bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 related olfactory dysfunction
Authors: Karamali Katerina , Elliott Michael , Hopkins Claire
Published: December 2021

Purpose of review

This article reviews the literature on COVID-19 related anosmia, focusing on the epidemiology, pathophysiology recovery rates, current available treatment options, and research regarding novel treatments.

Recent findings

Loss of sense of smell is one of the most prevalent symptoms reported by patients after COVID-19 infection. Even though there is a high self-reported recovery rate, recent studies have demonstrated that up to 7% of the patients remain anosmic more than 12 months after onset, leaving millions worldwide with severe olfactory dysfunction. Olfactory training remains the first line recommended treatment. Given the paucity of effective medical treatments options researchers are exploring novel therapeutic options.

Olfactory dysfunction remains a significant and persistent legacy of the COVID-19 pandemic, but heightened awareness may stimulate research that leads to the development of much-needed treatment options.
Effect of Autologous Serum Eye Drops on Corneal Haze after Corneal Cross-linking
Authors: Roldan Ana M. , De Arrigunaga Sofia , Ciolino Joseph B.
Published: December 2021

SIGNIFICANCE

Corneal haze remains a frequent post-operative finding in patients undergoing corneal cross-linking. It has been shown that autologous serum tears promote epithelial healing and reduce post-operative pain; however, the role in the prevention of corneal haze has not been reported.

PURPOSE

This study aimed to compare the effect of autologous serum tears versus preservative-free artificial tears on the prevention and resolution of post–cross-linking corneal haze.

METHODS

A retrospective cohort study was conducted in a sample population from one surgeon at a tertiary eye center from 2016 to 2019. Seventy-six eyes of consecutive patients who underwent cross-linking were included. Records were reviewed for corneal Scheimpflug densitometry values and maximum keratometry, epithelial healing time, and the use of either autologous serum tears or preservative-free artificial tears. Corneal densitometry values, expressed in standardized grayscale units (GSU), were recorded for the anterior 150-μm corneal stroma and in the 0.0 to 2.0 mm and 2.0 to 6.0 mm zones.

RESULTS

Forty-four eyes received autologous serum tears, whereas 32 eyes received preservative-free artificial tears. The baseline GSU of the anterior stromal 0 to 2 mm annulus and the 2 to 6 mm annulus did not significantly differ between groups (P = .50 and P = .40, respectively). There was a statistically significant increase in mean GSU for both anterior 0 to 2 mm and 2 to 6 mm zones between baseline and 1 month (P < .001) and 3 months (P < .001). When comparing the two groups, no statistically significant difference was found post-operatively between the mean GSU at 1 month for the anterior 0 to 2 mm (P = .38) nor the 2 to 6 mm zone (P = .12), or for the third month (P = .60 and P = .44, respectively).

CONCLUSIONS

Using Scheimpflug densitometry, we did not find a significant difference in the post–cross-linking corneal haze at 1 and 3 post-operative months between patients who use autologous serum tears and those who use preservative-free artificial tears.
Effect of Latanoprostene Bunod on Optic Nerve Head Blood Flow
Authors: Samaha Dan , Diaconu Vasile , Bouchard Jean François , Desalliers Charlene , Dupont Ariane
Published: December 2021

SIGNIFICANCE

Topical latanoprostene bunod increases capillary oxygen saturation and blood volume at the optic nerve head in healthy individuals.

PURPOSE

This study aimed to evaluate the effect of topical latanoprostene bunod on optic nerve blood volume and oxygen saturation in a population of healthy participants.

METHODS

In this prospective double-blind crossover study, 23 healthy participants aged from 21 to 62 years were recruited. Optic nerve head capillary blood volume (ONHvol) and oxygen saturation (ONHSaO2) baselines were measured over a period of 2 hours using multichannel spectroscopic reflectometry and were remeasured after a 7-day once-daily instillation regimen of either latanoprost 0.005% or latanoprostene bunod 0.024%. After a 30-day washout period, participants were crossed over to the alternate product, and measurements were repeated. Participants were used as their own baselines to calculate variation in ONHvol and ONHSaO2 across time and pharmacological agents. The Friedman test was used to establish significant differences in optic nerve head parameters from baseline values, and Conover post hoc analysis was carried for multiple between-group comparisons.

RESULTS

Latanoprostene bunod 0.024% induced a significant increase of 4% in ONHSaO2 compared with latanoprost 0.005% (P < .001). Furthermore, latanoprostene bunod increased ONHvol levels by more than twofold at all time points (P < .001 at T60, T90, and T120). The increase in ONHvol was 66.2% higher than levels achieved with latanoprost at T60 (P = .001), 47% higher at T90 (P < .001), and 45% higher at T120 (P < .01).

CONCLUSIONS

Latanoprostene bunod 0.024% induces a significant increase in optic nerve head blood volume and oxygen saturation in healthy subjects, when compared with latanoprost 0.005%. Future studies are needed to evaluate whether similar responses are elicited in patients suffering from glaucomatous optic neuropathy.
Patient Satisfaction in the Era of COVID-19: Virtual Visit versus In-person Visit Satisfaction
Authors: Roan Vivian D. , Sun Kristie J. , Valentim Carolina C. S. , Bheemidi Abhinav R. , Iyer Amogh , Singh Rishi P. , Talcott Katherine E.
Published: December 2021

SIGNIFICANCE

Teleophthalmology became widely used during the coronavirus 2019 pandemic; however, the quality of this care remains to be understood.

