bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Trauma Composite Score is superior to Injury Severity Score in predicting mortality across all ages
Authors: Keskey Robert C. , Slidell Mark B. , Bohr Nicole L. , Biermann Henry , Cirone Justin , Zakrison Tanya , Cone Jennifer , Wilson Kenneth , Hampton David
Published: July 2021

BACKGROUND

Injury Severity Score (ISS) is a widely used metric for trauma research and center verification; however, it does not account for age-related physiologic parameters. We hypothesized that a novel age-based injury severity metric would better predict mortality.

METHODS

Adult patients (≥18 years) sustaining blunt trauma (BT) or penetrating trauma (PT) were abstracted from the 2010 to 2016 National Trauma Data Bank. Admission vitals, Glasgow Coma Scale, ISS, mechanism, and outcomes were analyzed. Patients with incomplete/non-physiologic vital signs were excluded. For each age: (1) a cut point analysis was used to determine the ISS with the highest specificity and sensitivity for predicting mortality and (2) a linear discriminant analysis was performed using ISS, ISS greater than 16, Trauma and Injury Severity Score, and Revised Trauma Scale to compare each scoring system’s mortality prediction. A novel injury severity metric, the trauma component score (TCS), was developed for each age using significant (p < 0.05) variables selected from Abbreviated Injury Scale scores, Glasgow Coma Scale, vital signs, and gender. Receiver operator curves were developed and the areas under the curve were compared between the TCS and other systems.

RESULTS

There 777,794 patients studied (BT, 91.1%; PT, 8.9%). Blunt trauma patients were older (53.6 ± 21.3 years vs. 34.4 ± 13.8 years), had higher ISS scores (11.1 ± 8.5 vs. 8.5 ± 8.9), and lower mortality (2.9% vs. 3.4%) than PT patients (p < 0.05). When assessing the entire PT and BT cohort the optimal ISS cut point was 16. The optimal ISS was between 20 and 25 for BT younger than 70 years. For those older than 70 years, the optimal BT ISS steadily declined as age increased PT’s cut point was 16 or less for all ages assessed. When the injury metrics were compared by area under the curve, our novel TCS more accurately predicted mortality across all ages in both BT and PT (p < 0.001).

CONCLUSION

Injury Severity Score is a poor mortality predictor in older patients and those sustaining penetrating trauma. The age-based TCS is a superior metric for mortality prediction across all ages.

LEVEL OF EVIDENCE

Clinical outcomes, Level IV.
Firearm violence against children in the United States: Trends in the wake of the COVID-19 pandemic
Authors: Donnelly Megan R. , Grigorian Areg , Swentek Lourdes , Arora Jagmeet , Kuza Catherine M. , Inaba Kenji , Kim Dennis , Lekawa Michael , Nahmias Jeffry
Published: July 2021

BACKGROUND

This study aimed to evaluate the patterns of firearm violence against children before and after the COVID-19 pandemic, as well as the patterns of specific types of firearm violence against children over time (2016–2020).

METHODS

Retrospective firearm violence data were obtained from the Gun Violence Archive. The rate of firearm violence was weighted per 100,000 children. A scatterplot was created to depict the rate of total annual child-involved shooting incidents over time; with a linear trendline fit to 2016 to 2019 data to show projected versus actual 2020 firearm violence. All 50 states were categorized into either “strong gun law” (n = 25) or “weak gun law” (n = 25) cohorts. Multivariate linear regressions were performed for number of child-involved shootings over time.

RESULTS

There were a total of 1,076 child-involved shootings in 2020, 811 in 2019, and 803 in 2018. The median total child-involved shooting incidents per month per 100,000 children increased from 2018 to 2020 (0.095 vs. 0.124, p = 0.003) and from 2019 to 2020 (0.097 vs. 0.124, p = 0.010). Child killed by adult incidents also increased in 2020 compared with 2018 (p = 0.024) and 2019 (p = 0.049). The scatterplot demonstrates that total child-involved shootings in addition to both fatal and nonfatal firearm violence incidents exceeded the projected number of incidents extrapolated from 2016 to 2019 data. Multivariate linear regression demonstrated that, compared with weak gun law states, strong gun law states were associated with decreased monthly total child-involved shooting incidents between 2018 and 2020 (p < 0.001), as well as between 2019 and 2020 (p < 0.001).

CONCLUSION

Child-involved shooting incidents increased significantly in 2020 surrounding the COVID-19 pandemic. Given that gun law strength was associated with a decreased rate of monthly child-involved firearm violence, public health and legislative efforts should be made to protect this vulnerable population from exposure to firearms.

