bluuebunny/crossref_metadata_2025 huggingface dataset:
Encapsulation of bacteria in bilayer Pluronic thin film hydrogels: a safe format for engineered living materials
Authors: Bhusari Shardul , Kim Juhyun , Polizzi Karen , Sankaran Shrikrishnan , del Campo Aránzazu
Published: October 2022

In engineered living materials (ELMs) non-living matrices encapsulate microorganisms to acquire capabilities like sensing or biosynthesis. The confinement of the organisms to the matrix and the prevention of overgrowth and escape during the lifetime of the material is necessary for the application of ELMs into real devices. In this study, a bilayer thin film hydrogel of Pluronic F127 and Pluronic F127 acrylate polymers supported on a solid substrate is introduced. The inner hydrogel layer contains genetically engineered bacteria and supports their growth, while the outer layer acts as an envelope and does not allow leakage of the living organisms outside of the film for at least 15 days. Due to the flat and transparent nature of the construct, the thin layer is suited for microscopy and spectroscopy-based analyses. The composition and properties of the inner and outer layer are adjusted independently to fulfil viability and confinement requirements. We demonstrate that bacterial growth and light-induced protein production are possible in the inner layer and their extent is influenced by the crosslinking degree of the used hydrogel. Bacteria inside the hydrogel are viable long term, they can act as lactate-sensors and remain active after storage in phosphate buffer at room temperature for at least 3 weeks. The versatility of bilayer bacteria thin-films is attractive for fundamental studies and for the development of application-oriented ELMs.
NHA1 is a cation/proton antiporter essential for the water-conserving functions of the rectal complex inTribolium castaneum
Authors: Naseem Muhammad Tayyib , Beaven Robin , Koyama Takashi , Naz Sehrish , Su Mooney , Leader David P. , Klærke Dan , Calloe Kirstine , Denholm Barry , Halberg Kenneth Veland
Published: October 2022

More than half of all extant metazoan species on earth are insects. The evolutionary success of insects is intrinsically linked with their ability to osmoregulate, suggesting that they have evolved unique physiological mechanisms to maintain water balance. In beetles (Coleoptera)—the largest group of insects—a specialized rectal (‘cryptonephridial’) complex has evolved that recovers water from the rectum destined for excretion and recycles it back to the body. However, the molecular mechanisms underpinning the remarkable waterconserving functions of this system are unknown. Here, we introduce a transcriptomic resource,BeetleAtlas.org, for red flour beetleTribolium castaneum, and demonstrate its utility by identifying a cation/H+antiporter (NHA1) that is enriched and functionally significant in theTriboliumrectal complex. NHA1 localizes exclusively to a specialized cell type, the leptophragmata, in the distal region of the Malpighian tubules associated with the rectal complex. Computational modelling and electrophysiological characterization inXenopus oocytesshow that NHA1 acts as an electroneutral K+/H+antiporter. Furthermore, genetic silencing ofNha1dramatically increases excretory water loss and reduces organismal survival during desiccation stress, implying that NHA1 activity is essential for maintaining systemic water balance. Finally, we show that Tiptop, a conserved transcription factor, regulates NHA1 expression in leptophragmata and controls leptophragmata maturation, illuminating the developmental mechanism that establishes the novel functions of this cell. Together, our work provides the first insights into the molecular architecture underpinning the function of one most powerful water-conserving mechanisms in nature, the beetle rectal complex.

Significance Statement

Beetles are the largest group of insects, inhabiting a wide range of habitats on earth. Unique adaptations in overcoming water stress is critical to their success, yet the mechanisms underpinning this ability are unknown. Using genetics, electrophysiology, imaging and behavioral studies we show that a cation/H+(NHA1) transporter is exclusively localized to specialized cell type, the leptophragmata, in the Malpighian tubules associated with the rectal complex. Ion transport functions of NHA1 in leptophragmata underpin the movement of water from the rectum, from where it would be destined for excretion, to the Malpighian tubule and then recycled back to the body. This water recovery capability of rectal complex is essential for maintaining systemic water balance in beetles. This work provides the first insight into to the molecular architecture of one of most powerful water-conservation mechanisms in biology, and provides an important clue to the ecological and evolutionary success of the beetles.
Relish/NF-κB acts in intestinal stem cells to promote epithelial repair in Drosophila
Authors: Ferguson Meghan , Shin Minjeong , Foley Edan
Published: October 2022

Immune signals coordinate the repair of damaged epithelia by intestinal stem cells. However, it is unclear if immune pathways act autonomously within the stem cell to direct the damage response pathway. We consider this an important question, as stem cell dynamics are essential for formation and maintenance of the entire epithelium. We used Drosophila to determine the impact of stem cell-specific loss of NF-κB on tissue regeneration upon chemical injury. We found that loss of NF-κB enhanced cell death, impaired enterocyte renewal and increased mortality. Mechanistically, we showed that the Ras/ERK pathway is essential for NF-κB-dependent maintenance of cell viability and tissue repair. Combined, our data demonstrate that stem cell-intrinsic NF-κB activity is essential for an orderly repair of damaged intestinal epithelia.
Vestibular Compound Action Potentials and Macular Velocity Evoked by Sound and Vibration in the Guinea Pig
Authors: Pastras Christopher J. , Curthoys Ian S. , Rabbitt Richard D. , Brown Daniel J.
Published: October 2022