PURPOSE

This study aimed to compare patient satisfaction levels from virtual and in-person visits based on post-visit surveys, as well as investigate demographic characteristics that may predict patient satisfaction with virtual visits.

METHODS

Virtual (n = 2943) and in-person (n = 56,175) visits from March 19, 2020, to July 31, 2020, were identified using the electronic health record system. For in-person visits, a random subset of 3000 visits was acquired using a random number generator. Of these, 2266 virtual and 2590 in-person visits met the inclusion criteria. Patients who completed the Telemedicine for Medical Practice Survey and Medical Practice Survey were analyzed in this report. Nonparametric Mann-Whitney test was used to compare scores between groups.

RESULTS

Two hundred eleven virtual patients (9.31%; 82 phone, 115 video, 14 hybrid) and 307 in-person patients (11.85%) completed the Telemedicine for Medical Practice Survey and Medical Practice Survey, respectively. Satisfaction scores were similar and high in both groups—virtual visit satisfaction scores averaged 4.82, whereas in-person visit satisfaction averaged 4.85 (P = .80, θ = 0.501 [0.493 to 0.509]). Only one question yielded significantly different satisfaction scores, and no demographic variables were significant predictors of satisfaction scores.

CONCLUSIONS

Patient satisfaction is comparable between virtual and in-person visits, validating the continued usage of telemedicine for eye care visits.
Congenital Chylous Ascites: A Rare Cause of Infantile Ascites Treated With MCT-Based Diet and Octreotide
Authors: Rashid Rafia , Shafi Ahmed Syed , Mahmud Salahuddin
Published: December 2021

Congenital chylous ascites (CCAs) are a rare disease that results from the accumulation of chylomicron-rich lymphatic fluid within the peritoneal cavity due to maldevelopment of the intra-abdominal lymphatic system. Medium-chain triglyceride (MCT)-based diet, total parenteral nutrition (TPN), and repeated paracentesis are considered supportive management for CCA. Cases unresponsive to conservative treatment usually require surgical intervention. We report a case of CCA in a premature neonate treated successfully with intravenous infusion of octreotide (synthetic somatostatin analog), after failing to respond to supportive therapies. Due to the lack of standards in diagnosis and treatment, this disease constitutes a medical challenge, and individual therapy seems to be noteworthy.
Tenofovir Diphosphate in Dried Blood Spots in Pregnant and Postpartum Women With HIV in Kenya: A Novel Approach to Measuring Peripartum Adherence
Authors: Abuogi Lisa L. , Castillo-Mancilla Jose , Hampanda Karen , Owuor Kevin , Odwar Tobias , Onono Maricianah , Helova Anna , Turan Janet M. , Anderson Peter L.
Published: December 2021

Background:

Adherence to antiretroviral therapy (ART) among pregnant and postpartum women with HIV (PWLWH) is critical to promote maternal health and prevent HIV transmission. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is an objective assessment of cumulative ART adherence that has not been fully assessed in PWLWH.

Setting:

Southwestern Kenya.

Methods:

PWLWH receiving tenofovir disoproxil fumarate-based ART from 24 health facilities provided DBS samples at 3 time points [pregnancy/early postpartum (PP), 6 months PP, and 9–12 months PP]. Thresholds for daily adherence were defined as TFV-DP in DBS ≥650 fmol/punch in pregnancy and ≥950 PP. Descriptive analysis is presented. Cluster adjusted χ2 and t-tests were used to test for association with clinical and demographic factors.

Results:

A total of 419 DBS samples were collected from 150 PWLWH. Median TFV-DP in DBS was lowest, 552 fmol/punch [interquartile range (IQR), 395–759] in pregnancy and declined over time [914 (IQR, 644–1176) fmol/punch; early PP; 838 (IQR, 613–1063) fmol/punch 6 months PP; and 785 (IQR, 510–1009) fmol/punch 9–12 months; P < 0.001]. Only 42% of samples in pregnancy and 38.5% of samples in PP met thresholds for daily adherence. Clinical or demographic factors were not associated with suboptimal adherence levels.

Conclusion:

Cumulative ART exposure in PWLWH, quantified by TFV-DP in DBS, demonstrated a stepwise decrease (ie, adherence) PP. Most women demonstrated less than daily adherence throughout the peripartum period. Use of TFV-DP in DBS as a measure of cumulative ART adherence could help optimize health outcomes in PWLWH and their infants.
Genital Inflammation Is Not Associated With Decreased Vaginal Tenofovir Concentrations in Women Taking Oral PrEP
Authors: Morris Sheldon , Cottrell Mackenzie , Rawlings Stephen A. , Peterson Scott , Karris Maile , Pacheco Deedee , Chaillon Antoine , Kay Alexis , Chow Karen , Anderson Peter L. , Gianella Sara , Blumenthal Jill
Published: December 2021

Background:

We evaluated the association of inflammation and dysbosis on cervicovaginal fluid (CVF) tenofovir (TFV) concentrations in women taking oral tenofovir disoproxil fumarate/emtricitable for HIV pre-exposure prophylaxis (PrEP) in the United States.