LEVEL OF EVIDENCE

Epidemiological, level III.
ICTV Virus Taxonomy Profile: Bornaviridae
Authors: Rubbenstroth Dennis , Briese Thomas , Dürrwald Ralf , Horie (堀江真行) Masayuki , Hyndman Timothy H. , Kuhn Jens H. , Nowotny Norbert , Payne Susan , Stenglein Mark D. , Tomonaga (朝長啓造) Keizō ,   ICTV Report Consortium
Published: July 2021

Members of the family Bornaviridae produce enveloped virions containing a linear negative-sense non-segmented RNA genome of about 9 kb. Bornaviruses are found in mammals, birds, reptiles and fish. The most-studied viruses with public health and veterinary impact are Borna disease virus 1 and variegated squirrel bornavirus 1, both of which cause fatal encephalitis in humans. Several orthobornaviruses cause neurological and intestinal disorders in birds, mostly parrots. Endogenous bornavirus-like sequences occur in the genomes of various animals. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Bornaviridae, which is available at ictv.global/report/bornaviridae.
Comparative genomic insights into the epidemiology and virulence of plant pathogenic pseudomonads from Turkey
Authors: Dillon Marcus M. , Ruiz-Bedoya Tatiana , Bundalovic-Torma Cedoljub , Guttman Kevin M. , Kwak Haejin , Middleton Maggie A. , Wang Pauline W. , Horuz Sumer , Aysan Yesim , Guttman David S.
Published: July 2021

Pseudomonas

is a highly diverse genus that includes species that cause disease in both plants and animals. Recently, pathogenic pseudomonads from the

Pseudomonas syringae

and

Pseudomonas fluorescens

species complexes have caused significant outbreaks in several agronomically important crops in Turkey, including tomato, citrus, artichoke and melon. We characterized 169 pathogenic

Pseudomonas

strains associated with recent outbreaks in Turkey via multilocus sequence analysis and whole-genome sequencing, then used comparative and evolutionary genomics to characterize putative virulence mechanisms. Most of the isolates are closely related to other plant pathogens distributed among the primary phylogroups of

P. syringae

, although there are significant numbers of

P. fluorescens

isolates, which is a species better known as a rhizosphere-inhabiting plant-growth promoter. We found that all 39 citrus blast pathogens cluster in

P. syringae

phylogroup 2, although strains isolated from the same host do not cluster monophyletically, with lemon, mandarin orange and sweet orange isolates all being intermixed throughout the phylogroup. In contrast, 20 tomato pith pathogens are found in two independent lineages: one in the

P. syringae

secondary phylogroups, and the other from the

P. fluorescens

species complex. These divergent pith necrosis strains lack characteristic virulence factors like the canonical tripartite type III secretion system, large effector repertoires and the ability to synthesize multiple bacterial phytotoxins, suggesting they have alternative molecular mechanisms to cause disease. These findings highlight the complex nature of host specificity among plant pathogenic pseudomonads.
Genomic diversity, life strategies and ecology of marine HTVC010P-type pelagiphages
Authors: Du Sen , Qin Fang , Zhang Zefeng , Tian Zhen , Yang Mingyu , Liu Xinxin , Zhao Guiyuan , Xia Qian , Zhao Yanlin
Published: July 2021

SAR11 bacteria dominate ocean surface bacterioplankton communities, and play an important role in marine carbon and nutrient cycling. The biology and ecology of SAR11 are impacted by SAR11 phages (pelagiphages) that are highly diverse and abundant in the ocean. Among the currently known pelagiphages, HTVC010P represents an extremely abundant but under-studied phage group in the ocean. In this study, we have isolated seven new HTVC010P-type pelagiphages, and recovered 77 nearly full-length HTVC010P-type metagenomic viral genomes from marine metagenomes. Comparative genomic and phylogenomic analyses showed that HTVC010P-type pelagiphages display genome synteny and can be clustered into two major subgroups, with subgroup I consisting of strictly lytic phages and subgroup II mostly consisting of phages with potential lysogenic life cycles. All but one member of the subgroup II contain an integrase gene. Site-specific integration of subgroup II HTVC010P-type pelagiphage was either verified experimentally or identified by in silico genomic sequence analyses, which revealed that various SAR11 tRNA genes can serve as the integration sites of HTVC010P-type pelagiphages. Moreover, HTVC010P-type pelagiphage integration was confirmed by the detection of several Global Ocean Survey (GOS) fragments that contain hybrid phage–host integration sites. Metagenomic recruitment analysis revealed that these HTVC010P-type phages were globally distributed and most lytic subgroup I members exhibited higher relative abundance. Altogether, this study significantly expands our knowledge about the genetic diversity, life strategies and ecology of HTVC010P-type pelagiphages.
Quantifying contribution of Lipoprotein (a) to atherogenic lipoprotein burden – a novel particle-based approach
Authors: Chilazi Michael , Zheng Weili , Park Jihwan , Marvel Francoise A. , Khoury Shireen , Jones Steven R. , Martin Seth S.
Published: July 2021

Background

Elevated lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). As clinical LDL cholesterol [LDL-C] incorporates cholesterol from Lp(a) [Lp(a)-C], there is interest in quantifying the contribution of Lp(a)-C to LDL-C given implications for risk assessment, diagnosis, and treatment. Estimating Lp(a)-C is subject to inaccuracies; measuring Lp(a) particle number [Lp(a)-P] is more accurate.

Objective

To capture how Lp(a) contributes to the atherogenic lipoprotein burden, we demonstrate a particle-based approach using readily available measures of Lp(a)-P and apolipoprotein B (apoB).

Methods

Using the Very Large Database of Lipids (VLDbL), we compared Lp(a)-P (nmol/L) with all atherogenic particles (“non-HDL-P”). Non-HDL-P was calculated by converting apoB mass to molar concentration using the preserved molecular weight of apoB100 (512 kg/mol). We calculated the percentage of Lp(a)-P relative to non-HDL-P by Lp(a)-P deciles and stratified across sex, age, triglycerides, LDL-C, and non-HDL-C.

