bluuebunny/crossref_metadata_2025 huggingface dataset:
BFF and cellhashR: analysis tools for accurate demultiplexing of cell hashing data
Authors: Boggy Gregory J , McElfresh G W , Mahyari Eisa , Ventura Abigail B , Hansen Scott G , Picker Louis J , Bimber Benjamin N
Published: April 2022

Motivation

Single-cell sequencing methods provide previously impossible resolution into the transcriptome of individual cells. Cell hashing reduces single-cell sequencing costs by increasing capacity on droplet-based platforms. Cell hashing methods rely on demultiplexing algorithms to accurately classify droplets; however, assumptions underlying these algorithms limit accuracy of demultiplexing, ultimately impacting the quality of single-cell sequencing analyses.

Results

We present Bimodal Flexible Fitting (BFF) demultiplexing algorithms BFFcluster and BFFraw, a novel class of algorithms that rely on the single inviolable assumption that barcode count distributions are bimodal. We integrated these and other algorithms into cellhashR, a new R package that provides integrated QC and a single command to execute and compare multiple demultiplexing algorithms. We demonstrate that BFFcluster demultiplexing is both tunable and insensitive to issues with poorly behaved data that can confound other algorithms. Using two well-characterized reference datasets, we demonstrate that demultiplexing with BFF algorithms is accurate and consistent for both well-behaved and poorly behaved input data.

Availability and implementation

cellhashR is available as an R package at https://github.com/BimberLab/cellhashR. cellhashR version 1.0.3 was used for the analyses in this manuscript and is archived on Zenodo at https://www.doi.org/10.5281/zenodo.6402477.

Supplementary information

Supplementary data are available at Bioinformatics online.
Widespread cortical functional disconnection in gliomas: an individual network mapping approach
Authors: Silvestri Erica , Moretto Manuela , Facchini Silvia , Castellaro Marco , Anglani Mariagiulia , Monai Elena , D’Avella Domenico , Della Puppa Alessandro , Cecchin Diego , Bertoldo Alessandra , Corbetta Maurizio
Published: April 2022

Assessment of impaired/preserved cortical regions in brain tumours is typically performed via intraoperative direct brain stimulation of eloquent areas or task-based functional MRI. One main limitation is that they overlook distal brain regions or networks that could be functionally impaired by the tumour. This study aims (i) to investigate the impact of brain tumours on the cortical synchronization of brain networks measured with resting-state functional magnetic resonance imaging (resting-state networks) both near the lesion and remotely and (ii) to test whether potential changes in resting-state networks correlate with cognitive status. The sample included 24 glioma patients (mean age: 58.1 ± 16.4 years) with different pathological staging. We developed a new method for single subject localization of resting-state networks abnormalities. First, we derived the spatial pattern of the main resting-state networks by means of the group-guided independent component analysis. This was informed by a high-resolution resting-state networks template derived from an independent sample of healthy controls. Second, we developed a spatial similarity index to measure differences in network topography and strength between healthy controls and individual brain tumour patients. Next, we investigated the spatial relationship between altered networks and tumour location. Finally, multivariate analyses related cognitive scores across multiple cognitive domains (attention, language, memory, decision making) with patterns of multi-network abnormality. We found that brain gliomas cause broad alterations of resting-state networks topography that occurred mainly in structurally normal regions outside the tumour and oedema region. Cortical regions near the tumour often showed normal synchronization. Finally, multi-network abnormalities predicted attention deficits. Overall, we present a novel method for the functional localization of resting-state networks abnormalities in individual glioma patients. These abnormalities partially explain cognitive disabilities and shall be carefully navigated during surgery.
Heterosubtypic, cross-reactive immunity to human Cytomegalovirus glycoprotein B
Authors: Bilgilier Ceren , Schneider Martina , Kührer Kristina , Kilb Normann , Hartl Ramona , Topakian Thais , Kastner Marie-Theres , Herz Tobias , Nelson Cody S , Permar Sallie R , Roth Günter , Steininger Christoph
Published: April 2022

Cytomegalovirus (CMV) genome is highly variable and heterosubtypic immunity should be considered in vaccine development since it can enhance protection in a cross-reactive manner. Here, we developed a protein array to evaluate heterosubtypic immunity to CMV glycoprotein B (gB) in natural infection and vaccination. DNA sequences of four antigenic domains (AD1, AD2, AD4/5, and AD5) of gB were amplified from six reference and 12 clinical CMV strains, and the most divergent genotypes were determined by phylogenetic analysis. Assigned genotypes were in vitro translated and immobilized on protein array. Then, we tested immune response of variable serum groups (primarily infected patients, reactivated CMV infections and healthy individuals with latent CMV infection, as well gB-vaccinated rabbits) with protein in situ array (PISA). Serum antibodies of all patient cohorts and gB-vaccinated rabbits recognized many genetic variants of ADs on protein array, including but not limited to the subtype of infecting strain. High-grade cross-reactivity was observed. In several patients, we observed none or neglectable immune response to AD1 and AD2, while the same patients showed high antibody response to AD4/5 and AD5. Among the primary infected patients, AD5 was the predominant AD, in antibody response. The most successful CMV vaccine to date contains gB and demonstrates only 50% efficacy. In this study, we showed that heterosubtypic and cross-reactive immunity to CMV gB is extensive. Therefore, the failure of CMV gB vaccines cannot be explained by a highly, strain-specific immunity. Our observations suggest that other CMV antigens should be addressed in vaccine design.
The fecal shield is a double-edged sword for larvae of a leaf beetle
Authors: Huang Zheng-Zhong , Dong Ze-Qun , Liang Zu-Long , Zhang Bin , Xue Huai-Jun , Ge Si-Qin
Published: April 2022