Setting:

Thirty-five women in a HIV PrEP implementation study attended their week 24 visit at a San Diego research clinic and provided CVF specimens.

Methods:

Women in the Adherence Enhancement Guided by Individualized Texting and Drug Levels study had their CVF specimens evaluated for (1) sexually transmitted bacterial (Neisseria gonorrhoeae, Chlamydia trachomatis, Gardnerella, and Trichomonas vaginalis), viral (human papillomavirus, cytomegalovirus and herpes simplex virus-1/2) and fungal (Candida) infections; (2) microbiome composition by 16 S sequencing (V3–V4 region); and (3) cytokine profiles by enzyme-linked immunoassay (Interleukin-8, macrophage Inflammatory protein-1a, macrophage Inflammatory Protein-1b and interferon-γ-inducible protein-10). Univariate statistical analysis was used to determine factors associated with CVF TFV concentrations. CVF TFV of 100–1000 ng/mL benchmarked typical genital concentrations and TFV-diphosphate in dried blood spots of 700 fmol/punch was considered adequate adherence.

Results:

Thirty-five women had CVF specimens collected. No factor was associated with CVF TFV concentrations or discordance of blood and vaginal concentrations. Among 27 participants assessed for vaginosis (Candida, Gardnerella or Trichomonas), women with Gardnerella (n = 11) were more likely to have high (>1000 ng/mL) CVF TFV concentrations (82% versus 33%, P = 0.02).

Conclusions:

Presence of genital viruses, cytokines, or vaginal community state types were not associated with low CVF TFV concentrations in cisgender women taking oral tenofovir disoproxil fumarate/emtricitable for PrEP. The surprising association observed between presence of Gardnerella and higher vaginal TFV concentrations needs further evaluation.
Surfing the Big Data Wave: Omics Data Challenges in Transplantation
Authors: Ba Rokhaya , Geffard Estelle , Douillard Venceslas , Simon Françoise , Mesnard Laurent , Vince Nicolas , Gourraud Pierre-Antoine , Limou Sophie
Published: December 2021

In both research and care, patients, caregivers, and researchers are facing a leap forward in the quantity of data that are available for analysis and interpretation, marking the daunting “big data era.” In the biomedical field, this quantitative shift refers mostly to the -omics that permit measuring and analyzing biological features of the same type as a whole. Omics studies have greatly impacted transplantation research and highlighted their potential to better understand transplant outcomes. Some studies have emphasized the contribution of omics in developing personalized therapies to avoid graft loss. However, integrating omics data remains challenging in terms of analytical processes. These data come from multiple sources. Consequently, they may contain biases and systematic errors that can be mistaken for relevant biological information. Normalization methods and batch effects have been developed to tackle issues related to data quality and homogeneity. In addition, imputation methods handle data missingness. Importantly, the transplantation field represents a unique analytical context as the biological statistical unit is the donor–recipient pair, which brings additional complexity to the omics analyses. Strategies such as combined risk scores between 2 genomes taking into account genetic ancestry are emerging to better understand graft mechanisms and refine biological interpretations. The future omics will be based on integrative biology, considering the analysis of the system as a whole and no longer the study of a single characteristic.

In this review, we summarize omics studies advances in transplantation and address the most challenging analytical issues regarding these approaches.
Current concepts in acute vestibular syndrome and video-oculography
Authors: Mantokoudis Georgios , Otero-Millan Jorge , Gold Daniel R.
Published: December 2021

Purpose of review

We present here neuro-otological tests using portable video-oculography (VOG) and strategies assisting physicians in the process of decision making beyond the classical ‘HINTS’ testing battery at the bedside.

Recent findings

Patients with acute vestibular syndrome (AVS) experience dizziness, gait unsteadiness and nausea/vomiting. A variety of causes can lead to this condition, including strokes. These patients cannot be adequately identified with the conventional approach by stratifying based on risk factors and symptom type. In addition to bedside methods such as HINTS and HINTS plus, quantitative methods for recording eye movements using VOG can augment the ability to diagnose and localize the lesion. In particular, the ability to identify and quantify the head impulse test (VOR gain, saccade metrics), nystagmus characteristics (waveform, beating direction and intensity), skew deviation, audiometry and lateropulsion expands our diagnostic capabilities. In addition to telemedicine, algorithms and artificial intelligence can be used to support emergency physicians and nonexperts in the future.