Results

158,260 patients from the VLDbL were included. The fraction Lp(a)-P/non-HDL-P increased with rising Lp(a)-P. Lp(a)-P comprised on average 3% of atherogenic particles among the study population and 15% at the highest Lp(a)-P decile. Findings were similar when stratified by sex. When stratified by age, Lp(a)-P/non-HDL-P was highest among the youngest and oldest patients. Lp(a)-P/non-HDL-P decreased at higher levels of triglycerides and LDL-C owing to larger contributions from VLDL and LDL.

Conclusions

We demonstrate a particle-based approach to quantify the contribution of Lp(a) to total atherogenic particle burden using validated and widely available laboratory assays. Future research applying this method could define clinically meaningful thresholds and inform use in risk assessment and management.
COVID-19 and regional differences in the timeliness of hip-fracture surgery: an interrupted time-series analysis
Authors: Golinelli Davide , Lenzi Jacopo , Adorno Emanuele , Gianino Maria Michela , Fantini Maria Pia
Published: July 2021

Background

It is of great importance to examine the impact of the healthcare reorganization adopted to confront the COVID-19 pandemic on the quality of care provided by healthcare systems to non-COVID-19 patients. The aim of this study is to assess the impact of the COVID-19 national lockdown (March 9, 2020) on the quality of care provided to patients with hip fracture (HF) in Piedmont and Emilia-Romagna, 2 large regions of northern Italy severely hit by the pandemic.

Methods

We calculated the percentage of HF patients undergoing surgery within 2 days of hospital admission. An interrupted time-series analysis was performed on weekly data from December 11, 2019 to June 9, 2020 (≈6 months), interrupting the series in the 2nd week of March. The same data observed the year before were included as a control time series with no “intervention” (lockdown) in the middle of the observation period.

Results

Before the lockdown, 2-day surgery was 69.9% in Piedmont and 79.2% in Emilia-Romagna; after the lockdown, these proportions were equal to 69.8% (−0.1%) and 69.3% (− 9.9%), respectively. While Piedmont did not experience any drop in the amount of surgery, Emilia-Romagna exhibited a significantly decline at a weekly rate of –1.29% (95% CI = –1.71 to –0.88).

Divergent trend patterns in the 2 study regions reflect local differences in pandemic timing as well as in healthcare services capacity, management, and emergency preparedness.
Justification, safety, and efficacy of a third dose of mRNA vaccine in maintenance hemodialysis patients: a prospective observational study
Authors: Espi Maxime , Charmetant Xavier , Barba Thomas , Pelletier Caroline , Koppe Laetitia , Chalencon Elodie , Kalbacher Emilie , Mathias Virginie , Ovize Anne , Cart-Tanneur Emmanuelle , Bouz Christine , Pellegrina Laurence , Morelon Emmanuel , Juillard Laurent , Fouque Denis , Couchoud Cécile , Thaunat Olivier
Published: July 2021

Background

Patients on maintenance hemodialysis (MHD) are at high risk of infection with SARS-Cov-2 and death due to COVID-19. This vulnerable population has been prioritized for vaccination, but the level of protection achieved in these immunocompromised patients is unclear.

Objectives

To evaluate the protection of MHD patients against COVID-19 after 2 doses (2D) of BNT162b2, and the safety and impact on immune responses of a 3rddose (3D).

Design

Prospective observational.

Setting, Patients, intervention and measurements

REIN national registry was used to compare the severity of 1474 cases of COVID-19 diagnosed in MHD patients after 0, 1 or 2 doses of mRNA vaccine. Anti-spike receptor binding domain (RBD) IgG and interferon gamma-producing CD4+ and CD8+ specific-T cells were measured after 2D and 3D of BNT162b2 in a monocentric cohort of 75 MHD patients.

Results

Vaccination reduced disease severity but 11% of MHD patients infected after 2D still died. Tolerance to 3D of BNT162b2 was excellent. MHD patients with humoral response similar to healthy volunteers after 2D did not generate more immune effectors after 3D and had more side effects. In contrast, 2/3 of MHD patients with suboptimal response after 2D reached optimal titer of anti-RBD IgG and/or developed spike-specific CD8+ T cells after 3D. Presence of spike-specific CD4+ T cells after 2D was associated with response to 3D in multivariate analysis (OR=4.80 [1.23−21.54]; p=0.029).

Limitations

Limited number of patients injected with 3D.

Conclusion

Standard scheme of vaccination provides insufficient protection to some MHD patients. Anti-RBD IgG and specific CD4+ T cells should be measured after 2D. Among patients with suboptimal humoral response, those with specific CD4+ T cells could benefit of a 3rddose of vaccine.

Registration

NCT04881396

Funding Source

None
The accuracy of Japanese administrative data in identifying acute exacerbation of idiopathic pulmonary fibrosis
Authors: Anan Keisuke , Kataoka Yuki , Ichikado Kazuya , Kawamura Kodai , Johkoh Takeshi , Fujimoto Kiminori , Tobino Kazunori , Tachikawa Ryo , Ito Hiroyuki , Nakamura Takahito , Kishaba Tomoo , Inomata Minoru , Yamamoto Yosuke
Published: July 2021

Background

This study aimed to develop criteria for identifying patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) from Japanese administrative data and validate the pre-existing criteria.