To examine mechanisms responsible for vestibular afferent sensitivity to transient air conducted sounds (ACS) and inter-aural bone conducted vibration (BCV), we performed simultaneous measurements of stimulus-evoked vestibular compound action potentials (vCAPs), utricular macula or stapes velocity, and Vestibular Microphonics (VMs) in the anaesthetized guinea pig. For short duration punctate stimuli (<1ms), the vCAP increases magnitude in close proportion to macular velocity and temporal bone (ear-bar) acceleration, rather than other kinematic variables. For longer duration stimuli, the vCAP magnitude switches from acceleration sensitive to linear jerk sensitive. vCAP input-output (IO) functions suggest primary afferent response generation has the same origins for both BCV and ACS, with similar macular velocity thresholds and IO functions for both stimuli. Frequency tuning curves evoked by tone-burst stimuli also show the vCAP increases magnitude in proportion to macular velocity, while in contrast, the VM increases magnitude in proportion to macular displacement across the entire frequency bandwidth tested. The subset of vestibular afferent neurons responsible for synchronized firing and vCAPs make calyceal synaptic contacts with type I hair cells in the striolar region of the epithelium and have irregularly spaced inter-spike intervals at rest. Present results provide new insight into mechanical and neural mechanisms underlying synchronized action potentials in these sensitive afferents, with clinical relevance for understanding the activation and tuning of neurons responsible for driving rapid compensatory reflex responses.

Significant statement

Calyx-bearing afferents in the utricle have the remarkable ability to fire an action potential at a precise time following the onset of a transient stimulus and provide temporal information required for compensatory vestibular reflex circuits, but specifically how transient high-frequency stimuli lead to mechanical activation of hair cells and neural responses is poorly understood. Here, we dissect the relative contributions of mechanics, hair cell transduction, and action potential generation on short-latency responses to transient stimuli. Results provide a framework for the interpretation of synchronized vestibular afferent responses, with relevance to understanding origins of myogenic reflex responses commonly used in the clinic to assay vestibular function, and vestibular short latency potentials commonly used for vestibular phenotyping in rodents.
Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDA receptor antibody encephalitis mouse model
Authors: Zhou Jing , Greenfield Ariele L. , Loudermilk Rita , Bartley Christopher M. , Chen Chun , Chen Xiumin , Leroux Morgane , Lu Yujun , Necula Deanna , Ngo Thomas T. , Tran Baouyen T. , Honma Patrick , Lauderdale Kelli , Zhao Chao , Zhou Xiaoyuan , Wang Hong , Nicoll Roger A. , Wang Cong , Paz Jeanne T. , Palop Jorge J. , Wilson Michael R. , Pleasure Samuel J.
Published: October 2022

NMDA receptor mediated autoimmune encephalitis (NMDAR-AE) frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long-term effects of exposure to a patient-derived GluN1-specific monoclonal antibody (mAb) during a critical developmental period (from postnatal day 3 to day 12) in mice. We observed long-lasting sensory-motor deficits characteristic of NMDAR-AE, along with permanent changes in callosal axons within the primary somatosensory cortex (S1) in adulthood, including increased terminal branch complexity. This complexity was associated with paroxysmal recruitment of neurons in S1 in response to callosal stimulation. Particularly during complex motor tasks, mAb3-treated mice exhibited significantly reduced inter-hemispheric functional connectivity between S1 regions, consistent with pronounced sensory-motor behavioral deficits. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons, which could significantly impair sensory-motor integration and contribute to long-lasting sensory-motor deficits. Our study establishes a new model of NMDAR-AE and identifies novel cellular and network-level mechanisms underlying persistent sensory-motor deficits in this context. These insights lay the foundation for future research into molecular mechanisms and the development of targeted therapeutic interventions.

Graphical Abstract
May mineral composition trigger or limit the protein content in soybean (Glycine max (L.) Merrill) seeds? Insights from a survey on 95 varieties cultivated in Brazil
Authors: Montanha Gabriel Sgarbiero , Perez Lucas Coan , Brandão Julia Rossatto , de Camargo Rachel Ferraz , Tavares Tiago Rodrigues , de Almeida Eduardo , de Carvalho Hudson Wallace Pereira
Published: October 2022

Background and Aims

Soybean (Glycine max (L.) Merrill) stands out as the major source of protein and oil for human and animal nutrition. Nevertheless, the increase in soybean yield has been accompanied by a reduction in its protein content in the last few decades. Since this might be influenced by the elemental composition of the seeds, we herein aimed at determining the profile of mineral nutrients and protein of 95 soybean varieties broadly cultivated in Brazil, the world’s biggest soybean producer and exporter, to identify possible nutritional triggers for the protein content.

