bluuebunny/crossref_metadata_2025 huggingface dataset:
Model-independent discovery prospects for primordial black holes at LIGO
Authors: Lehmann Benjamin V , Profumo Stefano , Yant Jackson
Published: December 2020

Primordial black holes may encode the conditions of the early Universe, and may even constitute a significant fraction of cosmological dark matter. Their existence has yet to be established. However, black holes with masses below ${\sim}{1}{\, \mathrm{M}_\odot }$ cannot form as an endpoint of stellar evolution, so the detection of even one such object would be a smoking gun for new physics, and would constitute evidence that at least a fraction of the dark matter consists of primordial black holes. Gravitational wave detectors are capable of making a definitive discovery of this kind by detecting mergers of light black holes. But since the merger rate depends strongly on the shape of the black hole mass function, it is difficult to determine the potential for discovery or constraint as a function of the overall abundance of black holes. Here, we directly maximize and minimize the merger rate to connect observational results to the actual abundance of observable objects. We show that LIGO can discover mergers of light primordial black holes within the next decade even if such black holes constitute only a very small fraction of dark matter. A single merger event involving such an object would (i) provide conclusive evidence of new physics, (ii) establish the nature of some fraction of dark matter, and (iii) probe cosmological history at scales far beyond those observable today.
MitImpact 3: modeling the residue interaction network of the Respiratory Chain subunits
Authors: Castellana Stefano , Biagini Tommaso , Petrizzelli Francesco , Parca Luca , Panzironi Noemi , Caputo Viviana , Vescovi Angelo Luigi , Carella Massimo , Mazza Tommaso
Published: December 2020

Numerous lines of evidence have shown that the interaction between the nuclear and mitochondrial genomes ensures the efficient functioning of the OXPHOS complexes, with substantial implications in bioenergetics, adaptation, and disease. Their interaction is a fascinating and complex trait of the eukaryotic cell that MitImpact explores with its third major release. MitImpact expands its collection of genomic, clinical, and functional annotations of all non-synonymous substitutions of the human mitochondrial genome with new information on putative Compensated Pathogenic Deviations and co-varying amino acid sites of the Respiratory Chain subunits. It further provides evidence of energetic and structural residue compensation by techniques of molecular dynamics simulation. MitImpact is freely accessible at http://mitimpact.css-mendel.it.
Precise and broad scope genome editing based on high-specificity Cas9 nickases
Authors: Wang Qian , Liu Jin , Janssen Josephine M , Le Bouteiller Marie , Frock Richard L , Gonçalves Manuel A F V
Published: December 2020

RNA-guided nucleases (RGNs) based on CRISPR systems permit installing short and large edits within eukaryotic genomes. However, precise genome editing is often hindered due to nuclease off-target activities and the multiple-copy character of the vast majority of chromosomal sequences. Dual nicking RGNs and high-specificity RGNs both exhibit low off-target activities. Here, we report that high-specificity Cas9 nucleases are convertible into nicking Cas9D10A variants whose precision is superior to that of the commonly used Cas9D10A nickase. Dual nicking RGNs based on a selected group of these Cas9D10A variants can yield gene knockouts and gene knock-ins at frequencies similar to or higher than those achieved by their conventional counterparts. Moreover, high-specificity dual nicking RGNs are capable of distinguishing highly similar sequences by ‘tiptoeing’ over pre-existing single base-pair polymorphisms. Finally, high-specificity RNA-guided nicking complexes generally preserve genomic integrity, as demonstrated by unbiased genome-wide high-throughput sequencing assays. Thus, in addition to substantially enlarging the Cas9 nickase toolkit, we demonstrate the feasibility in expanding the range and precision of DNA knockout and knock-in procedures. The herein introduced tools and multi-tier high-specificity genome editing strategies might be particularly beneficial whenever predictability and/or safety of genetic manipulations are paramount.
‘Stat’ workflow modifications to expedite care after needlestick injuries
Authors: Smith J L , Banerjee R , Linkin D R , Schwab E P , Saberi P , Lanzi M
Published: December 2020

Background

Post-exposure prophylaxis (PEP) for human immunodeficiency virus (HIV) is recommended to start within hours of needlestick injuries (NSIs) among healthcare workers (HCWs). Delays associated with awaiting the results of testing from the source patient (whose blood was involved in the NSI) can lead to psychological consequences for the exposed HCW as well as symptomatic toxicities from empiric PEP.

Aims

After developing a ‘stat’ (immediate) workflow that prioritized phlebotomy and resulting of source patient bloodwork for immediate handling and processing, we retrospectively investigated whether our new workflow had (i) decreased HIV order-result interval times for source patient HIV bloodwork and (ii) decreased the frequency of HIV PEP prescriptions being dispensed to exposed HCWs.

Methods

We retrospectively analysed NSI records to identify source patient HIV order-result intervals and PEP dispensing frequencies across a 6-year period (encompassing a 54-month pre-intervention period and 16-month post-intervention period).

Results

We identified 251 NSIs, which occurred at similar frequencies before versus after our intervention (means 3.54 NSIs and 3.75 NSIs per month, respectively). Median HIV order-result intervals decreased significantly (P < 0.05) from 195 to 156 min after our intervention, while the proportion of HCWs who received one or more doses of PEP decreased significantly (P < 0.001) from 50% (96/191) to 23% (14/60).