Methods

This retrospective, multi-center validation study was conducted at eight institutes in Japan to verify the diagnostic accuracy of the disease name for AE-IPF. We used the Japanese Diagnosis Procedure Combination data to identify patients with a disease name that could meet the diagnostic criteria for AE-IPF, who were admitted to the eight institutes from January 2016 to February 2019. As a reference standard, two respiratory physicians performed a chart review to determine whether the patients had a disease that met the diagnostic criteria for AE-IPF. Furthermore, two radiologists interpreted the chest computed tomography findings of cases considered AE-IPF and confirmed the diagnosis. We calculated the positive predictive value (PPV) for each disease name and its combination.

Results

We included 830 patients; among them, 216 were diagnosed with AE-IPF through the chart review. We combined the groups of disease names and yielded two criteria: the criteria with the highest PPV (0.72 [95% confidence interval 0.62 to 0.81]) and that with a slightly less PPV (0.61 [0.53 to 0.68]) but more true positives. Pre-existing criteria showed a PPV of 0.40 (0.31 to 0.49).

Conclusion

The criteria derived in this study for identifying AE-IPF from Japanese administrative data show a fair PPV. Although these criteria should be carefully interpreted according to the target population, our findings could be utilized in future database studies on AE-IPF.
Identification of the Novel Pyroptosis-Related Gene Signature in Patients with Esophageal Adenocarcinoma
Authors: Zeng Ruijie , Huang Shujie , Zhuo Zewei , Wu Huihuan , Sha Weihong , Chen Hao
Published: July 2021

Esophageal adenocarcinoma (EAC) is a highly malignant type of digestive tract cancers with a poor prognosis despite therapeutic advances. Pyroptosis is an inflammatory form of programmed cell death, whereas the role of pyroptosis in EAC remains largely unknown. Herein, we identified a pyroptosis-related five-gene signature that was significantly correlated with the survival of EAC patients in The Cancer Genome Atlas (TCGA) cohort and an independent validation dataset. In addition, a nomogram based on the five-gene signature was constructed with novel prognostic values. Moreover, the genes in the pyroptosis-related signature,CASP1, GSDMB, IL1B, PYCARD, andZBP1, might be involved in immune response and regulation of the tumor microenvironment. Our findings indicate that the five-gene signature provides insights into the involvement of pyroptosis in EAC progression, and is promising in the risk assessment as well as prognosis for EAC patients in clinical practice.
Microbial diversity and sulfur cycling in an early earth analogue: From ancient novelty to modern commonality
Authors: Hahn C. Ryan , Farag Ibrahim F. , Murphy Chelsea L. , Podar Mircea , Elshahed Mostafa S. , Youssef Noha H.
Published: July 2021

Life emerged and diversified in the absence of molecular oxygen. The prevailing anoxia and unique sulfur chemistry in the Paleo-, Meso- and Neoarchean, and early Proterozoic eons may have supported microbial communities that are drastically different than those currently thriving on the earth’s surface. Zodletone spring in southwestern Oklahoma represents a unique habitat where spatial sampling could substitute for geological eons: from the anoxic, surficial light exposed sediments simulating a preoxygenated earth, to overlaid water column where air exposure simulates the relentless oxygen intrusion during the Neo Proterozoic. We document a remarkably diverse microbial community in the anoxic spring sediments, with 340/516 (65.89%) of genomes recovered in a metagenomic survey belonging to 200 bacterial and archaeal families that were either previously undescribed or that exhibit an extremely rare distribution on the current earth. Such diversity is underpinned by the widespread occurrence of sulfite-, thiosulfate, tetrathionate-, and sulfur-reduction, and paucity of sulfate-reduction machineries in these taxa; hence greatly expanding lineages mediating reductive sulfur cycling processes in the tree of life. Analysis of the overlaying water community demonstrated that oxygen intrusion lead to the development of a significantly less diverse community dominated by well-characterized lineages and a prevalence of oxidative sulfur cycling processes. Such transition from ancient novelty to modern commonality underscores the profound impact of the great oxygenation event on the earth’s surficial anoxic community. It also suggests that novel and rare lineages encountered in current anaerobic habitats could represent taxa once thriving in an anoxic earth, but have failed to adapt to earth’s progressive oxygenation.
The relationship between mucosal microbiota, colitis and systemic inflammation in Chronic Granulomatous Disorder
Authors: Davrandi Mehmet , Harris Stephanie , Smith Philip J , Murray Charles D , Lowe David M
Published: July 2021

Background

Chronic granulomatous disorder (CGD) is a primary immunodeficiency which is frequently complicated by an inflammatory colitis and is associated with systemic inflammation.

Objective

To investigate the role of the microbiome in the pathogenesis of colitis and systemic inflammation.

Methods

We performed 16S rDNA sequencing on mucosal biopsy samples from each segment of 10 CGD patients’ colons, and conducted compositional and functional pathway prediction analyses.