Methods

Energy dispersive fluorescence spectroscopy (EDXRF) was employed to determine the concentration of macro, i.e., (K), phosphorus (P), sulphur (S), calcium (Ca), and micronutrients, i.e., iron (Fe), manganese (Mn), zinc (Zn), and copper (Cu). The protein content was evaluated in soybean seeds by the Dumas method. The correlational and clustering assessment between nutrients and protein were determined through both univariate and multivariate non-parametric tests.

Results

Both protein and nutrient concentrations are not homogeneous across soybean seed varieties, and a clear positive association between protein and sulphur (S), zinc (Zn), and manganese (Mn) concentrations were observed.

Conclusion

The recorded results suggest that sulphur (S), zinc (Zn), and manganese (Mn) are the limiting nutrients for higher protein content in soybean seeds.
The Potential Regulation of A-to-I RNA editing on Genes in Parkinson’s Disease
Authors: Wu Sijia , Xue Qiuping , Qin Xinyu , Huang Liyu
Published: October 2022

Parkinson’s disease (PD), the second most common neurodegenerative disorder, was characterized by alpha-synuclein pathology and dopaminergic neuron degeneration. In previous studies, multiple genes have been demonstrated to involve in the regulations of these two processes, including EIF2AK2, AGO2, MCL1, EEF1A1, and AIMP2. The molecular mechanisms to mediate the transcript diversity of these genetic biomarkers were important to understand neurodegenerative pathogenesis and helpful for treatment design. In this study, we analyzed 372 PD patients to identify 9,897 A-to-I RNA editing events probably responsible for the controls of 6,286 genes. Due to the most potentially trans-regulatory associations between RNA editing events and genes, we tried to explain one possible pathway from the view of disturbed miRNA regulations on genes due to A-to-I RNA editing events. Specifically, we identified 72 RNA editing events probably interfering in miRNA regulations on their host genes, eight RNA editing events possibly altering miRNA competitions between their host genes and 1,146 other genes, and one RNA editing event modifying miRNA seed regions to potentially disturb its regulations on four genes. All the analyses revealed 25 RNA editing biomarkers in Parkinson’s pathogenesis through probably interfering in miRNA degradations on 133 PD-related genes.
Subcutaneous BCG vaccination protects against streptococcal pneumonia via regulating innate immune responses in the lung
Authors: Kang Alisha , Ye Gluke , Singh Ramandeep , Afkhami Sam , Bavananthasivam Jegarubee , Luo Xiangqian , Vaseghi-Shanjani Maryam , Zganiacz Anna , Jeyanathan Mangalakumari , Xing Zhou
Published: October 2022

Bacillus Calmette-Guérin (BCG) still remains the only licensed vaccine for TB and has been shown to provide nonspecific protection against unrelated pathogens. This has been attributed to the ability of BCG to modulate the innate immune system, known as trained innate immunity (TII). TII is associated with innate immune cells being in a hyper-responsive state leading to enhanced host defense against heterologous infections. Both epidemiological evidence and prospective studies demonstrate cutaneous BCG vaccine-induced TII provides enhanced innate protection against heterologous pathogens. Regardless of the extensive amounts of progress made thus far, the effect of cutaneous BCG vaccination against heterologous respiratory bacterial infections and the underlying mechanisms remain unknown. Here we show for the first time that s.c BCG vaccine-induced TII provides enhanced heterologous innate protection against pulmonary S. pneumoniae infection. We further demonstrate that this enhanced innate protection is mediated by accelerated neutrophilia in the lung and is independent of centrally trained circulating monocytes. New insight from this study will help design novel effective vaccination strategies against unrelated respiratory bacterial pathogens.
Denitrification by bradyrhizobia under feast and famine and the role of the bc1 complex in securing electrons for N2O reduction
Authors: Gao Yuan , Arntzen Magnus Øverlie , Kjos Morten , Bakken Lars R. , Frostegård Åsa
Published: October 2022

Rhizobia living as microsymbionts inside nodules have stable access to carbon substrates, but also have to survive as free-living bacteria in soil where they are starved for carbon and energy most of the time. Many rhizobia can denitrify, thus switch to anaerobic respiration under low O2tension using N-oxides as electron acceptors. The cellular machinery regulating this transition is relatively well-known from studies under optimal laboratory conditions, while little is known about this regulation in starved organisms. It is, for example, not known if the strong preference for N2O-over NO3--reduction in bradyrhizobia is retained under carbon limitation. Here we show that starved cultures of aBradyrhizobiumstrain with respiration rates 1-18% of well-fed cultures, reduced all available N2O before touching provided NO3-. Proteomics showed similar abundance of Nap (periplasmic NO3-reductase) and NosZ (N2O reductase), suggesting that competition between electron pathways to Nap and NosZ favoured N2O reduction also in starved cells, similar to well-fed cultures. This contrasts the general notion that NosZ activity diminishes under carbon limitation. The results suggest that bradyrhizobia carrying NosZ can act as strong sinks for N2O under natural conditions and that this criterion should be considered in the development of biofertilizers.

