulatory networks driving polyP production under stress, but highlight the remarkable complexity of this regulation and its connections to a broad range of stress-sensing pathways.

IMPORTANCE

Bacteria respond to changes in their environments with a complex regulatory network that controls the expression and activity of a wide range of effectors important for their survival. This stress response network is critical for the virulence of pathogenic bacteria and for the ability of all bacteria to grow in natural environments. Inorganic polyphosphate (polyP) is an evolutionarily ancient and almost universally conserved stress response effector that plays multiple roles in virulence, stress response, and survival in diverse organisms. This work provides new insights into the connections between well characterized nitrogen starvation and cell envelope stress response signaling pathways and the production of polyP inEscherichia coli.
Characterisation of the phase-variable autotransporter Lav reveals a role in host cell adherence and biofilm formation in Non-TypeableHaemophilus influenzae
Authors: Phillips Zachary N. , Garai Preeti , Tram Greg , Husna Asma-Ul , Staples Megan , Grimwood Keith , Jennison Amy V. , Jennings Michael P. , Brockman Kenneth L. , Atack John M.
Published: October 2021

Lav is an autotransporter protein found in pathogenicHaemophilusandNeisseriaspecies. Lav in non-typeableHaemophilus influenzae(NTHi) is phase-variable: the gene reversibly switches ON-OFF via changes in length of a locus-located GCAA(n)simple DNA sequence repeat tract. The expression status oflavwas examined in carriage and invasive collections of NTHi, where it was predominantly not expressed (OFF). Phenotypic study showedlavexpression (ON) results in increased adherence to host cells, and denser biofilm formation. A survey ofHaemophilusspp. genome sequences showedlavis present in ∼60% of NTHi strains, butlavis not present in most typeableH. influenzae. Sequence analysis revealed a total of five distinct variants of the Lav passenger domain present inHaemophilusspp., with these five variants showing a distinct lineage distribution. Determining the role of Lav in NTHi will help understand the role of this protein during distinct pathologies.
A novel automated approach for improving standardization of the marble burying test enables quantification of burying bouts and activity characteristics
Authors: Wahl Lucas , Punt A. Mattijs , Arbab Tara , Willuhn Ingo , Elgersma Ype , Badura Aleksandra
Published: October 2021

The marble burying test is a commonly used paradigm to screen phenotypes in mouse models of neurodevelopmental and psychiatric disorders. The current methodological approach relies solely on reporting the number of buried marbles at the end of the test. By measuring the proxy of the behavior (buried marbles), rather than the behavior itself (burying bouts), many important characteristics regarding the temporal aspect of this assay are lost. Here we introduce a novel, automated method to quantify mouse behavior throughout the duration of the marble burying test with the focus on the burying bouts. Using open-source software packages, we trained a supervised machine learning algorithm (the “classifier”) to distinguish burying behavior in freely moving mice. In order to confirm the classifier’s accuracy and uncover the behavioral meaning of the marble burying test, we performed marble burying test in three mouse models: Ube3am-/p+ (Angelman Syndrome model), Shank2-/- (autism model), and Sapap3-/- (obsessive-compulsive disorder model) mice. The classifier scored burying behavior accurately and consistent with the literature in the Ube3am-/p+ mice, which showed decreased levels of burying compared to controls. Shank2-/- mice showed a similar pattern of decreased burying behavior, which was not found in Sapap3-/- mice. Tracking mouse behavior throughout the test enabled us to quantify activity characteristics, revealing hypoactivity in Ube3am-/p+ and hyperactivity in the Shank2-/- mice, indicating that mouse activity is unrelated to burying behavior. Together, we demonstrate that our classifier is an accurate method for the analysis of the marble burying test, providing more information than the currently used methods.

Significance Statement

The marble burying test is widely used in phenotyping neurodevelopmental and neuropsychiatric disorder mouse models. Currently, its analysis consists of manually scoring the number of buried marbles upon the completion of the assay. This approach is not standardized across laboratories, and leaves out important variables such as movement characteristics and information about the burying bouts. This leads to divergent interpretations of the marble burying test, ranging from anxiety to cognitive impairment. We introduce a method that reliably tracks mouse behavior throughout the experiment, classifies the duration and number of the burying bouts, and is generalizable across laboratories. Using machine learning for measuring the actual burying behavior standardizes this method, and provides rich information about the burying characteristics.
Antibiotic resistance via bacterial cell shape-shifting
Authors: Ojkic Nikola , Serbanescu Diana , Banerjee Shiladitya
Published: October 2021

Bacteria have evolved to develop multiple strategies for antibiotic resistance by effectively reducing intra-cellular antibiotic concentrations or antibiotic binding affinities, but the role of cell morphology on antibiotic resistance remains poorly characterized. By analyzing cell morphological data of different bacterial species under antibiotic stress, we find that bacterial cells robustly reduce surface-to-volume ratio in response to most types of antibiotics. Using quantitative modelling we show that by reducing surface-to-volume ratio, bacteria can effectively reduce intracellular antibiotic concentration by decreasing antibiotic influx. The model predicts that bacteria can increase surface-to-volume ratio to promote antibiotic dilution if efflux pump activity is reduced, in agreement with data on membrane-transport inhibitors. Using the particular example of ribosome-targeting antibiotics, we present a systems-level model for the regulation of cell shape under antibiotic stress, and discuss feedback mechanisms that bacteria can harness to increase their fitness in the presence of antibiotics.
Dynamic Functional Brain Reconfiguration During Sustained Pain
Authors: Lee Jae-Joong , Lee Sungwoo , Lee Dong Hee , Woo Choong-Wan
Published: October 2021