Conclusion

Using a ‘stat’ workflow to prioritize source patient testing after NSIs, we achieved a modest decrease in order-result intervals and a dramatic decrease in HIV PEP dispensing rates. This simple intervention may improve HCWs’ physical and psychological health during a traumatic time.
Asleep Deep Brain Stimulator Placement in the Intraoperative Magnetic Resonance Imaging System Hybrid Operating Suite: 2-Dimensional Operative Video
Authors: Brock Andrea A , Kundu Bornali , Rolston John D
Published: December 2020

Asleep, image-guided deep brain stimulation (DBS) placement is rapidly gaining popularity because it offers greater patient comfort and comparable accuracy with frame-based methods using microelectrode recording.
1
In this video, we demonstrate our protocol to use the frameless, stereotactic ClearPoint system (MRI Interventions Inc, Irvine, California) to place DBS electrodes within an intraoperative magnetic resonance imaging hybrid operating suite (IMRIS; Deerfield Imaging Inc, Minnetonka, Minnesota).
1-4
This system uses a skull-mounted aiming device coupled with sequential, intraoperative magnetic resonance imaging guidance to direct DBS lead placement to subcortical targets.
2,5
Importantly, this method allows the patient to remain asleep during the operation and does not require medication holidays or additional microelectrode recording equipment. The literature indicates it has comparable accuracy
1,6
and outcomes
2
with the awake method. We demonstrate this technique with the case of a patient with Parkinson disease who required lead placement in the bilateral subthalamic nuclei.
7-9
The patient consented to the procedure and publication. Patient positioning, draping nuances, initial indirect targeting, and final direct targeting are demonstrated. Risks of the operation include a risk of hemorrhage, hardware failure, and infection.
10
DBS is currently an underutilized treatment option for patients with Parkinson disease.
11
Offering the asleep option may be more tolerable for many patients who are wary of awake surgery.
Innate immunology in COVID-19—a living review. Part II: dysregulated inflammation drives immunopathology
Authors: Rodrigues Patrícia R S , Alrubayyi Aljawharah , Pring Ellie , Bart Valentina M T , Jones Ruth , Coveney Clarissa , Lu Fangfang , Tellier Michael , Maleki-Toyserkani Shayda , Richter Felix C , Scourfield D Oliver , Gea-Mallorquí Ester , Davies Luke C
Published: December 2020

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dysregulated immune responses may contribute to disease progression. Here we have reviewed current knowledge of cellular innate immune responses to SARS-CoV-2 infection, highlighting areas for further investigation and suggesting potential strategies for intervention. We conclude that in severe COVID-19 initial innate responses, primarily type I interferon, are suppressed or sabotaged which results in an early interleukin (IL)-6, IL-10 and IL-1β-enhanced hyperinflammation. This inflammatory environment is driven by aberrant function of innate immune cells: monocytes, macrophages and natural killer cells dispersing viral pathogen-associated molecular patterns and damage-associated molecular patterns into tissues. This results in primarily neutrophil-driven pathology including fibrosis that causes acute respiratory distress syndrome. Activated leukocytes and neutrophil extracellular traps also promote immunothrombotic clots that embed into the lungs and kidneys of severe COVID-19 patients, are worsened by immobility in the intensive care unit and are perhaps responsible for the high mortality. Therefore, treatments that target inflammation and coagulation are promising strategies for reducing mortality in COVID-19.
Obstetric Anesthetic Management for Parturients with Hereditary Angioedema: A Case Report and Suggested Protocol
Authors: Clark Kathryn J , Sviggum Hans P , Jacob Adam K , Arendt Katherine W , Volcheck Gerald W , Szymanski Linda M , Sharpe Emily E
Published: December 2020

Hereditary angioedema (HAE) is a disease manifested by repeated episodes of localized submucosal or subcutaneous edematous episodes, potentially triggered by emotional stress, mechanical trauma, or intake of estrogens. We present our experience managing two parturients with HAE. Multidisciplinary care is essential for planning and executing the specialized care of these patients, and management included extensive planning among obstetric, anesthesiology, and allergy and immunology teams. Pregnancy has been shown to have a variable effect on triggering HAE episodes. First-line treatment includes C1 esterase inhibitor concentrate, which can also be used for prophylaxis in high-risk patients. Neuraxial analgesia is recommended to avoid general anesthesia and was established early in both individuals. Vaginal delivery was well tolerated without need for emergent treatment for angioedema symptoms.
Comparative risks of cardiovascular disease events among SLE patients receiving immunosuppressive medications
Authors: Choi May Y , Li Daniel , Feldman Candace H , Yoshida Kazuki , Guan Hongshu , Kim Seoyoung C , Everett Brendan M , Costenbader Karen H
Published: December 2020

Objectives

SLE patients have elevated cardiovascular disease (CVD) risk, but it is unclear whether this risk is affected by choice of immunosuppressive drug. We compared CVD risks among SLE patients starting MMF, CYC or AZA.