Importance

Legume cropped farmlands account for substantial N2O emissions globally. Legumes are commonly inoculated with N2-fixing bacteria, rhizobia, to improve crop yields. Rhizobia belonging toBradyrhizobium, the micro-symbionts of several economically important legumes, are generally capable of denitrification but many lack genes encoding N2O reductase and will be N2O sources. Bradyrhizobia with complete denitrification will instead act as sinks since N2O-reduction efficiently competes for electrons over nitrate reduction in these organisms. This phenomenon has only been demonstrated under optimal conditions and it is not known how carbon substrate limitation, which is the common situation in most soils, affects the denitrification phenotype. Here we demonstrate that bradyrhizobia retain their strong preference for N2O under carbon starvation. The findings add basic knowledge about mechanisms controlling denitrification and support the potential for developing novel methods for greenhouse gas mitigation based on legume inoculants with the dual capacity to optimize N2-fixation and minimize N2O emission.
Transcriptional and genetic sex differences for schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus
Authors: Benjamin Kynon JM , Arora Ria , Stolz Joshua M , D’Ignazio Laura , Collado-Torres Leonardo , Hyde Thomas M , Kleinman Joel E , Weinberger Daniel R , Paquola Apuã CM , Erwin Jennifer A
Published: October 2022

Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. To date, only the prefrontal cortex has been examined in large-scale transcriptome analyses for sex differences in schizophrenia. Here, we examined the BrainSeq Consortium RNA-sequencing and genotypes for the caudate nucleus (n=399), dorsolateral prefrontal cortex (DLPFC; n=377), and hippocampus (n=394) to characterize sex differences in schizophrenia. We identified genomic features (genes, transcripts, exons, and exon-exon junctions) associated with sex, sex-specific expression in schizophrenia, and sex-interacting expression quantitative trait loci (si-eQTL) associated with schizophrenia risk. We found 878 unique genes with sex differences across brain regions, including ANK3, which shows male-biased expression in the caudate nucleus. X-chromosome dosage was significantly decreased in the hippocampus of female and male individuals with schizophrenia. Our sex interaction model revealed 15 novel junctions dysregulated for schizophrenia in a sex-specific manner. Sex-specific schizophrenia analysis identified dozens of expressed, sex-specific features with enrichment in the transcriptional response of cellular stress. Finally, our si-eQTL analysis revealed 974 unique genes, 14 of which are associated with schizophrenia risk. Overall, our results increased the number of annotated sex-biased features, identified sex-specific schizophrenia genes, and provided the first annotation of si-eQTL in the human DLPFC and hippocampus. Altogether, these results point to the importance of sex-informed analysis of sexually dimorphic traits and inform personalized therapeutic strategies in schizophrenia.
Reduction in circulating monocytes correlates with persistent post-COVID pulmonary fibrosis in multi-omic comparison of long-haul COVID and IPF
Authors: Bingham Grace C. , Muehling Lyndsey M. , Li Chaofan , Huang Yong , Abebayehu Daniel , Noth Imre , Sun Jie , Woodfolk Judith A. , Barker Thomas H. , Bonham Catherine
Published: October 2022

Rationale: Up to 30% of COVID-19 patients experience persistent sequelae, including dyspnea, restrictive physiology, and early radiographic signs of pulmonary fibrosis (PF). The mechanisms that provoke post-COVID progressive PF are poorly understood, and biomarkers to identify at-risk patients are urgently needed. Methods: We evaluated a cohort of 14 symptomatic COVID survivors with impaired respiratory function and imaging worrisome for developing PF, including bilateral reticulation, traction bronchiectasis and/or honeycombing, and compared these to Idiopathic Pulmonary Fibrosis (IPF) patients and age-matched controls without respiratory disease. We performed single-cell RNA-sequencing and multiplex immunostaining on peripheral blood mononuclear cells collected at the COVID-19 patients’ first visit after ICU discharge. Six months later, symptoms, restriction and PF improved in some (Early-Resolving COVID PF), but persisted in others (Late-Resolving COVID PF). Results: Circulating monocytes were significantly reduced in Late-Resolving COVID PF patients compared to Early-Resolving COVID PF and non-diseased controls. Monocyte abundance correlated with pulmonary function tests FVC and DLCO. Differential expression analysis revealed MHC-II class molecules were upregulated on the CD8 T cells of Late-Resolving COVID PF patients but downregulated in monocytes. IPF patients had a similar decrease in monocyte abundance and marked decrease in monocyte HLA-DR protein expression compared to Late-Resolving COVID PF patients. Conclusion: Circulating monocyte abundance may distinguish between patients whose post-COVID PF resolves or persists. Furthermore, fibrotic progression coincided with decreases in HLA-DR expression on monocytes, a phenotype previously associated with dampened antigen stimulation and severe respiratory failure.
A joint transcriptome-wide association study across multiple tissues identifies new candidate susceptibility genes for breast cancer
Authors: Gao Guimin , Fiorica Peter N. , McClellan Julian , Barbeira Alvaro , Li James L. , Olopade Olufunmilayo I. , Im Hae Kyung , Huo Dezheng
Published: October 2022