Larvae of some leaf beetles carry masses of feces covering parts or all of the body, which is called a “fecal shield”. In general, the shield is thought to be a defense structure against natural enemies. However, some studies have suggested that defense effectiveness varies depending on the natural enemy. In this study, we used a fecal retention leaf beetle Ophrida xanthospilota (Coleoptera: Chrysomelidae), and 2 local generalist predators (an ant, Camponotus japonicus (Hymenoptera: Formicidae) and a stinkbug, Arma custos [Hemiptera: Pentatomidae]) as a system to test the hypothesis that the fecal shield of O. xanthospilota plays different roles in predation behavior of different predators and can provide multiple chemical communication signals in predator–prey interactions. Prey bioassays showed that the fecal shield of O. xanthospilota larvae repelled the ant C. japonicus while attracting the stinkbug A. custos. The results also strongly demonstrated that hexane extracts of the fecal shield significantly repelled C. japonicus, while dichloromethane (DCM) extracts did not inhibit ant predation. Interestingly, DCM extracts attracted A. custos, but hexane extracts did not. Therefore, we suggest that the fecal shield is a double-edged sword for the larvae of O. xanthospilota. Our results also indicated that the risk–benefit tradeoff of an insect should be estimated at a community level involving multiple enemies (predators and parasites) and herbivores, rather than in a single prey–predator pair.
The Epigraph Effect: A Digital Humanities Approach to Literary Influence and Tradition
Authors: Matthews Graham , Bond Francis
Published: April 2022

It is common to discover an epigraph in the opening pages of a novel that highlights one or more of the major themes and denotes the influence of another author on the composition of the text. Yet, the inclusion of an epigraph also bestows prestige on the citing text – helping the author to select his or her place in the wider literary tradition – and situates the text in a particular genre or historical period. In order to trace the development of what Gérard Genette dubbed the ‘epigraph effect’, we collected 16,963 epigraphs and recorded their provenance (author, work, date, and country of origin). This collection enables us to trace intertextual connections between authors throughout literary history and national traditions.
Reviving the view: evidence that macromolecule synthesis fuels bacterial spore germination
Authors: Zhou Bing , Alon Sima , Rao Lei , Sinai Lior , Ben-Yehuda Sigal
Published: April 2022

The Gram positive bacterium Bacillus subtilis and its relatives are capable of forming a durable dormant long-lasting spore. Although spores can remain dormant for years, they possess the remarkable capacity to rapidly resume life and convert into actively growing cells. This cellular transition initiates with a most enigmatic irreversible event, termed germination, lasting only for a few minutes. Germination is typified by a morphological conversion that culminates in loss of spore resilient properties. Yet, the molecular events occurring during this brief critical phase are largely unknown. The current widely accepted view considers germination to occur without the need for any macromolecule synthesis; however, accumulating data from our laboratory and others, highlighted here, provide evidence that both transcription and translation occur during germination and are required for its execution. We further underline numerous overlooked studies, conducted mainly during the 1960s–1970s, reinforcing this notion. We propose to revisit the fascinating process of spore germination and redefine it as a pathway involving macromolecule synthesis. We expect our perspective to shed new light on the awakening process of a variety of spore-forming environmental, commensal, and pathogenic bacteria and possibly be applicable to additional organisms displaying a quiescent life form.
Effects of Pre-Bunching Trees With a Tethered Feller-Buncher on Cable Logging Productivity and Costs: A Case Study in Southern Oregon
Authors: Chung Woodam , Morrissette Brett , Green Preston , Garrelts Brennan , Leshchinsky Ben , Belart Francisca , Sessions John , Wimer Jeff , Garland John
Published: April 2022

Winch-assist or tethered logging technology is rapidly being adopted by the forest industry across the western United States to replace conventional and dangerous manual tree falling in cable logging areas. Although the safety benefits of the technology are widely acknowledged, the effects of tethered mechanized timber falling and pre-bunching on the subsequent cable yarding operations have not been thoroughly investigated. We conducted a field study in southern Oregon to compare manual versus mechanized timber falling side-by-side for their impacts on the productivity and costs of cable logging operations. Our study shows that the costs of mechanized timber falling were higher than manual falling owing to high costs of tether equipment, but the ability of the felling machine to pre-bunch trees into piles along designated skyline corridors made subsequent cable yarding operations significantly more efficient. The efficiency gained during yarding was sufficient not only to offset cost increase in felling but also to reduce the total production costs of felling and yarding operations by 32% compared with cable yarding after manual timber falling.
A homing suppression gene drive with multiplexed gRNAs maintains high drive conversion efficiency and avoids functional resistance alleles
Authors: Yang Emily , Metzloff Matthew , Langmüller Anna M , Xu Xuejiao , Clark Andrew G , Messer Philipp W , Champer Jackson
Published: April 2022