VOG, telemedicine and artificial intelligence may assist physicians in the diagnostic process of AVS patients.
Hoyosella lacisalsi sp. nov., a halotolerant actinobacterium isolated from the Lake Gudzhirganskoe
Authors: Yang Qin , Guo Pu-Yu , Abidueva Elena Y. , Li Fei-Na , Xue Chun-mei , Liu Shao-Wei , Sun Cheng-Hang
Published: December 2021

A Gram-stain-positive, aerobic, non-motile, non-spore-forming and coccus-shaped strain, designated strain G463T, was isolated from the rhizosphere soil of Salicornia europaea L. collected from Lake Gudzhirganskoe in Siberia. Based on 16S rRNA gene phylogeny, strain G463T belonged to the genus

Hoyosella

, with the highest 16S rRNA gene sequence similarity to

Hoyosella altamirensis

DSM 45258T (96.1%). The major fatty acids were C17:1
ω8c, C16:0, C15 : 0 and C17:0. The strain contained meso-diaminopimelic acid as the cell-wall diagnostic diamino acid and arabinose, galactose and ribose as the whole-cell sugars. MK-8 and MK-7 were the predominant menaquinones. The polar lipid profile comprised diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, one unidentified phosphoglycolipid, two unidentified glycolipids and several unidentified lipids. Acetyl was the muramyl residue. Mycolic acids (C28–C34) were present. The G+C content of the genomic DNA was 68.3 mol%. Based on its phylogenetic, phenotypic and chemotaxonomic features, strain G463T was considered to represent a novel species of the genus

Hoyosella

, for which the name Hoyosella lacisalsi sp. nov. is proposed. The type strain is G463T (=JCM 33650T=CGMCC 1.17230T).
Cluster-specific gene markers enhance Shigella and enteroinvasive Escherichia coli in silico serotyping
Authors: Zhang Xiaomei , Payne Michael , Nguyen Thanh , Kaur Sandeep , Lan Ruiting
Published: December 2021

Shigella

and enteroinvasive

Escherichia coli

(EIEC) cause human bacillary dysentery with similar invasion mechanisms and share similar physiological, biochemical and genetic characteristics. Differentiation of

Shigella

from EIEC is important for clinical diagnostic and epidemiological investigations. However, phylogenetically,

Shigella

and EIEC strains are composed of multiple clusters and are different forms of

E. coli

, making it difficult to find genetic markers to discriminate between

Shigella

and EIEC. In this study, we identified 10

Shigella

clusters, seven EIEC clusters and 53 sporadic types of EIEC by examining over 17000 publicly available

Shigella

and EIEC genomes. We compared

Shigella

and EIEC accessory genomes to identify cluster-specific gene markers for the 17 clusters and 53 sporadic types. The cluster-specific gene markers showed 99.64% accuracy and more than 97.02% specificity. In addition, we developed a freely available in silico serotyping pipeline named

Shigella

EIEC Cluster Enhanced Serotype Finder (ShigEiFinder) by incorporating the cluster-specific gene markers and established

Shigella

and EIEC serotype-specific O antigen genes and modification genes into typing. ShigEiFinder can process either paired-end Illumina sequencing reads or assembled genomes and almost perfectly differentiated

Shigella

from EIEC with 99.70 and 99.74% cluster assignment accuracy for the assembled genomes and read mapping respectively. ShigEiFinder was able to serotype over 59

Shigella

serotypes and 22 EIEC serotypes and provided a high specificity of 99.40% for assembled genomes and 99.38% for read mapping for serotyping. The cluster-specific gene markers and our new serotyping tool, ShigEiFinder (installable package: https://github.com/LanLab/ShigEiFinder, online tool: https://mgtdb.unsw.edu.au/ShigEiFinder/), will be useful for epidemiological and diagnostic investigations.
Coalescent tree recording with selection for fast forward-in-time simulations
Authors: Matthey-Doret Remi
Published: December 2021

Forward simulations are increasingly important in evolutionary genetics to simulate selection with realistic demography, mating systems and ecology. To reach the performance needed for genome-wide simulations a number of new simulation techniques have been developed recently. Kelleher et al. (2018) introduced a technique consisting in recording the entire genetic history of the population and placing mutations on the coalescent tree. This method cannot model selection. I recently introduced a simulation technique that speed up fitness calculation by assuming that fitness effects among haplotypes are multiplicative (Matthey-Doret, 2021). More precisely, fitness measures are stored for subsets of the genome and, at time of reproduction, if no recombination happen within a given subset, then the fitness for this subset for the offspring haplotype is directly inferred from the parental haplotype. Here, I present and benchmark a hybrid of the above two techniques. The algorithm records the genetic history of a species, directly places the mutations on the tree and infers fitness of subsets of the genome from parental haplotypes. At recombinant sites, the algorithm explores the tree to reconstruct the genetic data at the recombining segment. I benchmarked this new technique implemented in SimBit and report an important improvement of performance compared to previous techniques to simulate selection. This improvement is particularly drastic at low recombination rate. Such developments of new simulation techniques are pushing the horizon of the realism with which we can simulate species molecular evolution.
Plant-based expression of SARS-CoV-2 antigen for use in an oral vaccine
Authors: Power Monique , Azad Taha , Bell John C. , MacLean Allyson M
Published: December 2021