Genome-wide association studies (GWAS) have identified more than 200 genomic loci for breast cancer risk, but specific causal genes in most of these loci have not been identified. In fact, transcriptome-wide association studies (TWAS) of breast cancer performed using gene expression prediction models trained in breast tissue have yet to clearly identify most target genes. To identify novel candidate genes, we performed a joint TWAS analysis that combined TWAS signals from multiple tissues. We used expression prediction models trained in 47 tissues from the Genotype-Tissue Expression data using a multivariate adaptive shrinkage method along with association summary statistics from the Breast Cancer Association Consortium and UK Biobank data. We identified 380 genes at 129 genomic loci to be significantly associated with breast cancer at the Bonferroni threshold (p < 2.36 × 10−6). Of them, 29 genes were located in 11 novel regions that were at least 1Mb away from published GWAS hits. The rest of TWAS-significant genes were located in 118 known genomic loci from previous GWAS of breast cancer. After conditioning on previous GWAS index variants, we found that 22 genes located in known GWAS loci remained statistically significant. Our study maps potential target genes in more than half of known GWAS loci and discovers multiple new loci, providing new insights into breast cancer genetics.
Early Surgery in Very Preterm Infants is Associated with Brain Abnormalities on Term MRI: A Propensity Score Analysis
Authors: Kojima Katsuaki , Liu Chunyan , Ehrlich Shelley , Kline-Fath Beth M , Jain Shipra , Parikh Nehal A ,   the Cincinnati Infant Neurodevelopment Early Prediction Study (CINEPS) Investigators
Published: October 2022

Objective

To investigate the association between exposure to surgery under general anesthesia during the newborn period and brain abnormalities and neurodevelopmental outcomes in very preterm infants. We hypothesized that exposure to surgery under general anesthesia was associated with structural brain abnormalities on MRI at term-equivalent age and neurodevelopmental impairments at two years corrected age.

Study design

This prospective observational study includes 392 infants born at or below 32 weeks’ gestational age. Participants completed brain MRI at term-equivalent age and Bayley-III assessment at two years corrected age. We assessed the MRI global brain abnormality score as our primary outcome. Our secondary outcomes were scores on the Bayley-III Cognitive, Language, and Motor subscales. We evaluated the independent effects of surgery on brain MRI abnormalities and neurodevelopmental outcomes using ANOVA analyses after propensity score matching.

Results

All infants completed brain MRI, and 338 (86%) completed neurodevelopmental testing. Forty-five received surgery under general anesthesia. Exposure to surgery was associated with worse MRI abnormalities. None of the developmental outcomes was associated with surgery after propensity score matching. The global brain abnormality score was associated with the Bayley Cognitive and Motor composite scores.

Conclusions

Very preterm infants exposed to surgery under general anesthesia were at higher risk of brain abnormalities on MRI at term but not adverse neurodevelopmental outcomes at two years. Global brain abnormality score on MRI was associated with neurodevelopmental outcomes at two years. Brain MRI measures at term may function as sensitive intermediate measures of neurodevelopmental outcomes for very preterm infants.
Design and validation of an automated radiation therapy treatment planning approach for locally advanced lung cancer
Authors: Pogue Joel A. , Cardenas Carlos E. , Harms Joseph , Soike Michael H. , Kole Adam J. , Schneider Craig S. , Veale Christopher , Popple Richard , Belliveau Jean-Guy , McDonald Andrew M. , Stanley Dennis N.
Published: October 2022

Purpose

Radiation therapy planning for locally-advanced non-small cell lung cancer (NSCLC) is challenging due to the balancing of target coverage and organs-at-risk (OAR) sparing. Using the Varian Ethos Treatment Planning System (TPS), we developed a methodology to automatically generate efficient, high-quality treatment plans for locally-advanced lung cancer patients.

Methods and Materials

Fifty patients previously treated with Eclipse-generated plans for inoperable Stage IIIA-IIIC NSCLC were included in this Institutional Review Board (IRB)-approved retrospective study. Fifteen patients were used to iteratively optimize an Ethos TPS planning template, and the remaining thirty-five patients had plans automatically generated without manual intervention using the created template. Ethos and Eclipse plan quality was then assessed using 1) standard dose volume histogram (DVH) metrics, 2) adherence to clinical trial objectives, and 3) radiation oncologist qualitative review.

Results

Ethos-generated plans showed improved primary and nodal planning target volume (PTVp and PTVn, respectively) V100% and V95% coverage (p<0.001) and reduced PTVp Dmax values (p=0.023). Furthermore, the Ethos template-generated plans had lower spinal cord Dmax, lungs V5Gy, and heart V25Gy, V30Gy, and V45Gy values (p≤0.021). However, Ethos esophagus metrics (mean, V35Gy, V50Gy, Dmax) and brachial plexus metrics (Dmax) were greater than Eclipse (p≤0.008), but were still clinically acceptable. A large majority (80%) of automatically generated plans had entirely “per protocol” or “variation acceptable” metrics. Three radiation oncologists qualitatively scored the Ethos plans; 78% of plans were scored as clinically acceptable during physician evaluation, with zero plans receiving scores requiring major changes.

