bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental history modulates adult olfactory behavioral preferences via regulation of chemoreceptor expression in Caenorhabditis
elegans
Authors: Kyani-Rogers Travis , Philbrook Alison , McLachlan Ian G , Flavell Steven W , O’Donnell Michael P , Sengupta Piali
Published: September 2022

Developmental experiences play critical roles in shaping adult physiology and behavior. We and others previously showed that adult Caenorhabditiselegans which transiently experienced dauer arrest during development (postdauer) exhibit distinct gene expression profiles as compared to control adults which bypassed the dauer stage. In particular, the expression patterns of subsets of chemoreceptor genes are markedly altered in postdauer adults. Whether altered chemoreceptor levels drive behavioral plasticity in postdauer adults is unknown. Here, we show that postdauer adults exhibit enhanced attraction to a panel of food-related attractive volatile odorants including the bacterially produced chemical diacetyl. Diacetyl-evoked responses in the AWA olfactory neuron pair are increased in both dauer larvae and postdauer adults, and we find that these increased responses are correlated with upregulation of the diacetyl receptor ODR-10 in AWA likely via both transcriptional and posttranscriptional mechanisms. We show that transcriptional upregulation of odr-10 expression in dauer larvae is in part mediated by the DAF-16 FOXO transcription factor. Via transcriptional profiling of sorted populations of AWA neurons from control and postdauer animals, we further show that the expression of a subset of additional chemoreceptor genes in AWA is regulated similarly to odr-10 in postdauer animals. Our results suggest that developmental experiences may be encoded at the level of olfactory receptor regulation, and provide a simple mechanism by which C. elegans is able to precisely modulate its behavioral preferences as a function of its current and past experiences.
Recognizing Early Childhood Education as a Human Right in International Law
Authors: Fredman Sandra , Donati Georgina , Richter Linda M , Naicker Sara N , Behrman Jere R , Lu Chunling , Cohrssen Caroline , Lopez Boo Florencia , Raghavan Chemba , Devercelli Amanda , Heymann Jody , Stein Alan ,   Harnessing Global Data to Advance Young Children’s Learning and Development Consortium
Published: September 2022

There is incontrovertible evidence that early learning opportunities shape long-term development and health. Nevertheless, early childhood care and education (ECCE) is not expressly mentioned as part of the right to education in the Convention on the Rights of the Child, the International Covenant on Economic, Social and Cultural Rights, and the Convention on the Rights of Persons with Disabilities. This paper argues that the right to education can nevertheless be regarded as including ECCE. We examine the treaties, General Comments, and 264 Concluding Observations by relevant UN monitoring bodies, covering 152 countries from 2015 to 2020, to determine whether the right to ECCE is regarded as part of States’ obligations and the content of the duty. These demonstrate consistently that States must provide affordable, accessible, quality, inclusive ECCE, with adequate resources. We argue that monitoring committees should draw these obligations together in one General Comment, thereby improving States’ accountability and guiding the delivery of ECCE.
Infliximab Trough Levels Are Associated With Transmural Sonographic Healing in Inflammatory Bowel Disease
Authors: Vaughan Rose , Murphy Elise , Nalder Michelle , Gibson Robert N , Ardalan Zaid , Boussioutas Alex , Christensen Britt
Published: September 2022

Background

Mucosal healing improves clinical outcomes in patients with inflammatory bowel disease (IBD) and is associated with higher infliximab trough levels (ITLs). Transmural healing, assessed by intestinal ultrasound (IUS), is emerging as an objective target in Crohn’s disease (CD) and ulcerative colitis (UC). This study explores the correlation between maintenance ITLs and sonographic transmural healing.

Methods

Patients on maintenance infliximab therapy were prospectively enrolled to undergo paired IUS examination and serum ITL. Infliximab trough levels were compared between patients with and without sonographic markers of inflammation using the Mann-Whitney U test.

Results

A prospective cohort of 103 patients (51% male; 79 CD; 24 UC; median duration of disease 8 years) underwent IUS and serum ITL testing. Forty-one percent of CD and 66% of UC patients demonstrated sonographic healing (bowel wall thickening ≤3 mm with no increase in color Doppler signal). Crohn’s disease patients with sonographic healing had higher median ITL compared with those with sonographic inflammation (4.8 μg/mL vs 3.1 μg/mL; P = .049). Additionally, the presence of hyperemia on Doppler was independently associated with lower ITL compared with those without hyperemia (2.1 μg/mL vs 4.2 μg/mL, respectively; P = .003). There was no significant association between ITL and other sonographic markers of inflammation. In UC, lower ITL was associated with hyperemia on Doppler imaging (P = .04). There was no association between ITL and sonographic healing or any other individual sonographic parameter of inflammation.