Oral and intra-nasal vaccines represent a key means of inducing mucosal-based immunity against infection with SARS-CoV-2, yet such vaccines represent only a minority of candidates currently in development. In this brief communication, we assessed the expression of the SARS-CoV-2 Receptor Binding Domain (RBD) subunit of the surface-exposed Spike glycoprotein in the leaves of nine edible plant species (lettuce, spinach, collard greens, tomato, cucumber, radish, arugula, pepper, and Coho greens), with a goal of identifying a suitable candidate for the development of an oral vaccine against COVID-19. We report lettuce (Lactuca sativa L. cv. Hilde II Improved) to be a preferred host to support in planta expression of SARS-CoV-2 RBD, representing an important first step towards development of a plant-based oral vaccine.
The single-cell transcriptional landscape of lung carcinoid tumors
Authors: Bischoff Philip , Trinks Alexandra , Wiederspahn Jennifer , Obermayer Benedikt , Pett Jan Patrick , Jurmeister Philipp , Elsner Aron , Dziodzio Tomasz , Rückert Jens-Carsten , Neudecker Jens , Falk Christine , Beule Dieter , Sers Christine , Morkel Markus , Horst David , Klauschen Frederick , Blüthgen Nils
Published: December 2021

Lung carcinoid tumors, also referred to as pulmonary neuroendocrine tumors or lung carcinoids, are rare neoplasms of the lung with a more favorable prognosis than other subtypes of lung cancer. Still, some patients suffer from relapsed disease and metastatic spread while no consensus treatment exists for metastasized carcinoids. Several recent single-cell studies have provided detailed insights into the cellular heterogeneity of more common lung cancers, such as adeno- and squamous cell carcinoma. However, the characteristics of lung carcinoids on the single-cell level are yet completely unknown.

To study the cellular composition and single-cell gene expression profiles in lung carcinoids, we applied single-cell RNA sequencing to three lung carcinoid tumor samples and normal lung tissue. The single-cell transcriptomes of carcinoid tumor cells reflected intertumoral heterogeneity associated with clinicopathological features, such as tumor necrosis and proliferation index. The immune microenvironment was specifically enriched in noninflammatory monocyte-derived myeloid cells. Tumor-associated endothelial cells were characterized by distinct gene expression profiles. A spectrum of vascular smooth muscle cells and pericytes predominated the stromal microenvironment. We found a small proportion of myofibroblasts exhibiting features reminiscent of cancer-associated fibroblasts. Stromal and immune cells exhibited potential paracrine interactions which may shape the microenvironment via NOTCH, VEGF, TGFβ and JAK/STAT signaling. Moreover, single-cell gene signatures of pericytes and myofibroblasts demonstrated prognostic value in bulk gene expression data.

Here, we provide first comprehensive insights into the cellular composition and single-cell gene expression profiles in lung carcinoids, demonstrating the non-inflammatory and vessel-rich nature of their tumor microenvironment, and outlining relevant intercellular interactions which could serve as future therapeutic targets.
Significant cross-species gene flow detected in the Tamias quadrivittatus group of North American chipmunks
Authors: Ji Jiayi , Jackson Donavan J. , Leaché Adam D. , Yang Ziheng
Published: December 2021

In the past two decades genomic data have been widely used to detect historical gene flow between species in a variety of plants and animals. The Tamias quadrivittatus group of North America chipmunks, which originated through a series of rapid speciation events, are known to undergo massive amounts of mitochondrial introgression. Yet in a recent analysis of targeted nuclear loci from the group, no evidence for cross-species introgression was detected, indicating widespread cytonuclear discordance. The study used heuristic methods that analyze summaries of the multilocus sequence data to detect gene flow, which may suffer from low power. Here we use the full likelihood method implemented in the Bayesian program BPP to reanalyze these data. We take a stepwise approach to constructing an introgression model by adding introgression events onto a well-supported binary species tree. The analysis detected robust evidence for multiple ancient introgression events affecting the nuclear genome, with introgression probabilities reaching 65%. We estimate population parameters and highlight the fact that species divergence times may be seriously underestimated if ancient cross-species gene flow is ignored in the analysis. Our analyses highlight the importance of using adequate statistical methods to reach reliable biological conclusions concerning cross-species gene flow.
Mycobacterium tuberculosisinfection, immune activation, and risk of HIV acquisition
Authors: Bender Ignacio Rachel A. , Long Jessica , Saha Aparajita , Nguyen Felicia K. , Joudeh Lara , Valinetz Ethan , Mendelsohn Simon C. , Scriba Thomas J. , Hatherill Mark , Janes Holly , Churchyard Gavin , Buchbinder Susan , Duerr Ann , Shah Javeed A. , Hawn Thomas R.
Published: December 2021

Background

Although immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses toM. tuberculosis(Mtb) infection, are not well characterized.

Methods

We conducted a nested case-control study within the Step MRKAd5 HIV-1 vaccine study. PBMCs from the last HIV-negative sample from incident HIV cases and controls who did not acquire HIV were stimulated withMtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining.

Combinatorialpolyfunctionality analysis ofantigen-specific T-cellsubsets (COMPASS) determined overallMtb-antigen-specific T cell activation. We measured inflammatory profiles with five Correlates of TB Risk (CoR) peripheral blood transcriptomic signatures. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether either cellular markers of TB-associated immune activation or transcriptomic predictors of TB disease states were associated with HIV acquisition.