Results

The microbiota in samples from colitis patients demonstrated reduced taxonomic alpha diversity compared to unaffected patients, even in apparently normal bowel segments. Functional pathway richness was similar between the colitic and non-colitic mucosa, although metabolic pathways involved in butyrate biosynthesis or utilisation were enriched in patients with colitis and correlated positively with faecal calprotectin levels. One patient with very severe colitis was dominated by Enterococcus spp., while among other patients Bacteroides spp. abundance correlated with colitis severity measured by faecal calprotectin and an endoscopic severity score. In contrast, Blautia abundance associated with low severity scores and mucosal health. Several taxa and functional pathways correlated with concentrations of inflammatory cytokines in blood but not with colitis severity. Notably, dividing patients into ‘High’ and ‘Low’ systemic inflammation groups demonstrated clearer separation than on the basis of colitis status in beta diversity analyses.

Conclusion

The microbiome is abnormal in CGD-associated colitis and altered functional characteristics probably contribute to pathogenesis. Furthermore, the relationship between the mucosal microbiome and systemic inflammation, independent of colitis status, implies that the microbiome in CGD can influence the inflammatory phenotype of the condition.

Key Messages

The colonic mucosal microbiome and bacterial metabolic pathways in patients with CGD colitis differ from patients without colitis, even in macroscopically normal bowel segments.

The mucosal microbiome and bacterial metabolic pathways in patients with CGD also differ according to the extent of systemic inflammation, independently from the presence of colitis, suggesting a role for the gut microbiota in the inflammatory phenotype of this condition.

Capsule summary

The pathogenesis of chronic granulomatous disorder (CGD)-associated colitis and other inflammatory complications is unclear. We demonstrate potentially treatable alterations in the mucosa-associated microbiome in CGD colitis and microbial differences which associate with systemic inflammation independently of colitis status.
Inhibitory control of synaptic signals preceding motor action in mouse frontal cortex
Authors: Zhang Chun-Lei , Koukouli Fani , Allegra Manuela , Ortiz Cantin , Kao Hsin-Lun , Maskos Uwe , Changeux Jean-Pierre , Schmidt-Hieber Christoph
Published: July 2021

Preparatory activity in the frontal cortex preceding movement onset is thought to represent a neuronal signature of motor planning. However, how excitatory and inhibitory synaptic inputs to frontal neurons are integrated during movement preparation remains unclear. Here we address this question by performing in vivo whole-cell patch-clamp recordings in the secondary motor cortex (MOs) of head-fixed mice moving on a treadmill. We find that both superficial and deep principal neurons show slowly increasing (~10 s) membrane potential and spike rate ramps preceding the onset of spontaneous, self-paced running periods. By contrast, in animals trained to perform a goal-directed task, both membrane potential and spike ramps are characterized by larger amplitudes and accelerated kinetics during preparation of goal-driven movement. To determine the role of local inhibitory neurons in shaping these task-dependent preparatory signals, we chemogenetically suppressed the activity of specific interneuron subpopulations in untrained animals. Inactivation of parvalbumin-positive (PV+) interneurons leads to depolarized membrane potential ramps with increased amplitudes during preparation of movement, while inactivation of somatostatin-positive (SOM+) interneurons abolishes membrane potential ramps. A computational model of the local MOs circuit shows that SOM+-mediated inhibition of PV+ interneurons in conjunction with recurrent connectivity among the principal neurons can reproduce slow ramping signals, while plasticity of excitatory synapses on SOM+ interneurons can explain the acceleration of these signals in trained animals. Together, our data reveal that local inhibitory neurons play distinct roles in controlling task-dependent preparatory ramping signals when MOs neurons integrate external inputs during motor planning.

Highlights

Principal neurons in MOs show slow preparatory membrane potential and firing rate ramps preceding the onset of spontaneous, self-paced running periods.

In animals trained to perform a goal-directed task, both membrane potential and spike ramps are faster and larger in amplitude.

Inactivation of PV+ interneurons disinhibits MOs principal neurons and increases the amplitude of membrane potential ramps, while inactivation of SOM+ interneurons abolishes membrane potential ramps.

Our modeling results suggest that the concerted action of external inputs and local inactivation shapes task-dependent preparatory motor signals in MOs neurons.
Discrete Roles of the Ir76b Ionotropic Co-Receptor Impact Olfaction, Blood Feeding, and Mating in the Malaria Vector Mosquito Anopheles coluzzii
Authors: Ye Zi , Liu Feng , Sun Huahua , Baker Adam , Zwiebel Laurence J.
Published: July 2021

Anopheline mosquitoes rely on their highly sensitive chemosensory apparatus to detect diverse chemical stimuli that drive the host-seeking and blood-feeding behaviors required to vector pathogens for malaria and other diseases. This process incorporates a variety of chemosensory receptors and transduction pathways. We have used advanced in vivo gene-editing and -labelling approaches to localize and functionally characterize the ionotropic co-receptor AcIr76b in the malaria mosquito Anopheles coluzzii, where it impacts both olfactory and gustatory systems. AcIr76b has a broad expression pattern in female adult antennal grooved pegs, T1 and T2 sensilla on the labellum, stylets, and tarsi, as well as the larval sensory peg. AcIr76b is co-localized with the Orco odorant receptor (OR) co-receptor in a subset of cells across the female antennae and labella. In contrast to Orco and Ir8a, chemosensory co-receptors that appear essential for the activity of their respective sets of chemosensory neurons in mosquitoes, AcIr76b-/- mutants maintain wild-type peripheral responses to volatile amines on the adult palps, labellum, and the larval sensory cone. Interestingly, AcIr76b-/- mutants display significantly increased responses to amines in antennal grooved peg sensilla while coeloconic sensilla reveal significant deficits in responses to several acids and amines. Behaviorally, AcIr76b mutants manifest significantly female-specific insemination deficits and, although AcIr76b-/- mutant females are able to locate, alight, and probe artificial blood hosts, they are incapable of blood feeding successfully. Taken together, our study reveals a multi-dimensional functionality of Ir76b in Anopheline olfactory and gustatory pathways that directly impacts the vectorial capacity of these mosquitoes.