Conclusions

Lower maintenance infliximab levels are associated with sonographic parameters of inflammation in UC and CD. Further studies are needed to determine whether targeting higher infliximab levels can increase sonographic healing.
Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir
Authors: Margot Nicolas A , Naik Vidula , VanderVeen Laurie , Anoshchenko Olena , Singh Renu , Dvory-Sobol Hadas , Rhee Martin S , Callebaut Christian
Published: September 2022

Background

Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study.

Methods

CAPELLA enrolled viremic HTE PWH with resistance to ≥3 of 4 of the main antiretroviral (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline resistance was evaluated in participants experiencing virologic failure.

Results

At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one-third of participants having exhausted all drugs from ≥3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection.

Conclusions

LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.
Correlations of inclusion-based rock-physics model inputs from Bayesian analysis
Authors: Spikes Kyle T , Sen Mrinal K
Published: September 2022

For any given rock-physics model, knowledge of correlations among its inputs helps to define geologically and physically meaningful and informed models for a given problem. These informed models can, in turn, reduce the uncertainty in forward and inverse problems. We use a Bayesian framework to identify such correlations among inputs of two rock-physics models. That framework makes use of velocity and porosity measurements on both dry and brine-saturated carbonate samples. Two inclusion-based rock-physics models, the self-consistent approximation and the differential effective medium model, are analyzed along with these data to identify the underlying correlations. To do so, the posterior distribution must be evaluated, which is based on a prior model and the calculated likelihood function. Exhaustive sampling of the posterior is convenient in this case because relatively few input parameters to consider. Results are multi-variate histograms that indicate maximum a posteriori values of the inputs. Correlations among the inputs become evident when the Bayesian analysis is repeated many times with different prior models. These correlated values provide the inputs to optimized maximum a posteriori models. The correlations identified for the two rock-physics models under study should be used in relevant applications. Finally, all rock-physics models, along with an appropriate data set, should be examined in a similar Bayesian framework.
Prevalence and risk estimation of cancer-predisposing genes for upper urinary tract urothelial carcinoma in Japanese
Authors: Sekine Yuya , Iwasaki Yusuke , Hakozaki Nozomi , Endo Mikiko , Kamatani Yoichiro , Matsuda Koichi , Murakami Yoshinori , Sano Takeshi , Akamatsu Shusuke , Kobayashi Takashi , Nakagawa Hidewaki , Numakura Kazuyuki , Narita Shintaro , Habuchi Tomonori , Momozawa Yukihide
Published: September 2022

Upper urinary tract urothelial carcinoma is a rare cancer that has been associated with mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2. In addition, patients with pathogenic variants of cancer-predisposing genes such as BRCA1 and BRCA2 have been reported. However, how cancer-predisposing genes affect the risk of upper urinary tract urothelial carcinoma in the Japanese population remains unclear. Thus, we performed a case–control sequencing study of 27 cancer-predisposing genes in 208 upper urinary tract urothelial carcinoma patients and 37 727 controls. Only MSH6 and MSH2 were observed with a value of P < 0.05. However, there was no difference in the prevalence of pathogenic variants of BRCA1/2, which does not support the use of a poly adenosine diphosphate-ribose polymerase inhibitor in patients with upper urinary tract urothelial carcinoma. Only mismatch repair genes were associated with patients with upper urinary tract urothelial carcinoma, but the prevalence of pathogenic variants in mismatch repair genes was lower than that reported in previous studies from other populations.
Prescribing unproven cancer drugs: physician perspectives on expanded access and right to try
Authors: Manley Haley , Sisk Bryan A , Master Zubin , Scott Christopher Thomas
Published: September 2022

Background

For gravely ill patients who have no treatment options and who are ineligible for clinical trials, the US Food and Drug Administration (FDA) established the Expanded Access Program (EAP). Motivated by efforts to weaken FDA regulation and sold as providing greater access to experimental drugs, the federal Right to Try Act (RTT) was passed in 2017. It reduces FDA oversight by not requiring physicians to report safety data and foregoes approval of protocols by local institutional review boards.