Conclusions

A standard Ethos template generated lung cancer radiotherapy plans with greater target coverage, increased spinal cord, heart, and lung V5Gy sparing, but increased esophagus and brachial plexus dose, compared to manually generated Eclipse plans. This template elucidates an efficient approach for generating automated, high quality lung radiation therapy treatment plans.
Population-level risk factors related to measles case fatality: a conceptual framework based on expert consultation and literature review
Authors: Sbarra Alyssa N. , Jit Mark , Mosser Jonathan F. , Ferrari Matthew , Cutts Felicity , Papania Mark , Kretsinger Katrina , McCarthy Kevin A. , Thakkar Niket , Gaythorpe Katy A. M. , Gamage Deepa , Krause L. Kendall , Dansereau Emily , Portnoy Allison
Published: October 2022

Introduction

A better understanding of population-level factors related to measles case fatality is needed to estimate measles mortality burden and impact of interventions such as vaccination. This study aimed to develop a conceptual framework of mechanisms associated with measles case fatality ratios (CFRs) and assess the scope of evidence available for related indicators in the published literature.

Methods

Using expert consultation, we developed a conceptual framework of mechanisms associated with measles CFR and identified population-level indicators potentially associated with each mechanism. We then conducted a literature review by searching PubMed on October 31, 2021 to determine and classify the scope of evidence for the indicators identified by expert consultation. Studies were included if they contained evidence of an association between an indicator and measles CFR and were excluded if they were from non-human studies or reported non-original data.

Results

Expert consultation identified five mechanisms in a conceptual framework of factors related to measles CFR: health system access and care-seeking behaviors, health system quality, measles control and epidemiology, nutritional status, and risk of secondary infection. Thirty-seven measurable population-level indicators were identified by expert consultation as proxies for the mechanisms. We identified 3772 studies for review and found 49 studies showing at least one significant association with CFR for 15 indicators and only non-significant associations for 5 indicators. Inadequate data were available to evaluate the remaining 17 indicators. A randomized controlled trial provided evidence for a relationship between vitamin A treatment and measles CFR. Average household size, educational attainment, first-dose coverage of measles-containing vaccine, human immunodeficiency virus prevalence, second-dose coverage of measles-containing vaccine, stunting prevalence, surrounding conflict, travel time to major city or settlement, travel time to nearest health care facility, under-five mortality rate, underweight prevalence, vitamin A deficiency prevalence, and wasting prevalence had quantitative observational level evidence. Level of health care available had qualitative evidence of a relationship with measles CFR.

Conclusion

To reduce uncertainty in measles CFR estimation, population-level factors representative of underlying mechanisms associated with CFR could be used. Our study used expert consultation and literature review to provide additional insights and a summary of the available evidence of these underlying mechanisms and indicators that could inform future estimations of measles CFR.
COVID treatment and in-hospital length of stay inequalities between race in the US over time
Authors: Althouse Benjamin M. , Baker Charlotte , Smits Peter D , Gratzl Samuel , Lee Ryan H , Cartwright Brianna M Goodwin , Simonov Michael , Wang Michael D , Stucky Nicholas L
Published: October 2022

Introduction

Demonstrated health inequalities persist in the United States. SARS-CoV-2 (COVID) has been no exception, with access to treatment and hospitalization differing across race or ethnic group. Here we aim to assess differences in treatment with remdesivir and hospital length of stay across four waves of the pandemic.

Methods

Using a subset of the Truveta data we examine odds ratios (OR) of in-hospital remdesivir treatment and risk ratios (RR) of in-hospital length of stay between Black or African American (Black) to white patients. We adjusted for confounding factors such as age, sex, and comorbidity status.

Results

There were statically significant lower rates of remdesivir treatment and longer in-hospital lengths of stay comparing Black patients to white patients early in the pandemic (OR for treatment: 0.88, 95% confidence interval [CI]: 0.80, 0.96; RR for length of stay: 1.17, CI: 1.06, 1.21). Rates became close to parity between groups as the pandemic progressed.

Conclusions

While inpatient remdesivir treatment rates increased and length of stay decreased over the beginning course of the pandemic, there are still inequalities in patient care.
Overexpression of Cancer- and Neurotransmitter-Associated Genes in the Nucleus Accumbens of Smokers
Authors: Stein Richard , Mamdani Firoza , Bunney Blynn , Cartagena Preston , Vawter Marquis P. , Schatzberg Alan F. , Barchas Jack , Lee Francis S. , Myers Richard , Watson Stanley J. , Akil Huda , Bunney William E. , Sequeira Adolfo
Published: October 2022