Chemosensory receptors play crucial roles across mosquito lifecycles where they often form functional complexes that require cognate co-receptors. To better understand mosquito chemosensory pathways in the malaria vector mosquito An. coluzzii we have utilized advanced gene editing approaches to localize and functionally characterize the ionotropic receptor co-receptor AcIr76b. Expression of AcIr76b was observed in antennal grooved pegs and other accessory olfactory appendages. Mutagenesis of AcIr76b uncovers both reduced and elevated neuronal responses to amines, which suggests a role in response modulation. In addition to olfactory phenotypes, AcIr76b mutants display significantly impaired mating and blood feeding capabilities. Our data reveals discrete roles of AcIr76b across olfactory and gustatory pathways and shed lights on the potential molecular target for vector control strategies.
Antisense-mediated repression of SAGA-dependent genes involves the HIR histone chaperone
Authors: Soudet Julien , Beyrouthy Nissrine , Pastucha Anna Marta , Maffioletti Andrea , Bakir Zahra , Stutz Françoise
Published: July 2021

Eukaryotic genomes are pervasively transcribed by RNA polymerase II (RNAPII), and transcription of long non-coding RNAs often overlaps with coding gene promoters. This might lead to coding gene repression in a process named Transcription Interference (TI). In Saccharomyces cerevisiae (S. cerevisiae), TI is mainly driven by antisense non-coding transcription and occurs through re-shaping of promoter Nucleosome-Depleted Regions (NDRs). In this study, we developed a genetic screen to identify new players involved in Antisense-Mediated Transcription Interference (AMTI). Among the candidates, we found the HIR histone chaperone complex known to be involved in de novo histone deposition. Using genome-wide approaches, we reveal that HIR-dependent histone deposition represses the promoters of SAGA-dependent genes via antisense non-coding transcription. However, while antisense transcription is enriched at promoters of SAGA-dependent genes, this feature is not sufficient to define the mode of gene regulation. We further show that the balance between HIR-dependent nucleosome incorporation and transcription factor binding at promoters directs transcription into a SAGA- or TFIID-dependent regulation. This study sheds light on a new connection between antisense non-coding transcription and the nature of coding transcription initiation.
CRISPR-VAE: A Method for Explaining CRISPR/Cas12a Predictions, and an Efficiency-aware gRNA Sequence Generator
Authors: Obeid Ahmad , AlMarzouqi Hasan
Published: July 2021

Deep learning has shown great promise in the prediction of the gRNA efficiency, which helps optimize the engineered gRNAs, and thus has greatly improved the usage of CRISPR-Cas systems in genome editing. However, the black box prediction of deep learning methods does not provide adequate explanation to the factors that increase efficiency; rectifying this issue promotes the usage of CRISPR-Cas systems in numerous domains. We put forward a framework for interpreting gRNA efficiency prediction, dubbed CRISPR-VAE, that improves understanding the factors that increase gRNA efficiency, and apply it to CRISPR/Cas12a (formally known as CRISPR/Cpf1). We further lay out a semantic articulation of such factors into position-wise k-mer rules. The paradigm consists of building an efficiency-aware gRNA sequence generator trained on available real data, and using it to generate a large amount of synthetic sequences with favorable traits, upon which the explanation of the gRNA prediction is based. CRISPR-VAE can further be used as a standalone sequence generator, where the user has low-level control ability. The framework can be readily integrated with different CRISPR-Cas tools and datasets, and its efficacy is confirmed. The complete implementation of the methods can be found at github.com/AhmadObeid/CRISPR-VAE.
Mapping the glycosyltransferase fold landscape using deep learning
Authors: Taujale Rahil , Zhou Zhongliang , Yeung Wayland , Moremen Kelley W , Li Sheng , Kannan Natarajan
Published: July 2021

Glycosyltransferases (GTs) play fundamental roles in nearly all cellular processes through the biosynthesis of complex carbohydrates and glycosylation of diverse protein and small molecule substrates. The extensive structural and functional diversification of GTs presents a major challenge in mapping the relationships connecting sequence, structure, fold and function using traditional bioinformatics approaches. Here, we present a convolutional neural network with attention (CNN-attention) based deep learning model that leverages simple secondary structure representations generated from primary sequences to provide GT fold prediction with high accuracy. The model learned distinguishing features free of primary sequence alignment constraints and, unlike other models, is highly interpretable and helped identify common secondary structural features shared by divergent families. The model delineated sequence and structural features characteristic of individual fold types, while classifying them into distinct clusters that group evolutionarily divergent families based on shared secondary structural features. We further extend our model to classify GT families of unknown folds and variants of known folds. By identifying families that are likely to adopt novel folds such as GT91, GT96 and GT97, our studies identify targets for future structural studies and expand the GT fold landscape.
The Phytochemical Diversity of Commercial Cannabis in the United States
Authors: Smith Christiana J. , Vergara Daniela , Keegan Brian , Jikomes Nick
Published: July 2021