Methods

This study explored the views of 17 neuro-oncologists from 15 different academic medical centers with varying experience with EAP and RTT using convenience sampling. We conducted semi-structured interviews and qualitative analysis to identify emerging themes.

Results

Most oncologists were confused between the two pathways, had little familiarity with RTT, and had little knowledge about experimental medicine available through either pathway. Oncologists reported a preference of enrolling patients in clinical trials over off-trial preapproval pathways with scant data. As a result, oncologists revealed concerns over properly evaluating risks for their patients.

Conclusion

Our findings suggest that neuro-oncologists need better resources and clearer mechanisms at their institutions to help navigate EAP and RTT in order to counsel patients interested in experimental medicine.
Predicting plant Rubisco kinetics from RbcL sequence data using machine learning
Authors: Iqbal Wasim A , Lisitsa Alexei , Kapralov Maxim V
Published: September 2022

Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is responsible for the conversion of atmospheric CO2 to organic carbon during photosynthesis, and often acts as a rate limiting step in the later process. Screening the natural diversity of Rubisco kinetics is the main strategy used to find better Rubisco enzymes for crop engineering efforts. Here, we demonstrate the use of Gaussian processes (GPs), a family of Bayesian models, coupled with protein encoding schemes, for predicting Rubisco kinetics from Rubisco large subunit (RbcL) sequence data. GPs trained on published experimentally obtained Rubisco kinetic datasets were applied to over 9000 sequences encoding RbcL to predict Rubisco kinetic parameters. Notably, our predicted kinetic values were in agreement with known trends, e.g. higher carboxylation turnover rates (Kcat) for Rubisco enzymes from C4 or crassulacean acid metabolism (CAM) species, compared with those found in C3 species. This is the first study demonstrating machine learning approaches as a tool for screening and predicting Rubisco kinetics, which could be applied to other enzymes.
Distribution, trends, and antifungal susceptibility ofCandidaspecies causing candidemia in Japan, 2010–2019: A retrospective observational study based on national surveillance data
Authors: Kajihara Toshiki , Yahara Koji , Nagi Minoru , Kitamura Norikazu , Hirabayashi Aki , Hosaka Yumiko , Abe Masahiro , Miyazaki Yoshitsugu , Sugai Motoyuki
Published: September 2022

The increasing incidence of candidemia and the emergence of drug-resistant Candida species are major concerns worldwide. Therefore, long-term surveillance studies are required. Here, we provide one of the largest longitudinal overviews of the trends in the prevalence of Candida species using national data of 57 001 candidemia isolates obtained from > 2000 hospitals for the 2010–2019 period in the Japan Nosocomial Infections Surveillance database. The proportion of Candida species, except Candida krusei and Candida guilliermondii, was almost the same during the study period. The proportion of C. guilliermondii surpassed that of C. krusei in 2014. The incidence of candidemia due to C. albicans (P < 0.0001), C. parapsilosis (P = 0.0002), and C. tropicalis (P < 0.0001) have decreased significantly over this period. Azole susceptibility of C. tropicalis was low, with 17.8% of isolates resistant to fluconazole and 13.5% resistant to voriconazole. The micafungin susceptibility of C. glabrata was low, with 8.0% of isolates showing resistance. The resistance rate of C. krusei toward amphotericin B fluctuated considerably (between 3.2% and 35.7%) over this period. The incidence rate of candidemia caused by C. parapsilosis and C. guilliermondii in hospitals responsible for bone marrow transplantation was significantly higher than that in other hospitals. Overall, our study suggests that in Japan, the species distribution of Candida was almost the same in this period and similar to that reported in North America and Europe. A relatively high resistance to azoles and micafungin was observed in C. glabrata, C. tropicalis, and C. krusei isolates, which require continued surveillance.
Could kilomasers pinpoint supermassive stars?
Authors: Nowak Katarzyna , Krause Martin G H , Schaerer Daniel
Published: September 2022