The effects of smoking in the human brain were explored at the molecular level in thenucleus accumbens(NAcc), a key brain region involved in tobacco addiction. Gene expression data from post-mortem NAcc were analyzed according to smoking habits: Never smokers, Former smokers and Current smokers at the time of death. The effect of smoking was determined using an ANCOVA model, controlling for potential confounders (psychiatric diagnosis, gender, age, post-mortem interval, and brain pH) followed by pair-wise post-hoc comparisons. Q-values (false discovery rate adjusted p-values) < 0.05 were used in combination with a fold change of > ±1.3 to identify the most relevant genes. The greatest number of differentially expressed genes (DEGs) were found in subjects with a recent history of smoking (Current smokers) compared to either Former or Never smokers. Only two genes were differentially expressed between Former and Never smokers, suggesting that the effects of smoking on gene expression in the brain may be transient. Ingenuity Pathway Analysis (IPA) of DEGs identified a significant over-representation of neurotransmitter system genes (glutamate, GABA) in Current smokers. IPA also revealed many genes associated with cancer in Current smokers compared to Former and Never smokers despite no known cancer in any subjects. Genes associated with neoplasms, glioblastoma, gliomas and tumor regulations are among the top 10 transcripts.Our findings show that active smokers have a significant increase in cancer-related genes and alterations in glutamate and GABA neurotransmitter systems in the NAcc. To our knowledge this is the first study to identify cancer-related genes in the NAcc in Current smokers who have no evidence of cancer.
Horizontal transferred T-DNA and haplotype-based phylogenetic analysis uncovers the origin of sweetpotato
Authors: Yan Mengxiao , Li Ming , Wang Yunze , Wang Xinyi , Moeinzadeh M-Hossein , Quispe-Huamanquispe Dora G. , Fan Weijuan , Wang Yuqin , Nie Haozhen , Wang Zhangying , Heider Bettina , Jarret Robert , Kreuze Jan F. , Gheysen Godelieve , Wang Hongxia , Bock Ralph , Vingron Martin , Yang Jun
Published: October 2022

The hexaploid sweetpotato is one of the most important root crops worldwide. However, its genetic origins are controversial. In this study, we identified two progenitors of sweetpotato by horizontal gene transferred IbT-DNA and haplotype-based phylogenetic analysis. The diploid progenitor is the diploid form of I. aequatoriensis, contributed the B1 subgenome, IbT-DNA2 and lineage 2 type of chloroplast genome to sweetpotato. The tetraploid progenitor of sweetpotato is I. batatas 4x, donating the B2 subgenome, IbT-DNA1 and lineage 1 type of chloroplast genome. Sweetpotato derived from the reciprocal cross between the diploid and tetraploid progenitors and a subsequent whole genome duplication. We also detected biased gene exchanges between subgenomes. The B1 to B2 subgenome conversions were almost 3-fold higher than the B2 to B1 subgenome conversions. This study sheds lights on the evolution of sweetpotato and paves a way for the improvement of sweetpotato.
Comparison of personality structures between methodologies: personality ratings and behavioural observations in Japanese macaques (Macaca fuscata)
Authors: Katayama Kosho , Nakamichi Masayuki , Yamada Kazunori
Published: October 2022

In this study, we aimed to clarify the structure of personality of Japanese macaques (Macaca fuscata) using two methods, personality ratings and behavioural observation, which are frequently used in primate personality studies. Principal component analysis of personality ratings sampled in two waves that were assessed with questionnaires (Stevenson-Hinde and Zunz questionnaire in Wave 1 and Hominoid Personality Questionnaire in Wave 2) revealed four components for each wave: Dominance, Aggressiveness, Dependency, and Component4 and Dominance, Aggressiveness, Sociability, and Activity. By calculating the correlation coefficients for principal component loadings of personality ratings, we compared the personality structure of other primates from previous studies with that of Japanese macaques. Based on these results, we propose that the factors common to macaques and capuchin monkeys fall into the following four categories of Dominance, which correlates with dominance rank; Excitability, which expresses aggression and neuroticism; Sociability, which indicates how actively they try to interact with others; and Activity, which expresses exploratory behaviour and openness. Analysis of data from behavioural observation extracted four components: Kin-biased-approaching, Grooming-diversity, Activity, and Aggressiveness. Principal component scores were calculated from each rating and behavioural observation data, and correlation coefficients were used to examine whether the same personality traits were found in both these methods. In this analysis, the raters did not collect behavioural data to ensure that data from both these methods did not overlap. No identical personality traits were found between the two methods. This result may indicate that there was no specific personality structure in Japanese macaques and that each method assessed different aspects of behavioural patterns pertaining to animal behaviour. It is difficult to assume from this study the cross-situational consistency conventionally assumed by personality psychology, and the results suggest that individuals vary in the way their behaviour changes in response to their environment, that is, coherence.
Notch signaling pathway in tooth shape variations
Authors: Mitsiadis Thimios A. , Pagella Pierfrancesco , Rodrigues Helder Gomes , Tsouknidas Alexander , Ramenzoni Liza L. , Radtke Freddy , Mehl Albert , Viriot Laurent
Published: October 2022

Evolutionary changes in vertebrates are linked to genetic alterations that often affect tooth-crown shape, which is a criterion of speciation events. The Notch pathway is highly conserved between species and controls morphogenetic processes in most developing organs, including teeth. Epithelial loss of the Notch-ligand Jagged1 in developing mouse molars affects the location, size and interconnections of their cusps that lead to minor tooth-crown shape modifications convergent to those observed along Muridae evolution. These alterations are due to the modulation of numerous genes, where Notch signaling is a hub for essential morphogenetic networks. A three-dimensional metamorphosis approach allowed tooth morphology prediction in individuals carrying Jagged1 mutations. These results shed new light on Notch/Jagged1-mediated signaling as one of the crucial components for dental variations in evolution.