Results

Among 465 participants, latentMtbinfection (LTBI) prevalence (21.5% controls vs 19.1% cases, p=0.51) andMtbantigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.76 (0.60, 0.95)), were associated with HIV acquisition in multivariable analysis. The Sweeney3 signature best predicted odds of acquiring HIV in unadjusted and adjusted analyses, including when restricted to LTBI-negative participants.

Conclusions

LTBI andMtbpolyfunctional antigen-specific CD4+ T cell immune activation were not identified as risk factors for HIV acquisition, but transcriptomic analyses demonstrated that two CoR signatures predicted HIV risk after adjustment for known behavioral and clinical risk factors. CoR signatures can demonstrate host gene expression associated with HIV acquisition, but the observed effects are likely not mediated throughMtbinfection.
The unequal impact of the COVID-19 pandemic on life expectancy across Chile
Authors: Mena Gonzalo E. , Aburto José Manuel
Published: December 2021

Objectives

To quantify the effect of the COVID-19 pandemic on life expectancy in Chile categorized by rural and urban, and to correlate life expectancy changes with socioeconomic factors at the municipal level.

Design

Retrospective cross-sectional demographic analysis using aggregated data.

Setting

Vital and demographic statistics from the national institute of statistics and department of vital statistics of ministry of health.

Participants

Aggregated national all-cause death data stratified by year (2000-2020), sex, and municipality.

Main Outcome measures

Stratified mortality rates using a Bayesian methodology. With this, we assessed the unequal impact of the pandemic in 2020 on life expectancy across Chilean municipalities for men and women and analyzed previous mortality trends since 2010.

Results

Life expectancy declined for both men and women in 2020. Urban areas were the most affected, with males losing 1.89 and females 1.33 in 2020. The strength of the decline in life expectancy correlated with indicators of social deprivation and poverty. Also, inequality in life expectancy between municipalities increased, largely due to excess mortality among the working-age population in socially disadvantaged municipalities.

Conclusions

Not only do people in poorer areas live shorter lives, they also have been substantially more affected by the COVID-19 pandemic, leading to increased population health inequalities. Quantifying the impact of the COVID-19 pandemic on life expectancy provides a more comprehensive picture of the toll.

Strengths and limitations

First study to analyze changes in life expectancy in Chile with small-area resolution.

We applied a hierarchical Bayesian methodology to estimate life expectancies in the past 20 years.

We show that COVID-19 led to declines in life expectancy in Chile greater than a year in magnitude. These declines correlated with poverty levels, indicating that socially deprived populations were hit the hardest.

We also show that inequality in life expectancy between municipalities increased due to excess mortality among the working-age population in socially disadvantaged municipalities.

The main limitation is that our estimates depend on accurate small-area stratified population estimates. We implemented several estimates and showed that our findings are robust to the choice of them.
Host immune responses to enzootic and invasive pathogen lineages vary in magnitude, timing, and efficacy
Authors: McDonald Coby A. , Guilherme Becker C. , Lambertini Carolina , Felipe Toledo L. , Haddad Célio F.B. , Zamudio Kelly R.
Published: December 2021

Infectious diseases of wildlife continue to pose a threat to biodiversity worldwide, yet pathogens are far from monolithic in virulence. Within the same pathogen species, virulence can vary considerably depending on strain or lineage, in turn eliciting variable host responses. One pathogen that has caused extensive biodiversity loss is the amphibian-killing fungus, Batrachochytrium dendrobatidis (Bd), which is comprised of a globally widespread hypervirulent lineage (Bd-GPL), and multiple geographically restricted lineages. Whereas host immunogenomic responses to Bd-GPL have been characterized in a number of amphibian species, immunogenomic responses to geographically-restricted, enzootic Bd lineages are unknown. To examine lineage- specific host immune responses to Bd, we exposed a species of pumpkin toadlet, Brachycephalus pitanga, which is endemic to Brazil’s Southern Atlantic Forest, to either the Bd-GPL or the enzootic Bd-Asia-2/Brazil (hereafter Bd-Brazil) lineage. We quantified functional immunogenomic responses over the course of infection using differential gene expression tests and coexpression network analyses. Host immune responses varied significantly with Bd lineage. Toadlet responses to Bd-Brazil were weak at early infection (26 genes differentially expressed), peaked by mid-stage infection (435 genes) and were nearly fully resolved by late-stage disease (9 genes). In contrast, responses to Bd-GPL were magnified and delayed; toadlets differentially expressed 97 genes early, 86 genes at mid-stage infection, and 728 genes by late-stage infection. Given that infection intensity did not vary between mid- and late-stage disease, this suggests that pumpkin toadlets may be at least partially tolerant to the geographically-restricted Bd- Brazil lineage. In contrast, mortality was higher in Bd-GPL-infected toadlets, suggesting that late-stage immune activation against Bd-GPL was not protective and was consistent with immune dysregulation previously observed in other species. Our results demonstrate that both the timing of immune response and the particular immune pathways activated are specific to Bd lineage. Within regions where multiple Bd lineages co-occur, and given continued global Bd movement, these differential host responses may influence not only individual disease outcome, but transmission dynamics at the population and community levels.
Identification and Validation of Novel Microtubule Suppressors with an Imidazopyridine Scaffold through Structure-Based Virtual Screening and Docking
Authors: Elseginy Samia A. , Oliveira A. Sofia F. , Shoemark Deborah K. , Sessions Richard B.
Published: December 2021