A strong nuclear kilomaser, W1, has been found in the nearby galaxy NGC 253, associated with a forming super star cluster. Kilomasers could arise from the accretion disc around supermassive stars (>103 M⊙), hypothetical objects that have been proposed as polluters responsible for the chemical peculiarities in globular clusters. The supermassive stars would form via runaway collisions, simultaneously with the cluster. Their discs are perturbed by stellar flybys, inspiralling and colliding stars. This raises the question if an accretion disc would at all be able to survive in such a dynamic environment and mase water lines. We investigated what the predicted maser spectrum of such a disc would look like using 2D hydrodynamic simulations and compared this to the W1 kilomaser. We derived model maser spectra from the simulations by using a general maser model for appropriate disc temperatures. All our model discs survived. The model maser spectra for the most destructive case for the simulations of M⋆ = 1000 M⊙ are a reasonable match with the W1 kilomaser spectrum in terms of scaling, flux values and some of the signal trends. Details in the spectrum suggest that a star of a few 1000 M⊙ might fit even better, with 10 000 M⊙ clearly giving too large velocities. Our investigations thus support the hypothesis that kilomasers could pinpoint supermassive stars.
Turbulence in outer protoplanetary discs: MRI or VSI?
Authors: Cui Can , Bai Xue-Ning
Published: September 2022

The outer protoplanetary discs (PPDs) can be subject to the magnetorotational instability (MRI) and the vertical shear instability (VSI). While both processes can drive turbulence in the disc, existing numerical simulations have studied them separately. In this paper, we conduct global 3D non-ideal magnetohydrodynamic (MHD) simulations for outer PPDs, with ambipolar diffusion and instantaneous cooling, and hence conductive to both instabilities. Given the range of ambipolar Elsässer numbers (Am) explored, it is found that the VSI turbulence dominates over the MRI when ambipolar diffusion is strong (Am = 0.1); the VSI and MRI can co-exist for Am = 1; and the VSI is overwhelmed by the MRI when ambipolar diffusion is weak (Am = 10). Angular momentum transport process is primarily driven by MHD winds, while viscous accretion due to MRI and/or VSI turbulence makes a moderate contribution in most cases. Spontaneous magnetic flux concentration and formation of annular substructures remain robust in strong ambipolar diffusion-dominated discs (Am ≤ 1) with the presence of the VSI. Ambipolar diffusion is the major contributor to the magnetic flux concentration phenomenon rather than advection.
Cytoprotective and genoprotective effects of taxifolin against oxidative damage in HTR-8/SVneo human trophoblast cells
Authors: Bruić Marija , Pirković Andrea , Vilotić Aleksandra , Jovanović-Krivokuća Milica , Spremo-Potparević Biljana
Published: September 2022

An increase of reactive oxygen species in the placenta and oxidative disbalance has been recognized as a significant factor contributing to pregnancy complications. Dietary intake of food rich in antioxidants during pregnancy could exert a protective role in the prevention of adverse outcomes such as preeclampsia, miscarriage, and others. Flavonoid taxifolin has shown numerous health-promoting effects in a large number of studies conducted on animals, as well as various human cell types in vitro. However, its effects on human placental cells—trophoblasts—have yet to be determined. Therefore, cytoprotective and genoprotective effects of taxifolin on trophoblast cell line HTR-8/SVneo under induced oxidative stress were explored in this study. Cytotoxicity of a range of taxifolin concentrations (1–150 µM) was evaluated using the MTT and crystal violet assays. A model of oxidative stress was achieved by exposing HTR-8/SVneo cells to H2O2. To determine cytoprotective and antigenotoxic effects, the cells were pre-incubated with three concentrations of taxifolin (10, 50, and 100 µM) and then exposed to H2O2. Taxifolin in concentrations of 1, 5, 10, 25, 50, and 100 µM showed no cytotoxic effects on HTR-8/SVneo cells, but 150 µM of taxifolin caused a significant decrease in adherent cell number, as detected by crystal violet assay. Pretreatment with the chosen concentrations of taxifolin showed a significant cytoprotective effect on H2O2-induced cytotoxicity, as determined by the MTT assay. Furthermore, taxifolin showed a significant reduction in H2O2-induced DNA damage, measured by comet assay. This study showed protective effects of taxifolin on human trophoblast cells exposed to oxidative damage. Further studies are needed to explore the underlying mechanisms.
Single and combined potential of polystyrene microparticles and fluoranthene in the induction of DNA damage in haemocytes of Mediterranean mussel (Mytilus galloprovincialis)
Authors: Kolarević Stoimir , Kračun-Kolarević Margareta , Marić Jovana Jovanović , Djordjević Jelena , Vuković-Gačić Branka , Joksimović Danijela , Martinović Rajko , Bajt Oliver , Ramšak Andreja
Published: September 2022