Gene drives are engineered alleles that can bias inheritance in their favor, allowing them to spread throughout a population. They could potentially be used to modify or suppress pest populations, such as mosquitoes that spread diseases. CRISPR/Cas9 homing drives, which copy themselves by homology-directed repair in drive/wild-type heterozygotes, are a powerful form of gene drive, but they are vulnerable to resistance alleles that preserve the function of their target gene. Such resistance alleles can prevent successful population suppression. Here, we constructed a homing suppression drive in Drosophila melanogaster that utilized multiplexed gRNAs to inhibit the formation of functional resistance alleles in its female fertility target gene. The selected gRNA target sites were close together, preventing reduction in drive conversion efficiency. The construct reached a moderate equilibrium frequency in cage populations without apparent formation of resistance alleles. However, a moderate fitness cost prevented elimination of the cage population, showing the importance of using highly efficient drives in a suppression strategy, even if resistance can be addressed. Nevertheless, our results experimentally demonstrate the viability of the multiplexed gRNAs strategy in homing suppression gene drives.
Psychometric Properties of The Five-Item Victimization of Exploitation (FIVE) Scale: A Measure of Financial Abuse of Older Adults
Authors: Hancock David W , Burnes David P R , Pillemer Karl A , Czaja Sara J , Lachs Mark S
Published: April 2022

Background and Objectives

Elder mistreatment affects at least 1 in 10 older adults. Financial abuse, or exploitation, of older adults is among the most commonly reported forms of abuse. Few validated measures exist to measure this construct. We aim to present a new psychometrically validated measure of financial abuse of older adults.

Research Design and Methods

Classical test theory and item response theory (IRT) methodologies were used to examine a five-item measure of financial abuse of older adults, administered as part of the New York State Elder Mistreatment Survey.

Results

Factor analysis revealed a single factor best fits the data, which we labeled as financial abuse. Moreover, IRT analyses revealed that these items discriminated well between abused and nonabused persons and provided information at high levels of the latent trait θ, as is expected in cases of abuse.

Discussion and Implications

The Five-Item Victimization of Exploitation Scale has acceptable psychometric properties and has been used successfully in large-scale survey research. We recommend this measure as an indicator of financial abuse in elder abuse, or mistreatment prevalence research studies.
Eclipse timing modelling of three post-common envelope binaries: hybrid solutions
Authors: Mai Xinyu , Mutel Robert L
Published: April 2022

We report 90 new observations of three post-common envelope binaries at primary eclipse spanning between 2018 December and 2022 February. We combine recent primary eclipse timing observations with previously published values to search for substellar circumbinary components consistent with timing variations from a linear ephemeris. We used a least-squares minimization fitting algorithm weighted by a Hill orbit stability function, followed by Bayesian inference, to determine best-fitting orbital parameters and associated uncertainties. For HS2231+2441, we find that the timing data are consistent with a constant period and that there is no evidence to suggest orbiting components. For HS0705 + 6700, we find both one- and two-component solutions stable for at least 10 Myr. For HW Vir, we find three- and four-component solutions that fit the timing data reasonably well, but are unstable on short time-scales, and therefore highly improbable. Conversely, solutions calculated using a Bayesian orbit stability prior result in a poor fit. The stable solutions significantly deviate from the ensemble timing data in both systems. We speculate that the observed timing variations for these systems, and very possibly other sdB binaries, may result from a combination of substellar component perturbations and an Applegate–Lanza mechanism.
The velocity statistics of turbulent clouds in the presence of gravity, magnetic fields, radiation, and outflow feedback
Authors: Hu Yue , Federrath Christoph , Xu Siyao , Mathew Sajay Sunny
Published: April 2022

The interaction of turbulence, magnetic fields, self-gravity, and stellar feedback within molecular clouds is crucial for understanding star formation. We study the effects of self-gravity and outflow feedback on the properties of the turbulent velocity via the SF over length-scales from ∼0.01 to 2 pc. We analyse a series of three-dimensional, magnetohydrodynamical (MHD) simulations of star cluster formation. We find outflow feedback can change the scaling of velocity fluctuations but still roughly being in between Kolmogorov and Burgers turbulence. We observe that self-gravity and protostellar outflows increase the velocity fluctuations over all length-scales. Outflows can amplify the velocity fluctuations by up to a factor of ∼7 on scales ∼0.01–0.2 pc and drive turbulence up to a scale of ∼1 pc. The amplified velocity fluctuations provide more support against gravity and enhance fragmentation on small scales. The self-gravity’s effect is more significant on smaller dense clumps and it increases the fraction of the compressive velocity component up to a scale of ∼0.2 pc. However, outflow feedback drives both solenoidal and compressive modes, but it induces a higher fraction of solenoidal modes relative to compressive modes. Thus, with outflows, the dense core ends up with a slightly higher fraction of solenoidal modes. We find that the compressible fraction is fairly constant with about 1/3 on scales ∼0.1–0.2 pc. The combined effect of enhanced velocity dispersion and reduced compressive fraction contributes to a reduction in the star formation rate.
Avoidance of Emergency Care in the Southeastern United States During the COVID-19 Pandemic
Authors: Gettler Erin , Stern Rebecca , Ni Bin , Munro Heather M , Steinwandel Mark , Aronoff David M , Gupta Deepak K , Sanderson Maureen , Shrubsole Martha J , Lipworth Loren
Published: April 2022