Methods

Using Medicaid Analytic eXtract (2000–2012), adult SLE patients starting MMF, CYC or AZA were identified and propensity scores (PS) were estimated for receipt of MMF vs CYC and MMF vs AZA. We examined rates of first CVD event (primary outcome), all-cause mortality, and a composite of first CVD event and all-cause mortality (secondary outcomes). After 1:1 PS-matching, Fine–Gray regression models estimated subdistribution hazard ratios (HRs.d.) for risk of CVD events. Cox regression models estimated HRs for all-cause mortality. The primary analysis was as-treated; 6- and 12-month intention-to-treat (ITT) analyses were secondary.

Results

We studied 680 PS-matched pairs of patients with SLE initiating MMF vs CYC and 1871 pairs initiating MMF vs AZA. Risk of first CVD event was non-significantly reduced for MMF vs CYC [HRs.d 0.72 (95% CI: 0.37, 1.39)] and for MMF vs AZA [HRs.d 0.88 (95% CI: 0.59, 1.32)] groups. In the 12-month ITT, first CVD event risk was lower among MMF than AZA new users [HRs.d 0.68 (95% CI: 0.47, 0.98)].

Conclusion

In this head-to-head PS-matched analysis, CVD event risks among SLE patients starting MMF vs CYC or AZA were not statistically reduced except in one 12-month ITT analysis of MMF vs AZA, suggesting longer-term use may convey benefit. Further studies of potential cardioprotective benefit of MMF are necessary.
Successes and challenges of implementing a lung cancer screening program in federally qualified health centers: a qualitative analysis using the Consolidated Framework for Implementation Research
Authors: Allen Caitlin G , Cotter Megan M , Smith Robert A , Watson Lesley
Published: December 2020

In recent years, studies have shown that low-dose computed tomography (LDCT) is a safe and effective way to screen high-risk adults for lung cancer. Despite this, uptake remains low, especially in limited-resource settings. The American Cancer Society (ACS) partnered with two federally qualified health centers and accredited screening facilities on a 2 year pilot project to implement an LDCT screening program. Both sites attempted to develop a referral program and care coordination practices to move patients through the screening continuum and identify critical facilitators and barriers to implementation. Evaluators conducted key informant interviews (N = 46) with clinical and administrative staff, as well as regional ACS staff during annual site visits. The Consolidated Framework for Implementation Research guided our analysis of factors associated with effective implementation and improved screening outcomes. One study site established a sustainable lung screening program, while the other struggled to overcome significant implementation barriers. Increased time spent with patients, disruption to normal workflows, and Medicaid reimbursement policies presented challenges at both sites. Supportive, engaged leaders and knowledgeable champions who provided clear implementation guidance improved staff engagement and were able to train, guide, and motivate staff throughout the intervention. A slow, stepwise implementation process allowed one site’s project champions to pilot test new processes and resolve issues before scaling up. This pilot study provides critical insights into the necessary resources and steps for successful lung cancer screening program implementation in underserved settings. Future efforts can build upon these findings and identify and address possible facilitators and barriers to screening program implementation.
A randomized controlled trial of online acceptance and commitment therapy to improve diet and physical activity among adults who are overweight/obese
Authors: Levin Michael E , Petersen Julie M , Durward Carrie , Bingeman Brittany , Davis Elizabeth , Nelson Cindy , Cromwell Shannon
Published: December 2020

Acceptance and commitment therapy (ACT) has shown benefit for improving diet, physical activity, and weight among adults who are overweight and obese. However, research to-date in this area has primarily evaluated ACT delivered through in-person interventions, which has more limited access relative to online formats. The present study evaluated an online guided self-help program that integrated ACT with nutrition education to improve healthy eating and physical activity. A sample of 79 adults who were overweight/obese was randomized to receive the 8-week ACT on Health program plus weekly phone coaching or to a waitlist. Participants completed 5.5 ACT sessions on average (out of 8) and reported moderately high program satisfaction. Participants in the ACT condition improved significantly more than the waitlist at posttreatment on the primary outcome of healthy eating index (HEI; based on 24-hr recall assessments) and almost all secondary outcomes assessing self-reported eating behaviors, weight, mental health, weight self-stigma, and psychological inflexibility. However, no intervention effects were found for self-reported physical activity. At 8-week follow-up, improvements were maintained for most outcomes in the ACT condition, but not for the HEI. Improvements in psychological inflexibility mediated treatment effects on some outcomes, but not HEI or weight. Overall, delivering ACT through online guided self-help combined with nutrition education appears promising for improving healthy eating, weight, and self-stigma, but results for physical activity and long-term behavior change are unclear, possibly due to limitations in the ACT on Health program.
The knockdown of LncRNA AFAP1-AS1 suppressed cell proliferation, migration, and invasion, and promoted apoptosis by regulating miR-545-3p/hepatoma-derived growth factor axis in lung cancer
Authors: Sun Jingping , Min Haiyan , Yu Lijiang , Yu Guiping , Shi Yujia , Sun Jinghua
Published: December 2020