Targeting the colchicine binding site of α/β tubulin microtubules can lead to suppression of microtubule dynamics, cell cycle arrest and apoptosis. Therefore, the development of microtubule (MT) inhibitors is considered a promising route to anticancer agents. Our approach to identify novel scaffolds as MT inhibitors depends on a 3D-structure-based pharmacophore approach and docking using three programs MOE, Autodock and BUDE (Bristol University Docking Engine) to screen a library of virtual compounds. From this work we identified the compound 7-(3-Hydroxy-4-methoxy-phenyl)-3-(3-trifluoromethyl-phenyl)-6,7-dihydro-3H-imidazo[4,5-b] pyridin-5-ol (6) as a novel inhibitor scaffold. This compound inhibited several types of cancer cell proliferation at low micromolar concentrations with low toxicity. Compound 6 caused cell cycle arrest in the G2/M phase and blocked tubulin polymerization at low micromolar concentration (IC50 = 6.1 ±0.1 μM), inducing apoptosis via activation of caspase 9, increasing the level of the pro-apoptotic protein Bax and decreasing the level of the anti-apoptotic protein Bcl2. In summary, our approach identified a lead compound with potential antimitotic and antiproliferative activity.
Co-radiation of Leptospira and Tenrecidae (Afrotheria) on Madagascar
Authors: Gomard Yann , Goodman Steven M. , Soarimalala Voahangy , Turpin Magali , Lenclume Guenaëlle , Ah-Vane Marion , Golden Christopher D. , Tortosa Pablo
Published: December 2021

Leptospirosis is a bacterial zoonosis caused by pathogenic Leptospira that are maintained in the kidney lumen of infected animals acting as reservoirs and contaminating the environment via infected urine. The investigation of leptospirosis through a One Health framework has been stimulated by notable genetic diversity of pathogenic Leptospira together with a high infection prevalence in certain animal reservoirs. Studies of Madagascar’s native mammal fauna have revealed a diversity of Leptospira with high levels of host-specificity. Native rodents, tenrecids, and bats shelter several distinct lineages and species of Leptospira, some of which have also been detected in acute human cases. Specifically, Leptospira mayottensis, first discovered in humans on Mayotte, an island neighboring Madagascar, was subsequently identified in a few species of Malagasy tenrecids, an endemic family of small mammals. Distinct L. mayottensis lineages were identified in shrew tenrecs (Microgale cowani and Nesogale dobsoni) on Madagascar, and later in spiny tenrecs (Tenrec ecaudatus) on Mayotte. These findings suggest that L. mayottensis (i) has co-radiated with tenrecids on Madagascar, and (ii) has recently emerged in human populations on Mayotte following the introduction of T. ecaudatus from Madagascar. Hitherto, L. mayottensis has not been detected in spiny tenrecs on Madagascar. In the present study, we broaden the investigation of Malagasy tenrecids and describe the presence of L. mayottensis in Malagasy T. ecaudatus and M. thomasi. These results confirm the hypothesis that L. mayottensis was introduced to Mayotte, presumably via T. ecaudatus, and provide additional data on the co-radiation of Leptospira and Tenrecidae.
CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis
Authors: Dunbar Andrew , Kim Dongjoo , Lu Min , Farina Mirko , Yang Julie L. , Park Young , Gobbo Francesca , Verachi Paola , Martelli Fabrizio , Karzai Abdul , Xiao Wenbin , Xia Lijuan , Elmansy Nada , Kleppe Maria , Chen Zhuo , Xiao Yang , McGovern Erin , Snyder Jenna , Krishnan Aishwarya , Hill Corrine , Cordner Keith , Zouak Anouar , Salama Mohamed E. , Yohai Jayden , Tucker Eric , Chen Jonathan , Zhou Jing , McConnell Tim , Koche Richard , Rampal Raajit , Migliaccio Anna Rita , Fan Rong , Levine Ross L. , Hoffman Ronald
Published: December 2021

Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-κB pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and two separate murine models of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched in a CXCL8/CXCR2 gene signature and display dose-dependent proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients at risk for continued fibrotic progression.
Cylindromatosis Drives Synapse Pruning and Weakening by Promoting Macroautophagy through Akt-mTOR Signaling
Authors: Zajicek Alexis S. , Ruan Hongyu , Dai Huihui , Skolfield Mary C. , Phillips Hannah L. , Burnette Wendi J. , Javidfar Behnam , Sun Shao-Cong , Akbarian Schahram , Yao Wei-Dong
Published: December 2021

The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux and, conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.
Drosophila gustatory projections are segregated by taste modality and connectivity
Authors: Engert Stefanie , Sterne Gabriella R. , Bock Davi D. , Scott Kristin
Published: December 2021