In a low-income cohort in the Southeastern United States, 5% of participants avoided emergency medical care during the coronavirus disease 2019 pandemic, primarily due to fear and visitor restrictions. Younger age, self-perceived lower health status, lack of a personal doctor, and decreased income were associated with greater likelihood of deferring emergency care.
Tonic endocannabinoid signaling supports sleep through development in both sexes
Authors: Martin Shenée C , Gay Sean M , Armstrong Michael L , Pazhayam Nila M , Reisdorph Nichole , Diering Graham H
Published: April 2022

Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in juvenile and adolescent mice of both sexes. We find that eCBs lack a daily rhythm in juvenile mice, while in adolescents AEA and related oleoyl ethanolamide are increased during the sleep phase in a circadian manner. Next, we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a noninvasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark-phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep-promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.
Enteric methane mitigation interventions
Authors: Fouts Julia Q , Honan Mallory C , Roque Breanna M , Tricarico Juan M , Kebreab Ermias
Published: April 2022

Mitigation of enteric methane (CH4) presents a feasible approach to curbing agriculture’s contribution to climate change. One intervention for reduction is dietary reformulation, which manipulates the composition of feedstuffs in ruminant diets to redirect fermentation processes toward low CH4 emissions. Examples include reducing the relative proportion of forages to concentrates, determining the rate of digestibility and passage rate from the rumen, and dietary lipid inclusion. Feed additives present another intervention for CH4 abatement and are classified based on their mode of action. Through inhibition of key enzymes, 3-nitrooxypropanol (3-NOP) and halogenated compounds directly target the methanogenesis pathway. Rumen environment modifiers, including nitrates, essential oils, and tannins, act on the conditions that affect methanogens and remove the accessibility of fermentation products needed for CH4 formation. Low CH4-emitting animals can also be directly or indirectly selected through breeding interventions, and genome-wide association studies are expected to provide efficient selection decisions. Overall, dietary reformulation and feed additive inclusion provide immediate and reversible effects, while selective breeding produces lasting, cumulative CH4 emission reductions.
Stand-Alone Cage Versus Anterior Plating for 1-Level and 2-Level Anterior Cervical Discectomy and Fusion
Authors: Zavras Athan G. , Nolte Michael T. , Sayari Arash J. , Singh Kern , Colman Matthew W.
Published: April 2022

Study Design:

Prospective, randomized controlled trial.

Objective:

The aim was to compare perioperative and radiographic outcomes between stand-alone and anterior plated 1 and 2-level anterior cervical discectomy and fusion (ACDF).

Summary of Background Data:

ACDF with interbody spacer and separate plate/screw construct (PLATE) may be associated with a higher incidence of postoperative dysphagia, increased operative time, and other complications. Therefore, some have opted to utilize an interbody cage with integrated screws and no plate (CAGE) with good results.

Materials and Methods:

Patients with 1-level to 2-level degenerative disease were prospectively enrolled and randomized into 1 of 2 treatment arms consisting of either PLATE or CAGE reconstruction. Patients were followed for a minimum of 1 year postoperatively. Primary endpoints included improvement on patient-reported outcome metrics, construct integrity, cervical alignment, successful arthrodesis, and subsequent revision surgeries.

Results:

Forty-six patients were included: 12 with 1-level PLATE, 12 with 1-level CAGE, 12 with 2-level PLATE, and 10 with 2-level CAGE. For 1-level ACDF, PLATE patients reported worse swallow function on Swallowing Quality of Life Questionnaire at 6 weeks (P=0.050) and 6 months (P=0.042). Pseudarthrosis requiring revision was observed in one PLATE patient. For 2-level ACDF CAGE patients reported worse disability on neck disability index (P=0.037) at 6 weeks, as well as worse neck disability index (P=0.017) and visual analog scale neck (P=0.010) at 6 months. However, PLATE patients reported worse swallow function on Swallowing Quality of Life Questionnaire at 6 weeks (P=0.038). There were no differences in the rates of fusion, loss of disc height correction, subsidence, or in sagittal parameters between cohorts for both 1-level and 2-level ACDF.

Conclusion:

There was greater incidence of transient postoperative dysphagia in both single and 2-level PLATE cohorts. However, early postoperative outcomes were worse for 2-level CAGE in certain patient-reported metrics. This suggests that although anterior instrumentation may be associated with a higher likelihood of dysphagia, it may also lead to higher short-term stability and improved patient-reported outcomes for 2-level fusion.
Beyond Vaccination Rates: A Synthetic Random Proxy Metric of Total SARS-CoV-2 Immunity Seroprevalence in the Community
Authors: Si Yajuan , Covello Leonard , Wang Siquan , Covello Theodore , Gelman Andrew
Published: April 2022

Background:

Explicit knowledge of total community-level immune seroprevalence is critical to developing policies to mitigate the social and clinical impact of SARS-CoV-2. Publicly available vaccination data are frequently cited as a proxy for population immunity, but this metric ignores the effects of naturally acquired immunity, which varies broadly throughout the country and world. Without broad or random sampling of the population, accurate measurement of persistent immunity post-natural infection is generally unavailable.