Lung cancer is one of the most common human cancers. Long noncoding RNA AFAP1-AS1 (LncRNA AFAP1-AS1) and microRNA-545-3p (miR-545-3p) were reported to play important roles in lung cancer development. This study aimed to elucidate the functional mechanisms of AFAP1-AS1 and miR-545-3p in lung cancer. Quantitative real time polymerase chain reaction was carried out to determine the levels of AFAP1-AS1, miR-545-3p and hepatoma-derived growth factor (HDGF). Cell proliferation, apoptosis, migration and invasion were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide assay, flow cytometry, and transwell migration and invasion assays, respectively. Furthermore, the interaction between miR-545-3p and AFAP1-AS1 or HDGF was predicted by bioinformatics analysis software starbase and confirmed by the dual luciferase reporter assay. Western blot assay was used to detect the protein level of HDGF. Besides, murine xenograft model was conducted through injecting A549 cells transfected with sh-AFAP1-AS1. The expression levels of AFAP1-AS1 and HDGF were increased, while miR-545-3p was decreased in lung cancer tissues and cells. AFAP1-AS1 knockdown suppressed lung cancer cell proliferation, migration, and invasion and induced apoptosis. Furthermore, AFAP1-AS1 mediated cell progression through regulating miR-545-3p expression. In addition, miR-545-3p negatively regulated the expression level of HDGF via binding 3′-untranslated region of HDGF. As expected, AFAP1-AS1 knockdown inhibited lung cancer progression via affecting miR-545-3p/HDGF axis. Besides, AFAP1-AS1 knockdown suppressed lung cancer tumor growth in vivo. Collectively, our results suggested that AFAP1-AS1 promoted the development of lung cancer via regulating miR-545-3p/HDGF axis, providing a potential target for the treatment of lung cancer.
Lumbar Perforator Flaps for Coverage of Extensive Defects With Osteomyelitis
Authors: Schaffer Clara , Guillier David , Raffoul Wassim , di Summa Pietro G.
Published: December 2020

Introduction

Lumbar osteomyelitis is a rare, although serious condition if not appropriately treated, potentially leading to neurologic complications, such as radiculopathy. Traditionally, studies have suggested the preferred use of muscle or myocutaneous flaps to prevent recurrent infections. However, late evidence suggests that radical debridement and dead space obliteration are more important than the type of flap. The lumbar perforator flap is a reliable local option with low donor site morbidity. It is a powerful tool for local trunk reconstruction, but its use in case of osteomyelitis is scarcely described. We aimed to report long-term outcomes of lumbar perforator flaps to cover lumbar soft tissue defects with chronic osteomyelitis.

Material and Methods

This retrospective investigation was performed on a prospectively maintained database including 7 consecutive patients (10 flaps), all presenting extensive defects of the posterior midline at L2-S1 level (defect size 287 ± 136 cm2 [average ± SD]). Four patients presented defects after recurrent tumor resection, whereas in 2 patients, the defect was due to vascular jeopardy of internal iliac arteries with consequent necrosis. Last defect derived from debridement of a neglected wound in a paraplegic patient. All patients had concomitant bone infection. Infectious details and postoperative complications were recorded.

Results

Patients were in general poor medical condition (including peripheral arterial disease, hypertension, diabetes, or a combination of these). Eight flaps were raised as propeller perforator, whereas 2 as V-Y perforator. One propelled flap had venous congestion on postoperative day 1 and required a revision surgery to be converted to V-Y. Subsequent partial flap necrosis was treated conservatively. One patient presented a wound dehiscence that required surgical revision. All flaps were closed primarily except for 1 patient whose flap presented a mild intraoperative congestion, which was treated by delayed closure on postoperative day 6, with uneventful outcome. Time to complete healing was 29 ± 17 days (mean ± SD). No flap loss occurred, and all patients benefited from effective coverage at a mean follow-up of 20 months.

Conclusions

Lumbar perforator flap is a reliable option to cover large soft tissue defects in the lumbar area despite chronic osteomyelitis, with low morbidity and acceptable cosmetic outcome.
Disease control across urban–rural gradients
Authors: Wells Konstans , Lurgi Miguel , Collins Brendan , Lucini Biagio , Kao Rowland R. , Lloyd Alun L. , Frost Simon D. W. , Gravenor Mike B.
Published: December 2020

Controlling the regional re-emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after its initial spread in ever-changing personal contact networks and disease landscapes is a challenging task. In a landscape context, contact opportunities within and between populations are changing rapidly as lockdown measures are relaxed and a number of social activities re-activated. Using an individual-based metapopulation model, we explored the efficacy of different control strategies across an urban–rural gradient in Wales, UK. Our model shows that isolation of symptomatic cases or regional lockdowns in response to local outbreaks have limited efficacy unless the overall transmission rate is kept persistently low. Additional isolation of non-symptomatic infected individuals, who may be detected by effective test-and-trace strategies, is pivotal to reducing the overall epidemic size over a wider range of transmission scenarios. We define an ‘urban–rural gradient in epidemic size' as a correlation between regional epidemic size and connectivity within the region, with more highly connected urban populations experiencing relatively larger outbreaks. For interventions focused on regional lockdowns, the strength of such gradients in epidemic size increased with higher travel frequencies, indicating a reduced efficacy of the control measure in the urban regions under these conditions. When both non-symptomatic and symptomatic individuals are isolated or regional lockdown strategies are enforced, we further found the strongest urban–rural epidemic gradients at high transmission rates. This effect was reversed for strategies targeted at symptomatic individuals only. Our results emphasize the importance of test-and-trace strategies and maintaining low transmission rates for efficiently controlling SARS-CoV-2 spread, both at landscape scale and in urban areas.
Metarhizium: jack of all trades, master of many
Authors: St. Leger Raymond J. , Wang Jonathan B.
Published: December 2020