Abstract

Pain is constructed through complex interactions among multiple brain systems, but it remains unclear how functional brain network representations are dynamically reconfigured over time while experiencing pain. Here, we investigated the dynamic changes in the functional brain networks during 20-min capsaicin-induced sustained orofacial pain. In the early stage, the orofacial areas of the primary somatomotor cortex were separated from the other primary somatomotor cortices and integrated with subcortical and frontoparietal regions, constituting a brain-wide pain supersystem. As pain decreased over time, the subcortical and frontoparietal regions were separated from this pain supersystem and connected to multiple cerebellar regions. Machine-learning models based on these dynamic network features showed significant predictions of changes in pain experience across two independent datasets (n = 48 and 74). This study provides new insights into how multiple brain systems dynamically interact to construct and modulate pain experience, potentially advancing our mechanistic understanding of chronic pain.
Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver
Authors: Sarkar Abby , Jin Yinhua , DeFelice Brian C. , Logan Catriona , Yang Yan , Anbarchian Teni , Wu Peng , Morri Maurizio , Neff Norma , Nguyen Huy , Rulifson Eric , Fish Matt , Martínez Jaimes Azalia M. , Nusse Roel
Published: October 2021

Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary changes influence liver homeostasis. Here, we show that a switch from ad libitum feeding to intermittent fasting, IF, promotes rapid hepatocyte proliferation. Mechanistically, IF-induced hepatocyte proliferation is driven by the combined action of intestinally produced, systemic endocrine FGF15 and localized WNT signaling. Hepatocyte proliferation during periods of fasting and re-feeding re-establishes a constant liver-to-body-mass ratio, thus maintaining the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.
A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation
Authors: Mackay Charles E. , Floen Miranda , Leo M. Dennis , Hasan Raquibul , Fernández-Peña Carlos , Singh Purnima , Malik Kafait U. , Jaggar Jonathan H.
Published: October 2021

Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the Pkd1 gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific Pkd1 knockout (Pkd1 ecKO) mice, we show that flow activates PC-1-mediated, Ca2+-dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation. PC-1-dependent vasodilation occurs over the entire functional shear stress range and primarily via the activation of nitric oxide synthase (NOS), with a smaller contribution from small-conductance Ca2+-activated K+ (SK) channels. EC-specific PC-1 knockout increases systemic blood pressure without altering kidney anatomy. PC-1 coimmunoprecipitates with polycystin-2 (PC-2, PKD2), a TRP polycystin channel, and clusters of both proteins locate in nanoscale proximity in the EC plasma membrane. Knockout of either PC-1 or PC-2 (Pkd2 ecKO mice) abolishes surface clusters of both PC-1 and PC-2 in ECs. Single knockout of PC-1 or PC-2 or double knockout of PC-1 and PC-2 (Pkd1/Pkd2 ecKO mice) similarly attenuates flow-mediated vasodilation. Flow stimulates non-selective cation currents in ECs that are similarly inhibited by either PC-1 or PC-2 knockout or by interference peptides corresponding to the C-terminus coiled-coil domains present in PC-1 or PC-2. In summary, we show that PC-1 regulates arterial contractility and demonstrate that this occurs through the formation of an interdependent signaling complex with PC-2 in endothelial cells. Flow stimulates PC-1/PC-2 clusters in the EC plasma membrane, leading to Ca2+ influx, NOS and SK channel activation, vasodilation and a reduction in blood pressure.
Roxadustat (FG‐4592) protects against ischaemia/reperfusion‐induced acute kidney injury through inhibiting the mitochondrial damage pathway in mice
Authors: Zhang Mei , Dong Rong , Yuan Jing , Da Jingjing , Zha Yan , Long Yanjun
Published: October 2021

Ischaemia–reperfusion (I/R) is one of the main factors of acute kidney injury (AKI). mitochondrial damage pathway are important features of I/R induced‐acute kidney injury (IRI‐AKI). Hypoxia‐inducible factor (HIF) expression in renal tubule segments is up‐regulated during AKI. Herein, we investigated the role of FG‐4592 in a mouse model of IRI‐AKI to confirm whether FG‐4592 is beneficial in AKI. We found that pretreatment with FG‐4592 significantly ameliorated renal function and renal histological damage in mice after IRI. Furthermore, these results suggest that pretreatment with FG‐4592 significantly reduced the tubular cells apoptosis (decreased TUNEL‐positive cells, Bax, caspase12 levels), attenuated mitochondrial damage (increased ATPβ, PPARγ, mitochondrial DNA copy number, and decreased cytoplasmic cytochrome C), and alleviated DNA damage after IRI. In conclusion, pretreatment with FG‐4592 may effectively prevent kidney from IRI possibly by via diminishing tubular cells injuries and protection of mitochondrial damage pathway. These results further validate that FG‐4592 may be an effective drug in the clinical treatment of IRI‐AKI.
Thinking of an Appellation of Origin? Proving the sensory typicity of traditional fresh Turrialba cheese
Authors: Fallas Rodríguez Pilar , Víquez Barrantes Diana , Cortés‐Muñoz Marianela , Cubero Castillo Elba
Published: October 2021

Traditional fresh Turrialba cheese was originally manufactured in Santa Cruz de Turrialba, Costa Rica. The sensory identity of this product was uncertain until now. This work describes the sensory diversity of fresh cheeses sold as Turrialba cheese and defines the sensory profile of the traditional product. Samples (22) were analysed using a generic quantitative descriptive analysis by 10 panellists. From the quantitative descriptive sensory analysis, a cluster containing only samples of the traditional product was found. The profile and intensity of the sensory characteristics of this group distinguished Turrialba cheese from other similar products, showing that sensory identity is an important factor for protection of this traditional food.