Methods:

To enable tracking of both naturally acquired and vaccine-induced immunity, we set up a synthetic random proxy based on routine hospital testing for estimating total immunoglobulin G (IgG) prevalence in the sampled community. Our approach analyzed viral IgG testing data of asymptomatic patients who presented for elective procedures within a hospital system. We applied multilevel regression and poststratification to adjust for demographic and geographic discrepancies between the sample and the community population. We then applied state-based vaccination data to categorize immune status as driven by natural infection or by vaccine.

Results:

We validated the model using verified clinical metrics of viral and symptomatic disease incidence to show the expected biologic correlation of these entities with the timing, rate, and magnitude of seroprevalence. In mid-July 2021, the estimated immunity level was 74% with the administered vaccination rate of 45% in the two counties.

Conclusions:

Our metric improves real-time understanding of immunity to COVID-19 as it evolves and the coordination of policy responses to the disease, toward an inexpensive and easily operational surveillance system that transcends the limits of vaccination datasets alone.
A Study of a Novel Controlled Focal Septa Release Method for Improving Cellulite
Authors: Layt Craig
Published: April 2022

Background:

Cellulite is a common and often emotionally distressing condition among affected individuals. The dimpled appearance is caused by fibrous connective tissue, or septa, which tether the dermis to underlying fascia. A novel, minimally invasive, controlled focal septa release method was developed to selectively identify, target and manually release the tethers in a precise manner from a single insertion point (Revelle Aesthetics). The following pilot study evaluated the safety and feasibility of this method for treating subjects with moderate-to-severe cellulite.

Methods:

Female subjects (N = 10), 21–55 years old underwent unilateral controlled, focal fibrous septa release on the buttocks and thighs. Local anesthesia was administered using standard techniques. Cellulite depressions were marked with the subject standing at rest. Target septa were identified in the marked areas by applying tension with the device to reproduce the dimple appearance on the skin. Once identified, the contributing septa were severed with the device. For eight subjects, access was achieved with one small incision in the gluteal crease. Study assessments occurred on posttreatment days 1, 3, 14, 30, and 90.

Results:

All procedures were successfully completed with no serious or unexpected adverse events and the procedure was well tolerated. Mild adverse events were transient bruising and soreness. Target septa can be visualized on the skin by applying tension with the device. Multiple depressions can be treated from a single entry point.

Conclusion:

These results confirm the safety and feasibility of the controlled focal fibrous septa release method to treat moderate and severe cellulite. Additional trials are ongoing.
The Pathogenesis of Pierre Robin Sequence through a Review of SOX9 and Its Interactions
Authors: Al-Qattan Mohammad M. , Almohrij Saad A.
Published: April 2022

Background:

The literature does not offer any review of the pathogenesis of the clinical features of syndromes with Pierre Robin sequence (PRS). The senior author (MMA) proposed a hypothesis that SOX9 and its interactions may play a key role in this pathogenesis. The current review aims to test this hypothesis.

Methods:

Three literature searches were made: the first aimed to document the main syndromes associated with PRS; and the second was to document the main functions of SOX9 in development; and the third was to investigate if SOX9 and its interactions may play a role in the pathogenesis.

Results:

SOX9 is the main positive regulator in the development of the mandibular cartilage and it also enhances collagen type II (the main collagen type in cartilage) expression in the mandibular cartilage. Furthermore, SOX9 participates in neural crest development, binds to the exon junction complex, and participates in sex determination. The interactions of SOX9 could explain the pathogenesis of the clinical features of syndromic PRS. These included interactions with collagen type II (in Strickler syndrome), exon junction complex (in Richier-Costa–Periera syndrome), glucose (in Catel–Manzke syndrome), RNA-binding proteins (in TARP syndrome), and the spliceosome (in cerebra-costo-mandibular syndrome). Finally, SOX9 mutations cause campomelic dysplasia.

Conclusions:

The review supports the hypothesis of the participation of SOX9 in the pathogenesis of the clinical features of syndromic and nonsyndromic PRS. This should guide future research on the topic.
Modeling a Lossy Dieletric Polymer-based Thermoacoustic High Power Microwave Directed Energy Exposure Detection System
Authors: Frey James J. , Cobb Richard G. , McClory John W.
Published: April 2022