The legal status of Cannabis is changing, fueling an increased diversity of Cannabis-derived products. Because Cannabis contains dozens of chemical compounds with potential psychoactive or medicinal effects, understanding its phytochemical diversity is crucial. The legal Cannabis industry heavily markets products to consumers based on widely used labelling systems purported to predict the effects of different Cannabis “strains.” We analyzed the cannabinoid and terpene content of tens of thousands of commercial Cannabis samples across six US states, finding distinct chemical phenotypes (chemotypes) which are reliably present. After careful descriptive analysis of the phytochemical diversity and comparison to the commercial labels commonly attached to Cannabis samples, we show that commercial labels do not consistently align with the observed chemical diversity. However, certain labels are statistically overrepresented for specific chemotypes. These results have important implications for the classification of commercial Cannabis, the design of animal and human research, and the regulation of legal Cannabis marketing.
Variation in mechanical and structural properties of enamel in primate molars
Authors: Towle Ian , Loho Thomas , Salem Amira , Loch Carolina
Published: July 2021

Mechanical properties of enamel are known to vary across molar crowns in some primates, but the association of this variation with phylogeny, structural properties and tribological behaviour is not well understood. In this study, 20 molars from a range of primate taxa (n=15) were studied using nanoindentation, micro-CT scanning, and SEM imaging. After micro-CT scanning, teeth were sectioned in the lingual-buccal plane through the mesial cusps. Five positions (buccal lateral, buccal cuspal, occlusal middle, lingual cuspal, lingual lateral) were studied in three locations (inner, middle, outer enamel regions). The results show middle enamel had the highest hardness and elastic modulus values in all positions. ‘Non-functional’ molar sides (lingual in lower molars and buccal in upper molars) had higher hardness values than their ‘functional’ counterparts. Increase in prism size was associated with a decrease in hardness in some tooth positions, and mineral density showed a significant relationship with elastic modulus values. Variation in enamel structure variation (e.g., enamel Schmelzmuster, Hunter-Schreger band thickness), may also be crucial in explaining variation in mechanical properties, with decussation zones associated with higher mechanical properties values. Primate enamel is not a homogeneous material, with variation in mechanical and structural properties across the crown likely associated with functional differences and variation in force distribution. Overall structural and mechanical patterns were similar in the primate species studied despite substantial differences in diet, suggesting these properties are potentially evolutionary conserved.
Predicting RNA splicing from DNA sequence using Pangolin
Authors: Zeng Tony , Li Yang I
Published: July 2021

Recent progress in deep learning approaches have greatly improved the prediction of RNA splicing from DNA sequence. Here, we present Pangolin, a deep learning model to predict splice site strength in multiple tissues that has been trained on RNA splicing and sequence data from four species. Pangolin outperforms state of the art methods for predicting RNA splicing on a variety of prediction tasks. We use Pangolin to study the impact of genetic variants on RNA splicing, including lineage-specific variants and rare variants of uncertain significance. Pangolin predicts loss-of-function mutations with high accuracy and recall, particularly for mutations that are not missense or nonsense (AUPRC = 0.93), demonstrating remarkable potential for identifying pathogenic variants.
Target-specific control of olfactory bulb periglomerular cells by GABAergic and cholinergic basal forebrain inputs
Authors: De Saint Jan Didier
Published: July 2021

The olfactory bulb (OB), the first relay for odor processing, receives dense GABAergic and cholinergic long-range projections from basal forebrain (BF) nuclei that provide information about the internal state and behavioral context of the animal. However, the targets, impact and dynamics of these afferents are still unclear. I studied how BF synaptic inputs modulate activity in diverse subtypes of periglomerular (PG) interneurons using optogenetic stimulation and loose cell-attached or whole-cell patch-clamp recording in OB slices from adult mice. GABAergic BF inputs potently blocked PG cells firing except in a minority of calretinin-expressing cells in which GABA release elicited spiking. Parallel cholinergic projections excited a previously overlooked PG cell subtype via synaptic activation of M1 muscarinic receptors. Low frequency stimulation of the cholinergic axons drove persistent firing in these PG cells thereby increasing tonic inhibition in principal neurons. Taken together, these findings suggest that modality-specific BF inputs can orchestrate inhibition in OB glomeruli using multiple, potentially independent, inhibitory or excitatory target-specific pathways.
Developmental increase of inhibition drives decorrelation of neural activity
Authors: Chini Mattia , Pfeffer Thomas , Hanganu-Opatz Ileana L.
Published: July 2021