The genusMetarhiziumandPochonia chlamydosporiacomprise a monophyletic clade of highly abundant globally distributed fungi that can transition between long-term beneficial associations with plants to transitory pathogenic associations with frequently encountered protozoans, nematodes or insects. Some very common ‘specialist generalist’ species are adapted to particular soil and plant ecologies, but can overpower a wide spectrum of insects with numerous enzymes and toxins that result from extensive gene duplications made possible by loss of meiosis and associated genome defence mechanisms. These species use parasexuality instead of sex to combine beneficial mutations from separate clonal individuals into one genome (Vicar of Bray dynamics). More weakly endophytic species which kill a narrow range of insects retain sexuality to facilitate host–pathogen coevolution (Red Queen dynamics).Metarhiziumspecies can fit into numerous environments because they are very flexible at the genetic, physiological and ecological levels, providing tractable models to address how new mechanisms for econutritional heterogeneity, host switching and virulence are acquired and relate to diverse sexual life histories and speciation. Many new molecules and functions have been discovered that underpinMetarhiziumassociations, and have furthered our understanding of the crucial ecology of these fungi in multiple habitats.
Conexivisphaera calida gen. nov., sp. nov., a thermophilic sulfur- and iron-reducing archaeon, and proposal of Conexivisphaeraceae fam. nov., Conexivisphaerales ord. nov., and Conexivisphaeria class. nov. in the phylum Thaumarchaeota
Authors: Kato Shingo , Ohnishi Masafumi , Nagamori Mai , Yuki Masahiro , Takashina Tomonori , Ohkuma Moriya , Itoh Takashi
Published: December 2020

A thermoacidophilic, anaerobic, and iron- and sulfur-reducing archaeon, strain NAS-02T, was isolated from a terrestrial hot spring in Japan, as previously reported. This organism is the first non-ammonia-oxidizing isolate in the phylumThaumarchaeota. Here, we proposeConexivisphaera calidagen. nov., sp. nov. to accommodate this strain. The type strain of the type species is NAS-02T(=JCM 31663T=DSM 105898T). The values of 16S rRNA gene similarity and average amino acid identity between NAS-02Tand its closest relatives are <86 and <42 %, respectively. Based on the phylogeny and physiology, we propose the familyConexivisphaeraceaefam. nov., the orderConexivisphaeralesord. nov. and the classConexivisphaeriaclass. nov. to accommodate the novel genus.
Geomonas silvestris sp. nov., Geomonas paludis sp. nov. and Geomonas limicola sp. nov., isolated from terrestrial environments, and emended description of the genus Geomonas
Authors: Itoh Hideomi , Xu Zhenxing , Masuda Yoko , Ushijima Natsumi , Hayakawa Chie , Shiratori Yutaka , Senoo Keishi
Published: December 2020

Three bacterial strains, designated Red330T, Red736T and Red745T, were isolated from forest and paddy soils in Japan. Strains Red330T, Red736T and Red745T are flagella-harbouring and strictly anaerobic bacteria forming red colonies. A 16S rRNA gene sequence-based phylogenetic tree showed that all three strains were located in a cluster, including the type strains of

Geomonas

species, which were recently separated from the genus

Geobacter

within the family

Geobacteraceae

. Similarities of the 16S rRNA gene sequences among the three strains and

Geomonas oryzae

S43T, the type species of the genus

Geomonas

, were 96.3–98.5 %. The genome-related indexes, average nucleotide identity, digital DNA–DNA hybridization, and average amino acid identity, among the three strains and

G. oryza

e S43T were 74.7–86.8 %, 21.2–33.3 % and 70.4–89.8 %, respectively, which were lower than the species delineation thresholds. Regarding the phylogenetic relationships based on genome sequences, the three strains clustered with the type strains of

Geomonas

species, which were independent from the type strains of

Geobacter

species. The distinguishableness of the three isolated strains was supported by physiological and chemotaxonomic properties, with the profile of availability of electron donors and cellular fatty acids composition being particularly different among them. Based on genetic, phylogenetic and phenotypic properties, the three isolates represent three novel independent species in the genus

Geomonas

, for which the names Geomonas silvestris sp. nov., Geomonas paludis sp. nov. and Geomonas limicola sp. nov. are proposed. The type strains are Red330T (=NBRC 114028T=MCCC 1K03949T), Red736T (=NBRC 114029T=MCCC 1K03950T) and Red745T (=NBRC 114030T=MCCC 1K03951T), respectively.
Chronic cigarette smoke exposure and pneumococcal infection induce oropharyngeal microbiota dysbiosis and contribute to long-lasting lung damage in mice
Authors: Hilty Markus , Wüthrich Tsering M. , Godel Aurélie , Adelfio Roberto , Aebi Susanne , Burgener Sabrina S. , Illgen-Wilcke Brunhilde , Benarafa Charaf
Published: December 2020