Presented are design considerations for a potential detection and measurement technique that could provide operational awareness of high power microwave (HPM) directed energy weapon exposure for force health protection applications, leveraging thermoacoustic (TA) wave generation as the field interaction mechanism. The HPM electromagnetic frequency (EMF) regime, used in applications in both the counter-materiel and non-lethal counter-personnel design space, presents real-time personnel exposure warning challenges due to the potentially wide variation in time and frequency domain characteristics of the incident beam. As with other EM-thermal interactions, the thermoacoustic wave effect provides the potential to determine EM energy and power deposition without the need to measure ambient field intensity values or overload-sensitive EMF survey equipment. Following measurement of relevant EM, thermal, and elastic material property values, a carbon-filled polytetrafluoroethylene (CF-PTFE) lossy dielectric medium subject to pulsed HPM was computationally modeled using the commercial finite element method multi-physics simulation software package COMSOL. The simulation was used to explore the impacts of various material properties on TA signal output as a function of simulated incident field power density, EM frequency, and pulse length, thereby informing the selection of system components for the further development of a full TA-based HPM detection chain.
Endoscopic Balloon Dilation of Gastric Stenosis secondary to Polyarteritis Nodosa and Arterial Thrombosis in an Adolescent
Authors: Peña-Vélez Rubén , Roldán-Montijo Mariana , Imbett-Yepez Sharon , Ramírez-Mayans Jaime , Loredo-Mayer Alejandro , Montijo-Barrios Ericka
Published: April 2022

A 13-year-old female with polyarteritis nodosa underwent a partial gastrectomy for ischemic necrosis and gastric perforation following left gastric artery thrombosis. She later presented with vomiting, early satiety, weight loss, and severe malnutrition, when she was diagnosed with an occlusive gastric stricture. She successfully underwent repeated therapeutic endoscopic balloon dilations until the endpoint of 15–18 mm lumen was achieved without any complications, and her symptoms resolved.
Prehospital synergy: Tranexamic acid and blood transfusion in patients at risk for hemorrhage
Authors: Deeb Andrew-Paul , Hoteit Lara , Li Shimena , Guyette Francis X. , Eastridge Brian J. , Nirula Raminder , Vercruysse Gary A. , O’Keeffe Terence , Joseph Bellal , Neal Matthew D. , Sperry Jason L. , Brown Joshua B.
Published: April 2022

BACKGROUND

Growing evidence supports improved survival with prehospital blood products. Recent trials show a benefit of prehospital tranexamic acid (TXA) administration in select subgroups. Our objective was to determine if receiving prehospital packed red blood cells (pRBC) in addition to TXA improved survival in injured patients at risk of hemorrhage.

METHODS

We performed a secondary analysis of all scene patients from the Study of Tranexamic Acid during Air and ground Medical Prehospital transport trial. Patients were randomized to prehospital TXA or placebo. Some participating EMS services utilized pRBC. Four resuscitation groups resulted: TXA, pRBC, pRBC+TXA, and neither. Our primary outcome was 30-day mortality and secondary outcome was 24-hour mortality. Cox regression tested the association between resuscitation group and mortality while adjusting for confounders.

RESULTS

A total of 763 patients were included. Patients receiving prehospital blood had higher Injury Severity Scores in the pRBC (22 [10, 34]) and pRBC+TXA (22 [17, 36]) groups than the TXA (12 [5, 21]) and neither (10 [4, 20]) groups (p < 0.01). Mortality at 30 days was greatest in the pRBC+TXA and pRBC groups at 18.2% and 28.6% compared with the TXA only and neither groups at 6.6% and 7.4%, respectively. Resuscitation with pRBC+TXA was associated with a 35% reduction in relative hazards of 30-day mortality compared with neither (hazard ratio, 0.65; 95% confidence interval, 0.45–0.94; p = 0.02). No survival benefit was observed in 24-hour mortality for pRBC+TXA, but pRBC alone was associated with a 61% reduction in relative hazards of 24-hour mortality compared with neither (hazard ratio, 0.39; 95% confidence interval, 0.17–0.88; p = 0.02).

CONCLUSION

For injured patients at risk of hemorrhage, prehospital pRBC+TXA is associated with reduced 30-day mortality. Use of pRBC transfusion alone was associated with a reduction in early mortality. Potential synergy appeared only in longer-term mortality and further work to investigate mechanisms of this therapeutic benefit is needed to optimize the prehospital resuscitation of trauma patients.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Developing a National Trauma Research Action Plan: Results from the geriatric research gap Delphi survey
Authors: Joseph Bellal , Saljuqi Abdul Tawab , Phuong Jimmy , Shipper Edward , Braverman Maxwell A. , Bixby Pamela J. , Price Michelle A. , Barraco Robert D. , Cooper Zara , Jarman Molly , Lack William , Lueckel Stephanie , Pivalizza Evan , Bulger Eileen ,   the Geriatric Trauma Panel
Published: April 2022

BACKGROUND

Treating older trauma patients requires a focus on the confluence of age-related physiological changes and the impact of the injury itself. Therefore, the primary way to improve the care of geriatric trauma patients is through the development of universal, systematic multidisciplinary research. To achieve this, the Coalition for National Trauma Research has developed the National Trauma Research Action Plan that has generated a comprehensive research agenda spanning the continuum of geriatric trauma care from prehospital to rehabilitation.

METHODS

Experts in geriatric trauma care and research were recruited to identify current gaps in clinical geriatric research, generate research questions, and establish the priority of these questions using a consensus-driven Delphi survey approach. Participants were identified using established Delphi recruitment guidelines ensuring heterogeneity and generalizability. On subsequent surveys, participants were asked to rank the priority of each research question on a nine-point Likert scale, categorized to represent low-, medium-, and high-priority items. The consensus was defined as more than 60% of panelists agreeing on the priority category.