Throughout development, the brain transits from early highly synchronous activity patterns to a mature state with sparse and decorrelated neural activity, yet the mechanisms underlying this process are unknown. The developmental transition has important functional consequences, as the latter state allows for more efficient storage, retrieval and processing of information. Here, we show that, in the mouse medial prefrontal cortex (mPFC), neural activity during the first two postnatal weeks decorrelates following specific spatial patterns. This process is accompanied by a concomitant tilting of excitation/inhibition (E-I) ratio towards inhibition. Using optogenetic manipulations and neural network modeling, we show that the two phenomena are mechanistically linked, and that a relative increase of inhibition drives the decorrelation of neural activity. Accordingly, in two mouse models of neurodevelopmental disorders, subtle alterations in E-I ratio are associated with specific impairments in the correlational structure of spike trains. Finally, capitalizing on EEG data from newborn babies, we show that an analogous developmental transition takes place also in the human brain. Thus, changes in E-I ratio control the (de)correlation of neural activity and, by these means, its developmental imbalance might contribute to the pathogenesis of neurodevelopmental disorders.
An explainable prediction framework for engineering problems: case studies in reinforced concrete members modeling
Authors: Tahmassebi Amirhessam , Motamedi Mehrtash , Alavi Amir H. , Gandomi Amir H.
Published: July 2021

Purpose

Engineering design and operational decisions depend largely on deep understanding of applications that requires assumptions for simplification of the problems in order to find proper solutions. Cutting-edge machine learning algorithms can be used as one of the emerging tools to simplify this process. In this paper, we propose a novel scalable and interpretable machine learning framework to automate this process and fill the current gap.

Design/methodology/approach

The essential principles of the proposed pipeline are mainly (1) scalability, (2) interpretibility and (3) robust probabilistic performance across engineering problems. The lack of interpretibility of complex machine learning models prevents their use in various problems including engineering computation assessments. Many consumers of machine learning models would not trust the results if they cannot understand the method. Thus, the SHapley Additive exPlanations (SHAP) approach is employed to interpret the developed machine learning models.

Findings

The proposed framework can be applied to a variety of engineering problems including seismic damage assessment of structures. The performance of the proposed framework is investigated using two case studies of failure identification in reinforcement concrete (RC) columns and shear walls. In addition, the reproducibility, reliability and generalizability of the results were validated and the results of the framework were compared to the benchmark studies. The results of the proposed framework outperformed the benchmark results with high statistical significance.

Originality/value

Although, the current study reveals that the geometric input features and reinforcement indices are the most important variables in failure modes detection, better model can be achieved with employing more robust strategies to establish proper database to decrease the errors in some of the failure modes identification.
The physical, emotional and behavioral symptoms of health problems among employees before and during the COVID-19 epidemic
Authors: Rožman Maja , Tominc Polona
Published: July 2021

Purpose

The coronavirus disease 2019 (COVID-19) epidemic has caused stress for everyone and impacted the lives of people globally. Such stress increases troubles for the employees. Therefore, the aim of the paper is to identify symptoms of health problems that employees face during the COVID-19 epidemic. Also, the aim of the paper is to examine if there are statistically significant differences in the physical, emotional and behavioral symptoms of health problems among employees before the COVID-19 epidemic and employees during the COVID-19 epidemic.

Design/methodology/approach

The research is based on a survey of 950 employees in Slovenian companies. The factor analysis and the t-test for two independent samples were used to test the hypotheses of the research.

Findings

The results show that physical, emotional and behavioral symptoms of health problems of employees during the COVID-19 epidemic are intensified as compared to the before COVID-19 epidemic era.

Originality/value

The results highlight the measures with which companies can reduce the problem of different symptoms of employees during the COVID-19 epidemic. The results can be useful for employers and for managers who want to create an adequate working environment for employees during the COVID-19 epidemic.
SpaceX Hyperloop: a future technology disruption of the transportation system?
Authors: Harris Wesley L. , Wonglimpiyarat Jarunee
Published: July 2021

Purpose

This paper aims to discuss the possibility that Hyperloop using air levitation technology would create a revolution in the future industry of transportation. It also analyses the financing dimension in bringing Hyperloop technology towards full-scale commercialisation.

Design/methodology/approach

The study uses a case study of SpaceX Hyperloop. The analyses if Hyperloop would bring about a paradigmatic shift in the transportation industry are based on the classical economic theories of technology S-curves (Utterback and Abernathy, 1975; Fisher and Pry, 1971) and Schumpeter’s model of economic development (Schumpeter, 1939, 1967). The three factors influencing a paradigmatic change (a shift in technoeconomic paradigm) according to Freeman and Perez (1988) are also explored.

Findings

The analyses of findings have shown that Hyperloop has not yet met three factors influencing a paradigmatic change. However, the Hyperloop technology has the potential to create a new market of mass transportation. In terms of technology financing, SpaceX needs the right financing infrastructure – corporate venture arm, the crowdfunding platform, initial coin offering, as well as debt and equity financing to accelerate the process of commercialisation. As the project moves forward, Hyperloop technology would create a market for itself (innovation to create the demand and not demand to create innovation).v

Originality/value

Although the body of literature on technology management is already voluminous, there has been a scarcity of past research devoted to elucidating the technology disruption and technology financing. This research study has applied the concepts of technology S-curves to better understand if SpaceX Hyperloop would bring about a paradigm shift or revolution in the future of the transportation industry. The research findings would help fill an identified knowledge gap in the body of research in technology disruption and financing.