Environmental factors, such as cigarette smoking or lung infections, may influence chronic obstructive pulmonary disease (COPD) progression by modifying the respiratory tract microbiome. However, whether the disease itself induces or maintains dysbiosis remains undefined. In this longitudinal study, we investigated the oropharyngeal microbiota composition and disease progression of mice (in cages of 5–10 mice per cage) before, during and up to 3 months after chronic cigarette smoke exposure or exposure to room air for 6 months. Cigarette smoke exposure induced pulmonary emphysema measurable at the end of exposure for 6 months, as well as 3 months following smoke exposure cessation. Using both classical culture methods and 16S rRNA sequencing, we observed that cigarette smoke exposure altered the relative composition of the oropharyngeal microbiota and reduced its diversity (P <0.001). More than 60 taxa were substantially reduced after 6 months of smoke exposure (P <0.001) However, oropharyngeal microbiota disordering was reversed 3 months after smoke exposure cessation and no significant difference was observed compared to age-matched control mice. The effects of lung infection with

Streptococcus pneumoniae

on established smoke-induced emphysema and on the oropharyngeal microbiota were also evaluated. Inoculation with

S. pneumoniae

induced lung damage and altered the microbiota composition for a longer time compared to control groups infected but not previously exposed to smoke (P=0.01). Our data demonstrate effects of cigarette smoke and pneumococcus infection leading to altered microbiota and emphysema development. The reversal of the disordering of the microbiota composition, but not lung damage, following smoke exposure cessation and after clearance of infection suggest that changes in lung structure are not sufficient to sustain a disordered microbiota in mice. Whether changes in the airway microbiota contribute to inducing emphysema requires further investigation.
The Defensive Behavior of Indiana Mite-Biting Honey Bees AgainstVarroa destructorand the Structure of Bee Mandibles
Authors: Smith Jada , Cleare Xaryn L. , Given Krispn , Li-Byarlay Hongmei
Published: December 2020

The honey bee (Apis mellifera) is the most important managed pollinator to sustainable agriculture and our ecosystem. Yet managed honey bee colonies in the United States experience 30–40% losses annually. Among the many biotic stressors, the parasitic miteVarroa destructoris considered one of the main causes of colony losses. Bees’ mite-biting behavior has been selected as aVarroa-tolerant orVarroa-resistant trait in the state of Indiana for more than a decade. A survey of damaged mites from the bottom of a colony can be used as an extended phenotype to evaluate the mite-biting behavior of a colony. In this study, on average, 37% of mites sampled from the breeding stocks of 59 colonies of mite biters in Indiana were damaged or mutilated, which is significantly higher than the 19% of damaged mites found in commercial colonies in the southern United States. Indiana mite biter colonies had a higher proportion of damaged mites, although among the damaged mites, the number of missing legs was not significantly higher. In addition, the morphology of pollen-forager worker bee mandibles was compared by X-ray microcomputed tomography for six parameters in two populations, and a difference was detected in one parameter. Our results provide scientific evidence that potentially explains the defensive mechanism againstVarroamites: structural changes in the worker bee mandibles.
Editing of the TRIM5 gene decreases the permissiveness of human T lymphocytic cells to HIV-1
Authors: Désaulniers Kevin , Ortiz Levine , Dufour Caroline , Claudel Alix , Plourde Mélodie B. , Merindol Natacha , Berthoux Lionel
Published: December 2020

TRIM5α is a cytoplasmic antiretroviral effector upregulated by type I interferons (IFN-I). We previously showed that two points mutations, R332G/R335G, in the retroviral capsid-binding region confer human TRIM5α the capacity to target and strongly restrict HIV-1 upon over-expression of the mutated protein. Here, we used CRISPR-Cas9-mediated homology-directed repair (HDR) to introduce these two mutations in the endogenous human TRIM5 gene. We found 6 out of 47 isolated cell clones containing at least one HDR-edited allele. One clone (Clone 6) had both alleles containing R332G but only one of the two alleles containing R335G. Upon challenge with an HIV-1 vector, clone 6 was significantly less permissive compared to unmodified cells, whereas the cell clones with monoallelic modifications were only slightly less permissive. Following IFN-β treatment, inhibition of HIV-1 infection in clone 6 was significantly enhanced (~40-fold inhibition). TRIM5α knockdown confirmed that HIV-1 was inhibited by the edited TRIM5 gene products. Quantification of HIV-1 reverse transcription products showed that inhibition occurred through the expected mechanism. In conclusion, we demonstrate the feasibility of potently inhibiting a viral infection through editing of innate effector genes. Our results also emphasize the importance of biallelic modification in order to reach significant levels of inhibition by TRIM5α.
On a wing and a prayer: limitations and gaps in global bat wing morphology trait data
Authors: Crane Matt , Silva Inês , Grainger Matthew J. , Gale George A.
Published: December 2020