In this study, the possible ‘vector effect’ within the exposure of Mediterranean mussels (Mytilus galloprovincialis) to polystyrene microplastics with adsorbed fluoranthene was investigated by applying the multibiomarker approach. The major focus was placed on genotoxicological endpoints as to our knowledge there are no literature data on the genotoxicity of polystyrene microparticles alone or with adsorbed fluoranthene in the selected experimental organisms. DNA damage was assessed in haemocytes by comet assay and micronucleus test. For the assessment of neurotoxicity, acetylcholinesterase activity was measured in gills. Glutathione S-transferase was assessed in gills and hepatopancreas since these enzymes are induced for biotransformation and excretion of lipophilic compounds such as hydrocarbons. Finally, differences in physiological response within the exposure to polystyrene particles, fluoranthene, or particles with adsorbed fluoranthene were assessed by the variation of heart rate patterns studied by the noninvasive laser fibre-optic method. The uniform response of individual biomarkers within the exposure groups was not recorded. There was no clear pattern in variation of acetylcholinesterase or glutathione S-transferase activity which could be attributed to the treatment. Exposure to polystyrene increased DNA damage which was detected by the comet assay but was not confirmed by micronucleus formation. Data of genotoxicity assays indicated differential responses among the groups exposed to fluoranthene alone and fluoranthene adsorbed to polystyrene. Change in the heart rate patterns within the studied groups supports the concept of the Trojan horse effect within the exposure to polystyrene particles with adsorbed fluoranthene.
Advanced transcriptomic analysis reveals the role of efflux pumps and media composition in antibiotic responses ofPseudomonas aeruginosa
Authors: Rajput Akanksha , Tsunemoto Hannah , Sastry Anand V , Szubin Richard , Rychel Kevin , Chauhan Siddharth M , Pogliano Joe , Palsson Bernhard O
Published: September 2022

Pseudomonas aeruginosa is an opportunistic pathogen and major cause of hospital-acquired infections. The virulence of P. aeruginosa is largely determined by its transcriptional regulatory network (TRN). We used 411 transcription profiles of P. aeruginosa from diverse growth conditions to construct a quantitative TRN by identifying independently modulated sets of genes (called iModulons) and their condition-specific activity levels. The current study focused on the use of iModulons to analyze the biofilm production and antibiotic resistance of P. aeruginosa. Our analysis revealed: (i) 116 iModulons, 81 of which show strong association with known regulators; (ii) novel roles of regulators in modulating antibiotics efflux pumps; (iii) substrate-efflux pump associations; (iv) differential iModulon activity in response to beta-lactam antibiotics in bacteriological and physiological media; (v) differential activation of ‘Cell Division’ iModulon resulting from exposure to different beta-lactam antibiotics and (vi) a role of the PprB iModulon in the stress-induced transition from planktonic to biofilm lifestyle. In light of these results, the construction of an iModulon-based TRN provides a transcriptional regulatory basis for key aspects of P. aeruginosa infection, such as antibiotic stress responses and biofilm formation. Taken together, our results offer a novel mechanistic understanding of P. aeruginosa virulence.
Domain function and predicted structure of three heterodimeric endonuclease subunits of RNA editing catalytic complexes in Trypanosoma brucei
Authors: Carnes Jason , McDermott Suzanne M , Lewis Isaac , Tracy Maxwell , Stuart Kenneth
Published: September 2022