Significance statement

Dental microevolution changes in vertebrates are regulated by the Notch signaling pathway.
Mapping the potential distribution of the principal vector of Crimean-Congo hemorrhagic fever virus Hyalomma marginatum in Europe
Authors: Celina Seyma S. , Černý Jiří , Samy Abdallah M.
Published: October 2022

Crimean-Congo haemorrhagic fever (CCHF) is the most widely distributed tick-borne viral disease in humans. The virus is widely expanded across western China, South Asia, and the Middle East to southeastern Europe and Africa. Its causative agent, Crimean-Congo haemorrhagic fever virus (CCHFV), is among the deadliest human pathogens in Africa and Eurasia. The historical known distribution of the CCHFV vector Hyalomma marginatum in Europe included most of the Mediterranean and the Balkan countries, Ukraine, and southern Russia. Further expansion of its potential distribution is possibly occurred in and out of the Mediterranean region. This study updated the map of the principal vector of CCHFV, H. marginatum, in the Old World. The model estimated the environmental suitability of H. marginatum in the Old World, including Europe. On the continental European scale, the model anticipated a widespread potential distribution, covering southern, western, central, and eastern Europe, as far north as southern parts of Scandinavian countries. The distribution of H. marginatum also covered the countries across the central part of Europe where the species is not autochthonous. All models were statistically robust and performed better than random (p < 0.001). Based on the results of the model, climatic conditions could hamper the successful overwintering of H. marginatum and their survival as adults in many areas of the region. Regular updates of the models, using updated occurrence, current, and future climatic data are recommended to regularly assess the areas at risk.

Hyalomma marginatum is a vector of numerous highly important human and animal pathogens. It is the main vector of Crimean-Congo haemorrhagic fever virus (CCHFV) in Europe. This study updated the potential distribution of H. marginatum on a global scale, including Europe, with a particular focus on Central Europe. The model predicted a widespread potential distribution of H. marginatum on the continental European scale, anticipating occurrences of H. marginatum in southern, western, central, and eastern Europe, as far north as southern parts of Scandinavian countries. In Central Europe, H. marginatum populations have not been established in any of the countries yet, but the presence of the species has been reported from all countries in the region. Their potential spread northwards and establishment of permanent populations of H. marginatum in the north are therefore of great importance, in particular since the immature stages of H. marginatum are frequently found on migratory birds flying northwards to temperate Europe. Our ecological niche model of H. marginatum in Central Europe anticipated its distribution in all countries of the region. Our prediction for current global potential distribution of this tick species can help in understanding disease risk areas associated with this vector.
Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection
Authors: Ghorbani Peyman , Kim Sang Yong , Smith Tyler K.T. , Minarrieta Lucía , Robert-Gostlin Victoria , Kilgour Marisa K. , Ilijevska Maja , Alecu Irina , Snider Shayne A. , Margison Kaitlyn D. , Nunes Julia R.C. , Woo Daniel , Pember Ciara , O’Dwyer Conor , Ouellette Julie , Kotchetkov Pavel , St-Pierre Julie , Bennett Steffany A.L. , Lacoste Baptiste , Blais Alexandre , Nair Meera G. , Fullerton Morgan D.
Published: October 2022

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated upregulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably,Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded byRetnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with intestinal helminthsHeligmosomoides polygyrusorNippostrongylus brasiliensiswere treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolismin vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity toH. polygyruswith increased egg burden, but there were no differences in intestinal worm count nor differences inN. brasiliensisparasite burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

Abstract Figure
Two opposing effects of monovalent cations on the stability of i-motif structure
Authors: Kim Sung Eun , Hong Seok-Cheol
Published: October 2022

At acidic pH, cytosine-rich single-stranded DNA can be folded into a tetraplex structure called i-motif (iM). In recent studies, the effect of monovalent cations on the stability of iM structures has been addressed, but a consensus about the issue has not been reached yet. Thus, we investigated the effects of various factors on the stability of iM structures using fluorescence resonance energy transfer (FRET)-based analysis for three types of iM derived from human telomere sequences. We confirmed that the iM structure is destabilized as the concentration of monovalent cations (Li+, Na+, K+) increases and that Li+ has the greatest tendency of destabilization. This cation-induced destabilization is rather unexpected and specific to the iM structure, considering the cation’s electrostatic effect of supporting DNA folding. Monovalent cations of different kinds promote the flexibility of single-stranded DNA (ssDNA) and the stability of folded DNA structures to different degrees, suggesting that the size of cation be a key factor in its function. All taken together, we conclude that the stability of iM structures is controlled by the subtle balance of the two counteractive effects of monovalent cations, electrostatic screening and disruption of cytosine base pairing.