Species’ life history traits have a wide variety of applications in ecological and conservation research, particularly when assessing threats. The development and growth of global species trait databases are critical for improving trait-based analyses; however, it is vital to understand the gaps and biases of available data. Bats are an extremely diverse and widely distributed mammalian order, with many species facing local declines and extinction. We conducted a literature review for bat wing morphology, specifically wing loading and aspect ratio, to identify issues with data reporting and ambiguity. We collected data on field methodology, trait terminology, and data reporting and quality. We found several issues regarding semantic ambiguity in trait definitions and data reporting. Globally we found that bat wing morphology trait coverage was low. Only six bat families had over 40% trait coverage, and of those none consisted of more than 11 total species. We found similar biases in trait coverage across IUCN Redlist categories with threatened species having lower coverage. Geographically, North America, Europe, and the Indomalayan regions showed higher overall trait coverage, while both the Afrotropical and Neotropical ecoregions showed poor trait coverage. The underlying biases and gaps with bat wing morphology data have implications for researchers conducting global trait-based assessments. Implementing imputation techniques may address missing data, but only for smaller regional subsets with substantial trait coverage. However, due to the low overall trait coverage, increasing species representation in the database should be prioritized. We suggest adopting an Ecological Trait Standard vocabulary to reduce semantic ambiguity in bat wing morphology traits to improve data compilation and clarity. Additionally, we advocate that researchers adopt an Open Science approach to facilitate the growth of a bat wing morphology trait database.
Molecular and physiological responses predict acclimation limits in juvenile brook trout (Salvelinus fontinalis)
Authors: Mackey Theresa E. , Hasler Caleb T. , Durhack Travis , Jeffrey Jennifer D. , Macnaughton Camille J. , Ta Kimberly , Enders Eva C. , Jeffries Ken M.
Published: December 2020

Brook trout (Salvelinus fontinalis) populations are at risk of exposure to high water temperatures in the species’ native range in eastern North America. We quantified the physiological and molecular responses of juvenile brook trout to six acclimation temperatures that span the thermal distribution of the species (5, 10, 15, 20, 23, and 25°C). Using quantitative PCR (qPCR), we measured the mRNA transcript abundance of temperature-induced cellular stress genes to identify a potential sub-lethal temperature threshold for brook trout between 20–23°C. Brook trout exhibited an upregulation of stress-related genes (heat shock protein 90-beta;heat shock cognate 71 kDa protein;glutathione peroxidase 1) and a downregulation of transcription factors and osmoregulation-related genes (Na+/K+/2Cl−co-transporter-1-a;nuclear protein 1) at temperatures ≥20°C. We also used respirometry to assess the effects of the acclimation temperatures on oxygen consumption. Standard metabolic rate results indicated that energy expenditure was higher at temperatures ≥20°C. We then examined the effects of acclimation temperature on metabolic rate and blood plasma parameters in fish exposed to an acute exhaustive exercise and air exposure stress. Fish acclimated to temperatures ≥20°C exhibited elevated levels of plasma cortisol, muscle lactate, and plasma glucose after exposure to the acute stressors. After 24 h of recovery, fish showed longer metabolic recovery times at 15 and 20°C and cortisol levels remaining elevated at temperatures ≥20°C. Our findings suggest that brook trout may have a limited ability to acclimate to temperatures >20°C and increases in temperatures beyond 20°C may impact brook trout populations.
An empirical evaluation of functional alignment using inter-subject decoding
Authors: Bazeille Thomas , DuPre Elizabeth , Richard Hugo , Poline Jean-Baptiste , Thirion Bertrand
Published: December 2020

Inter-individual variability in the functional organization of the brain presents a major obstacle to identifying generalizable neural coding principles. Functional alignment—a class of methods that matches subjects’ neural signals based on their functional similarity—is a promising strategy for addressing this variability. To date, however, a range of functional alignment methods have been proposed and their relative performance is still unclear. In this work, we benchmark five functional alignment methods for inter-subject decoding on four publicly available datasets. Specifically, we consider three existing methods: piecewise Procrustes, searchlight Procrustes, and piecewise Optimal Transport. We also introduce and benchmark two new extensions of functional alignment methods: piecewise Shared Response Modelling (SRM), and intra-subject alignment. We find that functional alignment generally improves inter-subject decoding accuracy though the best performing method depends on the research context. Specifically, SRM and Optimal Transport perform well at both the region-of-interest level of analysis as well as at the whole-brain scale when aggregated through a piecewise scheme. We also benchmark the computational efficiency of each of the surveyed methods, providing insight into their usability and scalability. Taking inter-subject decoding accuracy as a quantification of inter-subject similarity, our results support the use of functional alignment to improve inter-subject comparisons in the face of variable structure-function organization. We provide open implementations of all methods used.
Neuropredictome: a data-driven predictome for cognitive, psychiatric, medical, and lifestyle factors on the brain
Authors: Sultan Syed Fahad , Parodi Lilianne R. Mujica , Skiena Steven
Published: December 2020