Each of the three similar RNA Editing Catalytic Complexes (RECCs) that perform gRNA-directed uridine insertion and deletion during Trypanosoma brucei mitochondrial (mt) mRNA editing has a distinct endonuclease activity that requires two related RNase III proteins, with only one competent for catalysis. We identified multiple loss-of-function mutations in the RNase III and other motifs of the non-catalytic KREPB6, KREPB7, and KREPB8 components by random mutagenesis and screening. These mutations had various effects on growth, editing, and both the abundances and RECC associations of these RNase III protein pairs in bloodstream form (BF) and procyclic form (PF) cells. Protein structure modelling predicted that the Zinc Finger (ZnF) of each paired RNase III protein contacts RNA positioned at the heterodimeric active site which is flanked by helices of a novel RNase III-Associated Motif (RAM). The results indicate that the protein domains of the non-catalytic subunits function together in RECC integrity, substrate binding, and editing site recognition during the multistep RNA editing process. Additionally, several mutants display distinct functional consequences in different life cycle stages. These results highlight the complementary roles of protein pairs and three RECCs within the complicated T. brucei mRNA editing machinery that matures mt mRNAs differentially between developmental stages.
Yeast transcriptional device libraries enable precise synthesis of value-added chemicals from methanol
Authors: Zhu Qiaoyun , Liu Qi , Yao Chaoying , Zhang Yuanxing , Cai Menghao
Published: September 2022

Natural methylotrophs are attractive methanol utilization hosts, but lack flexible expression tools. In this study, we developed yeast transcriptional device libraries for precise synthesis of value-added chemicals from methanol. We synthesized transcriptional devices by fusing bacterial DNA-binding proteins (DBPs) with yeast transactivation domains, and linking bacterial binding sequences (BSs) with the yeast core promoter. Three DBP–BS pairs showed good activity when working with transactivation domains and the core promoter of PAOX1 in the methylotrophic yeast, Pichia pastoris. Fine-tuning of the tandem BSs, spacers and differentiated input promoters further enabled a constitutive transcriptional device library (cTRDL) composed of 126 transcriptional devices with an expression strength of 16–520% and an inducible TRDL (iTRDL) composed of 162 methanol-inducible transcriptional devices with an expression strength of 30–500%, compared with PAOX1. Selected devices from iTRDL were adapted to the dihydromonacolin L biosynthetic pathway by orthogonal experimental design, reaching 5.5-fold the production from the PAOX1-driven pathway. The full factorial design of the selected devices from the cTRDL was adapted to the downstream pathway of dihydromonacolin L to monacolin J. Monacolin J production from methanol reached 3.0-fold the production from the PAOX1-driven pathway. Our engineered toolsets ensured multilevel pathway control of chemical synthesis in methylotrophic yeasts.
Splicing of branchpoint-distant exons is promoted by Cactin, Tls1 and the ubiquitin-fold-activated Sde2
Authors: Anil Anupa T , Choudhary Karan , Pandian Rakesh , Gupta Praver , Thakran Poonam , Singh Arashdeep , Sharma Monika , Mishra Shravan Kumar
Published: September 2022

Intron diversity facilitates regulated gene expression and alternative splicing. Spliceosomes excise introns after recognizing their splicing signals: the 5′-splice site (5′ss), branchpoint (BP) and 3′-splice site (3′ss). The latter two signals are recognized by U2 small nuclear ribonucleoprotein (snRNP) and its accessory factors (U2AFs), but longer spacings between them result in weaker splicing. Here, we show that excision of introns with a BP-distant 3′ss (e.g. rap1 intron 2) requires the ubiquitin-fold-activated splicing regulator Sde2 in Schizosaccharomyces pombe. By monitoring splicing-specific ura4 reporters in a collection of S. pombe mutants, Cay1 and Tls1 were identified as additional regulators of this process. The role of Sde2, Cay1 and Tls1 was further confirmed by increasing BP–3′ss spacings in a canonical tho5 intron. We also examined BP-distant exons spliced independently of these factors and observed that RNA secondary structures possibly bridged the gap between the two signals. These proteins may guide the 3′ss towards the spliceosome's catalytic centre by folding the RNA between the BP and 3′ss. Orthologues of Sde2, Cay1 and Tls1, although missing in the intron-poor Saccharomyces cerevisiae, are present in intron-rich eukaryotes, including humans. This type of intron-specific pre-mRNA splicing appears to have evolved for regulated gene expression and alternative splicing of key heterochromatin factors.
Impact of Antibiotics on the Lung Microbiome and Lung Function in Children With Cystic Fibrosis 1 Year After Hospitalization for an Initial Pulmonary Exacerbation
Authors: Inam Zaina , Felton Erin , Burrell Aszia , Chaney Hollis , Sami Iman , Koumbourlis Anastassios C , Freishtat Robert J , Zemanick Edith T , Crandall Keith A , Hahn Andrea
Published: September 2022

Background

Cystic fibrosis (CF) is characterized by recurrent pulmonary exacerbations (PEx) and lung function decline. PEx are frequently treated with antibiotics. However, little is known about the effects of antibiotics on the airway microbiome of persons with CF over time. The purpose of this study was to evaluate changes in the microbiome and lung function in persons with CF over 1 year following an initial study pulmonary exacerbation (iPEx).