Gustatory sensory neurons detect caloric and harmful compounds in potential food and convey this information to the brain to inform feeding decisions. To examine the signals that gustatory neurons transmit and receive, we reconstructed gustatory axons and their synaptic sites in the adult Drosophila melanogaster brain, utilizing a whole-brain electron microscopy volume. We reconstructed 87 gustatory projections from the proboscis labellum in the right hemisphere and 57 from the left, representing the majority of labellar gustatory axons. Gustatory neurons contain a nearly equal number of interspersed pre-and post-synaptic sites, with extensive synaptic connectivity among gustatory axons. Morphology- and connectivity-based clustering revealed six distinct groups, likely representing neurons recognizing different taste modalities. The vast majority of synaptic connections are between neurons of the same group. This study resolves the anatomy of labellar gustatory projections, reveals that gustatory projections are segregated based on taste modality, and uncovers synaptic connections that may alter the transmission of gustatory signals.
The Gulf Coast tick, Amblyomma maculatum (Ixodida: Ixodidae) and spotted fever group Rickettsia in the highly urbanized northeastern US
Authors: Bajwa Waheed I. , Tsynman Leonid , Egizi Andrea M. , Tokarz Rafal , Maestas Lauren P. , Fonseca Dina M.
Published: December 2021

We report the multi-year collection of the Gulf Coast tick, Amblyomma maculatum Koch (Acaridae: Ixodida: Ixodidae) in Staten Island, New York City (NYC) as well as their detection in Brooklyn, NYC, and in Atlantic and Cumberland counties in southern NJ, USA. The first detections on all sites were of adults but in Freshkills Park on Staten Island larvae were collected in a following year. Based on known observations on birds of this tick species, it is likely A. maculatum are expanding north on migratory birds, which are now often seen in Freshkills Park. The presence of larvae indicates that adults are being successful at finding hosts in Staten Island. We describe the landscape features of the area in Staten Island where populations were highest and larvae were detected, which could have facilitated the establishment of A. maculatum. Notably, we also report the presence of human pathogens Rickettsia parkeri in 5/10 (50%) of adults tested and R. felis in 1/24 (4.17%) of larvae tested. In addition to established populations in Staten Island we found evidence of A. maculatum in NJ and other NYC boroughs, suggesting current or future establishment is possible. The failure thus far to detect established populations in these areas may be due to inherent difficulties in detecting low density, spatially heterogeneous incipient populations, which could require targeted surveillance efforts for this species. We discuss the consequences to public health of the establishment of A. maculatum and detection of two additional rickettsial pathogens in the densely populated Northeastern US.
Ion Permeation, Selectivity, and Electronic Polarization in Fluoride Channels
Authors: Yue Zhi , Wang Zhi , Voth Gregory A
Published: December 2021

Fluoride channels (Fluc) export toxic F- from the cytoplasm. Crystallography and mutagenesis have identified several conserved residues crucial for fluoride transport, but the transport mechanism at the molecular level has remained elusive. Herein we have applied constant-pH molecular dynamics and free energy sampling methods to investigate fluoride transfer through a Fluc protein from Escherichia coli. We find that fluoride is facile to transfer in its charged form, i.e., F-, by traversing through a non-bonded network. The extraordinary F- selectivity is gained by the hydrogen-bonding capability of the central binding site and the Coulombic filter at the channel entrance. The F- transfer rate calculated using an electronically polarizable force field is significantly more accurate compared to the experimental value than that calculated using a more standard additive force field, suggesting an essential role for electronic polarization in the F- - Fluc interactions.
Development and validation of inducible protein degradation and quantitative phosphoproteomics to identify kinase-substrate relationships
Authors: Hards Rufus , Howarth Charles L. , Wiredu Kwame , LaCroix Ian , Valle Juan Mercado del , Adamo Mark , Kettenbach Arminja N. , Holland Andrew J. , Gerber Scott A.
Published: December 2021

Phosphorylation signaling is an essential post-translational regulatory mechanism that governs almost all eukaryotic biological processes and is controlled by an interplay between protein kinases and phosphatases. Knowledge of direct substrates of kinases provides evidence of mechanisms that relate activity to biological function. Linking kinases to their protein substrates can be achieved by inhibiting or reducing kinase activity and quantitative comparisons of phosphoproteomes in the presence and absence of kinase activity. Unfortunately, most of the human kinases lack chemical inhibitors with selectivity required to unambiguously assign protein substrates to their respective kinases. Here, we develop and validate a chemical proteomics strategy for linking kinase activities to protein substrates via targeted protein degradation and quantitative phosphoproteomics and apply it to the well-studied, essential mitotic regulator polo-like kinase 1 (Plk1). We leveraged the Tir1/auxin system to engineer HeLa cells with endogenously homozygous auxin-inducible degron (AID)-Plk1). We used HeLa cells and determined the impact of AID-tagging on Plk1 activity, localization, protein interactors, and substrate motifs. Using quantitative proteomics, we show that of over 8,000 proteins quantified, auxin addition is highly selective for degrading AID-Plk1 in mitotic cells. Comparison of phosphoproteome changes in response to chemical Plk1 inhibition to auxin-induced degradation revealed a striking degree of correlation. Finally, we explored basal protein turnover as a potential basis for clonal differences in auxin-induced degradation rates for AID-Plk1 cells. Taken together, our work provides a roadmap for the application of AID technology as a general strategy for the kinome-wide discovery of kinase-substrate relationships.