RESULTS

A total of 24 subject matter experts generated questions in 109 key topic areas. After editing for duplication, 514 questions were included in the priority ranking. By round 3, 362 questions (70%) reached 60% consensus. Of these, 161 (44%) were high, 198 (55%) medium, and 3 (1%) low priority.

CONCLUSION

Among the questions prioritized as high priority, questions related to three types of injuries (i.e., rib fracture, traumatic brain injury, and lower extremity injury) occurred with the greatest frequency. Among the 25 highest priority questions, the key topics with the highest frequency were pain management, frailty, and anticoagulation-related interventions. The most common types of research proposed were interventional clinical trials and comparative effectiveness studies, outcome research, and health care systems research.
Cg1246, a new player in mycolic acid biosynthesis in Corynebacterium glutamicum
Authors: de Sousa-d'Auria Célia , Constantinesco Florence , Bayan Nicolas , Constant Patricia , Tropis Maryelle , Daffé Mamadou , Graille Marc , Houssin Christine
Published: April 2022

Mycolic acids are key components of the complex cell envelope of

Corynebacteriales

. These fatty acids, conjugated to trehalose or to arabinogalactan form the backbone of the mycomembrane. While mycolic acids are essential to the survival of some species, such as

Mycobacterium tuberculosis

, their absence is not lethal for Corynebacterium glutamicum, which has been extensively used as a model to depict their biosynthesis. Mycolic acids are first synthesized on the cytoplasmic side of the inner membrane and transferred onto trehalose to give trehalose monomycolate (TMM). TMM is subsequently transported to the periplasm by dedicated transporters and used by mycoloyltransferase enzymes to synthesize all the other mycolate-containing compounds. Using a random transposition mutagenesis, we recently identified a new uncharacterized protein (Cg1246) involved in mycolic acid metabolism. Cg1246 belongs to the DUF402 protein family that contains some previously characterized nucleoside phosphatases. In this study, we performed a functional and structural characterization of Cg1246. We showed that absence of the protein led to a significant reduction in the pool of TMM in

C. glutamicum

, resulting in a decrease in all other mycolate-containing compounds. We found that, in vitro, Cg1246 has phosphatase activity on organic pyrophosphate substrates but is most likely not a nucleoside phosphatase. Using a computational approach, we identified important residues for phosphatase activity and constructed the corresponding variants in

C. glutamicum

. Surprisingly complementation with these non-functional proteins fully restored the defect in TMM of the Δcg1246 mutant strain, suggesting that in vivo, the phosphatase activity is not involved in mycolic acid biosynthesis.
The potyviral protein 6K2 from Turnip mosaic virus increases plant resilience to drought
Authors: Prakash Ved , Nihranz Chad T. , Casteel Clare L.
Published: April 2022

Drought is a major cause of yield loss for crops worldwide. Climate change is predicted to increase global crop losses due to drought through rising temperature and decreased water availability. Virus infection can increase drought tolerance of infected plants compared to non-infected plants; however, the mechanisms mediating virus-induced drought tolerance remain unclear. In this study, we demonstrate Turnip mosaic virus (TuMV) infection increases Arabidopsis thaliana survival under drought compared to uninfected plants. To determine if specific TuMV proteins mediate drought tolerance, we cloned the coding sequence for each of the major viral proteins and generated transgenic A. thaliana that constitutively express each protein. Three TuMV proteins, 6K1, 6K2, and NIa-Pro, enhanced drought tolerance of A. thaliana when expressed constitutively in plants compared to controls. Expression of 6K2 also increased plant biomass relative to controls, but had no impact on root biomass, trichome numbers, or on the number of stomata. While drought induced transcripts related to abscisic acid (ABA) biosynthesis and ABA levels in control plants, compared to under well-watered conditions, there were no changes in ABA or related transcripts in plants expressing 6K2 under drought conditions compared to well-watered. 6K2 expression also conveyed drought tolerance in another host plant, Nicotiana benthamiana, when expressed using a virus over expression construct derived from Foxtail mosaic virus (FoMV). Although the exact mechanisms are still unknown, these results suggest 6K2-induced drought tolerance is ABA-independent and that plant viruses may represent novel sources of drought tolerance for crop plants.
Transmission of human influenza A virus in pigs selects for adaptive mutations on the HA gene
Authors: Mo Jong-suk , Abente Eugenio J. , Sutton Troy C. , Ferreri Lucas M. , Geiger Ginger , Gauger Phillip C. , Perez Daniel R. , Vincent Baker Amy L. , Rajao Daniela S.
Published: April 2022

Influenza A viruses (IAV) cause respiratory diseases in many host species, including humans and pigs. The spillover of IAV between swine and humans has been a concern for both public health and the swine industry. With the emergence of the triple reassortant internal gene (TRIG) constellation, establishment of human-origin IAVs in pigs has become more common, leading to increased viral diversity. However, little is known about the adaptation processes that are needed for a human-origin IAV to transmit and become established in pigs. We generated a reassortant IAV containing surface gene segments from a human IAV strain and internal gene segments from the 2009 pandemic and TRIG IAV lineages and demonstrated that it can replicate and transmit in pigs. Sequencing and variant calling analysis identified a mutant that emerged during replication in pigs, which was mapped to a region near the receptor binding site of the hemagglutinin (HA). The variant was present in all contact pigs and replicated more efficiently in differentiated swine tracheal cells compared to the virus containing the wildtype human-origin HA. These results show that variants are selected quickly after replication of human-origin HA in pigs, leading to improved fitness in the swine host, likely contributing to transmission.