Methods

Twenty children aged ≤18 years with CF were enrolled in the study, which occurred prior to the routine administration of highly effective modulator therapy. Respiratory samples and spirometry were obtained at a minimum of quarterly visits and up to 1 year after an iPEx. Metagenomic sequencing was performed, and bacterial taxa were assigned using MetaPhlAn 2.0. Paired t test, analysis of variance, and generalized least squares regression were used to compare outcome variables.

Results

The mean age of study participants at the time of the iPEx was 10.6 years. There were 3 ± 1.6 PEx treated with antibiotics per person during the study period. Bacterial richness was similar at 1 year compared to iPEx (40.3 vs 39.3, P = .852), whereas the mean Shannon diversity index was significantly higher at 1 year (2.84 vs 1.62, P < .001). The number of PEx treated with antibiotics was not associated with changes in microbial diversity but was associated with changes in lung function.

Conclusions

In our 1-year prospective study, we found that microbial diversity increased despite decreases in lung function associated with repeated PEx events requiring antibiotic therapy.
Disseminated Mycoplasma Orale Infection in Patients With Phosphoinositide-3-Kinase Regulatory Subunit 1 Mutations
Authors: Totten Arthur H , Uzel Gulbu , Khil Pavel P , Youn Jung-Ho , Treat Jennifer , Soutar Craig D , Holland Steven M , Dekker John P , Zerbe Christa S
Published: September 2022

Mycoplasma orale is a rare cause of invasive infection in immunodeficient hosts. Phosphatidylinositol 3-kinase, regulatory subunit 1 (PI3KR1) mutations predispose patients to sinopulmonary infections, alongside bronchiectasis autoimmunity and lymphoproliferation. We report 2 cases of PI3KR1 deficiency with invasive M orale and effective treatment options.
Starspots, chromospheric emission lines, and flares of zero-age main-sequence stars
Authors: Yamashita Mai , Itoh Yoichi , Oasa Yumiko
Published: September 2022

Zero-age main-sequence (ZAMS) stars are considered to have enormous starspots and show strong chromospheric emission lines because of their strong surface magnetic field. We discuss the dynamo activities of ZAMS stars with respect to their periodic light variation caused by a starspot and with respect to the strength of the chromospheric emission lines. The light curves of 33 ZAMS stars in IC 2391 and IC 2602 were obtained from TESS (Transiting Exoplanet Survey Satellite) photometric data. The light curves can be grouped into the following four categories: single frequency, possible shape changer, beater, and complex variability. The amplitudes of the light curves are 0.001–0.145 mag, similar to those of ZAMS stars in Pleiades. The starspot coverages are $0.1\%$–$21\%$. We found that the light variations and Ca ii emission line strength of ZAMS stars in IC 2391, IC 2602, and the Pleiades cluster are as large as those of the most active superflare stars and two orders larger than those of the Sun, and are located on the extensions of the superflare stars. These results suggest that superflare stars link the properties of the Sun to those of the ZAMS stars of ages between 30 and 120 Myr. ZAMS stars with a single frequency or possible shape change in the light curve tend to have both large light variation, indicating large spot coverage, and saturated Ca ii emission line strength. ZAMS stars with beat or complex variability have small spot coverage and a faint Ca ii emission line. We also detected 21 flares in the TESS light curves of 12 ZAMS stars in IC 2391 and IC 2602, where most of these stars have saturated chromospheric Ca ii emission lines. The energies of the flares are estimated to be ∼1033–1035 erg, which is comparable with the energy of a superflare.
Mendel: From genes to genome
Authors: Sussmilch Frances C , Ross John J , Reid James B
Published: September 2022