Most neuroimaging studies individually provide evidence on a narrow aspect of the human brain function, on distinct data sets that often suffer from small sample sizes. More generally, the high technical and cost demands of neuroimaging studies (combined with the statistical unreliability of neuroimaging pilot studies) may lead to observational bias, discouraging discovery of less obvious associations that nonetheless have important neurological implications. To address these problems, we built a machine-learning based classification framework,NeuroPredictome, optimized for the reliability and robustness of its associations. NeuroPredictome is grounded in a large-scale dataset, UK-Biobank (N=19,831), which includes resting and task functional MRI as well as structural T1-weighted and diffusion tensor imaging. Participants were assessed with respect to a comprehensive set of 5,034 phenotypes, including the physical and lifestyle factors most relevant to general medicine. Results generated by data-driven classifiers were then cross-validated, using deep-learning textual analyses, against 14,371 peer-reviewed research articles, providing an unbiased hypothesis-generator of linkages between diverse phenotypes and the brain. Our results show that neuroimaging reveals as many neurological links to physical and lifestyle factors as to cognitive factors, supporting a more integrative approach to medicine that considers disease interactions between multiple organs and systems.
Distant Residues Modulate Conformational Opening in SARS-CoV-2 Spike Protein
Authors: Ray Dhiman , Le Ly , Andricioaei Ioan
Published: December 2020

Infection by SARS-CoV-2 involves the attachment of the receptor binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down-to-up conformational change in the spike protein, the change that presents the RBD to the receptor. To date, computational and experimental studies that search for therapeutics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and is therefore a hotspot for drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. This allows for a deeper understanding of the underlying molecular recognition events and prediction of the highest-effect key mutations in distant, allosteric sites, with implications for therapeutics. Also, these sites can appear in emerging mutants with possibly higher transmissibility and virulence, and pre-identifying them can give clues for designing pancoronavirus vaccines against future outbreaks. Our model, based on time-lagged independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD opening. Residues involved in the most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predictedab-initiofrom our model. Conversely, broad spectrum therapeutics like drugs and monoclonal antibodies can target these key distant-but-conserved regions of the spike protein.

Significance Statement

The novel coronavirus (SARS-CoV-2) pandemic resulted in the largest public health crisis in recent times. Significant drug design effort against SARS-CoV-2 is focused on the receptor binding domain (RBD) of the spike protein, although this region is highly prone to mutations causing therapeutic resistance. We applied deep data analysis methods on all-atom molecular dynamics simulations to identify key non-RBD residues that play a crucial role in spike-receptor binding and infection. textcol-orredBecause the non-RBD residues are typically conserved across multiple coronaviruses, they can be targeted by broad spectrum antibodies and drugs to treat infections from new strains that might appear during future epidemics.
Conserved tandem arginines for PbgA/YejM allowSalmonellato regulate LpxC and control lipopolysaccharide biogenesis during infection
Authors: Giordano Nicole P. , Mettlach Joshua A. , Dalebroux Zachary D.
Published: December 2020

Salmonella entericaserovar Typhimurium uses PbgA/YejM, a conserved multi-pass transmembrane protein with a soluble periplasmic domain (PD), to balance the glycerophospholipid (GPL) and lipopolysaccharide (LPS) concentrations within the outer membrane (OM). The lipid homeostasis and virulence defects ofpbgAΔ191-586mutants, which are deleted for the PD, can be suppressed by substitutions in three LPS regulators, LapB/YciM, FtsH, and LpxC. We reasoned thatS. Typhimurium uses the PbgA PD to regulate LpxC through functional interactions with LapB and FtsH. In the stationary phase of growth,pbgAΔ191-586mutants accumulated LpxC and overproduced LPS precursors, known as lipid A-core molecules. Trans-complementation fully decreased the LpxC and lipid A-core levels for the mutants, while substitutions in LapB, FtsH, and LpxC variably reduced the concentrations. PbgA binds lipid A-core, in part, using dual arginines, R215 and R216, which are located near the plasma membrane. Neutral, conservative, and non-conservative substitutions were engineered at these positions to test whether the side-chain charges for residues 215 and 216 influenced LpxC regulation. Salmonellae that expressed PbgA with dual alanines or aspartic acids overproduced LpxC, accumulated lipid A-core and short-LPS molecules, and were severely attenuated in mice. Bacteria that expressed PbgA with tandem lysines were fully virulent in mice and yielded LpxC and lipid A-core levels that were similar to the wild type. Thus,S.Typhimurium uses the cationic charge of PbgA R215 and R216 to down-regulate LpxC and decrease lipid A-core biosynthesis in response to host stress and this regulatory mechanism enhances their virulence during bacteremia.

IMPORTANCE

Salmonella entericaserovar Typhimurium causes self-limiting gastroenteritis in healthy individuals and severe systemic disease in immunocompromised humans. The pathogen manipulates the immune system of its host by regulating the lipid, protein, and polysaccharide content of the outer membrane (OM) bilayer. Lipopolysaccharides (LPS) comprise the external leaflet of the OM, and are essential for establishing the OM barrier and providing gram-negative microbes with intrinsic antimicrobial resistance. LPS molecules are potent endotoxins and immunomodulatory ligands that bind host-pattern receptors, which control host resistance and adaptation during infection. Salmonellae use the cationic charge of dual arginines for PbgA/YejM to negatively regulate LPS biosynthesis. The mechanism involves PbgA binding to an LPS precursor and activating a conserved multi-protein signal transduction network that cues LpxC proteolysis, the rate-limiting enzyme. The cationic charge of the tandem arginines is critical for the ability of salmonellae to survive intracellularly and to cause systemic disease in mice.