Importance

Influenza A viruses (IAV) cause respiratory disease in several species, including humans and pigs. The bidirectional transmission of IAV between humans and pigs plays a significant role in the generation of novel viral strains, greatly impacting viral epidemiology. However, little is known about the evolutionary processes that allow human IAV to become established in pigs. In this study, we generated reassortant viruses containing human seasonal HA and NA on different constellations of internal genes and tested their ability to replicate and transmit in pigs. We demonstrated that a virus containing a common internal gene constellation currently found in U.S. swine was able to transmit efficiently via the respiratory route. We identified a specific amino acid mutation that was fixed in the respiratory contact pigs that was associated with improved replication in primary swine tracheal epithelial cells, suggesting it was crucial for the transmissibility of the human virus in pigs.
Unsuppressed HIV infection impairs T cell responses to SARS-CoV-2 infection and abrogates T cell cross-recognition
Authors: Nkosi Thandeka , Chasara Caroline , Mbatha Anele , Nsimbi Mza , Papadopoulos Andrea O , Nguni Tiza L , Karim Farina , Moosa Mohomed Yunus S , Gazy Inbal , Jambo Kondwani ,   COMMIT-KZN, Hanekom Willem , Sigal Alex , Ndhlovu Zaza M
Published: April 2022

HIV infection has been identified as one of the major risk factors for severe COVID-19 disease, but the mechanisms underpinning this susceptability are still unclear. Here, we assessed the impact of HIV infection on the quality and epitope specificity of SARS-CoV-2 T cell responses in the first wave and second wave of the COVID-19 epidemic in South Africa. Flow cytometry was used to measure T cell responses following PBMC stimulation with SARS-CoV-2 peptide pools. Culture expansion was used to determine T cell immunodominance hierarchies and to assess potential SARS-CoV-2 escape from T cell recognition. HIV-seronegative individuals had significantly greater CD4+and CD8+T cell responses against the Spike protein compared to the viremic PLWH. Absolute CD4 count correlated positively with SARS-CoV-2 specific CD4+and CD8+T cell responses (CD4 r= 0.5, p=0.03; CD8 r=0.5, p=0.001), whereas T cell activation was negatively correlated with CD4+T cell responses (CD4 r= −0.7, p=0.04). There was diminished T cell cross-recognition between the two waves, which was more pronounced in individuals with unsuppressed HIV infection. Importantly, we identify four mutations in the Beta variant that resulted in abrogation of T cell recognition. Together, we show that unsuppressed HIV infection markedly impairs T cell responses to SARS-Cov-2 infection and diminishes T cell cross-recognition. These findings may partly explain the increased susceptibility of PLWH to severe COVID-19 and also highlights their vulnerability to emerging SARS-CoV-2 variants of concern.

One sentence summary

Unsuppressed HIV infection is associated with muted SARS-CoV-2 T cell responses and poorer recognition of the Beta variant.
Heat and humidity sensors that alert mosquitoes to nearby human hosts
Authors: Laursen Willem J. , Budelli Gonzalo , Chang Elaine C. , Gerber Rachel , Tang Ruocong , Greppi Chloe , Albuquerque Rebecca , Garrity Paul A.
Published: April 2022

Mosquito-borne diseases sicken >500,000,000 people annually, killing >500,0001. Mosquito host-seeking is guided by multiple host-associated cues, which combine to drive blood feeding in a manner that remains poorly understood2,3. While heat is a powerful mosquito attractant, recent studies indicate that disruption of heat seeking has little impact on host detection by the malaria vectorAnopheles gambiae4, suggesting other cues act alongside heat in the complex sensory environment of a human host. Here we show mosquitoes requireIr93a(an Ionotropic Receptor5) to maintain attraction to a human host and feed on warmed blood. UsingIr93a, we uncover the previously uncharacterized mosquito hygrosensory system, and showIr93ais required for humidity detection by humidity sensors (hygrosensors) as well as temperature detection by thermosensors, and for attraction to each stimulus. These findings indicate that hygrosensation and thermosensation function in parallel, driving host proximity detection in response to the overlapping heat and humidity gradients humans produce6,7. These host cue sensors appear to have arisen by co-opting existing sensors of physical cues rather thande novo, asIr93a-dependent thermo- and hygro-sensors support physiological homeostasis in non-blood-feeding insects8–11. WhileIr93ais conserved among arthropods, reliance on heat and humidity evolved independently in multiple blood-feeding lineages, suggesting multiple, vector-specific implementations of this common host-seeking strategy.