Two hundred years after the birth of Gregor Mendel, it is an appropriate time to reflect on recent developments in the discipline of genetics, particularly advances relating to the prescient friar’s model species, the garden pea (Pisum sativum L.). Mendel’s study of seven characteristics established the laws of segregation and independent assortment. The genes underlying four of Mendel’s loci (A, LE, I, and R) have been characterized at the molecular level for over a decade. However, the three remaining genes, influencing pod color (GP), pod form (V/P), and the position of flowers (FA/FAS), have remained elusive for a variety of reasons, including a lack of detail regarding the loci with which Mendel worked. Here, we discuss potential candidate genes for these characteristics, in light of recent advances in the genetic resources for pea. These advances, including the pea genome sequence and reverse-genetics techniques, have revitalized pea as an excellent model species for physiological–genetic studies. We also discuss the issues that have been raised with Mendel’s results, such as the recent controversy regarding the discrete nature of the characters that Mendel chose and the perceived overly-good fit of his segregations to his hypotheses. We also consider the relevance of these controversies to his lasting contribution. Finally, we discuss the use of Mendel’s classical results to teach and enthuse future generations of geneticists, not only regarding the core principles of the discipline, but also its history and the role of hypothesis testing.
Mosquito tagging using DNA-barcoded nanoporous protein microcrystals
Authors: Stuart Julius D , Hartman Daniel A , Gray Lyndsey I , Jones Alec A , Wickenkamp Natalie R , Hirt Christine , Safira Aya , Regas April R , Kondash Therese M , Yates Margaret L , Driga Sergei , Snow Christopher D , Kading Rebekah C
Published: September 2022

Conventional mosquito marking technology for mark–release–recapture (MRR) is quite limited in terms of information capacity and efficacy. To overcome both challenges, we have engineered, lab-tested, and field-evaluated a new class of marker particles, in which synthetic, short DNA oligonucleotides (DNA barcodes) are adsorbed and protected within tough, crosslinked porous protein microcrystals. Mosquitoes self-mark through ingestion of microcrystals in their larval habitat. Barcoded microcrystals persist trans-stadially through mosquito development if ingested by larvae, do not significantly affect adult mosquito survivorship, and individual barcoded mosquitoes are detectable in pools of up to at least 20 mosquitoes. We have also demonstrated crystal persistence following adult mosquito ingestion. Barcode sequences can be recovered by qPCR and next-generation sequencing (NGS) without detectable amplification of native mosquito DNA. These DNA-laden protein microcrystals have the potential to radically increase the amount of information obtained from future MRR studies compared to previous studies employing conventional mosquito marking materials.
Long Noncoding RNA Lx8-SINE B2 Interacts with Eno1 to Regulate Self-Renewal and Metabolism of Embryonic Stem Cells
Authors: Chen Fuquan , Li Xiaomin , Feng Xiao , Gao Tingting , Zhang Weiyu , Cheng Zhi , Zhao Xuan , Chen Ruiqing , Lu Xinyi
Published: September 2022

Long noncoding RNAs (lncRNAs) emerge as important orchestrators of biological processes in embryonic stem cells (ESCs). LncRNA Lx8-SINE B2 was recently identified as an ESC-specific lncRNA that marks pluripotency. Here, we studied the function of lncRNA Lx8-SINE B2 in ESCs. Depletion of Lx8-SINE B2 disrupted ESC proliferation, repressed the expression of pluripotency genes, activated differentiation genes, and inhibited reprogramming to induced pluripotent stem cells. The reduction of the colony formation ability of ESCs upon Lx8-SINE B2 knockdown was accompanied by the elongation of the G1 phase and the shortening of the S phase. Transcriptome analysis revealed that Lx8-SINE B2 deficiency affected multiple metabolic pathways, particularly glycolysis. Mechanistically, Lx8-SINE B2 functions as a cytoplasmic lncRNA and interacts with the glycolytic enzyme Eno1 as shown by RNA pull-down and RNA localization analysis. Lx8-SINE B2 and Eno1 interact with and regulate each other’s expression, hence promoting the expression of metabolic genes and influencing glycolysis. In conclusion, we have identified lncRNA Lx8-SINE B2 as a novel regulator of ESC proliferation, cell cycle, and metabolism through working with Eno1.
Occurrence and Distribution of Physiological Races of Exserohilum turcicum in Maize-Growing Regions of Mexico
Authors: Muñoz-Zavala Carlos , Loladze Alexander , Vargas-Hernández Mateo , García-León Elizabeth , Alakonya Amos Emitati , Tovar-Pedraza Juan Manuel , Goodwin Paul H. , Leyva-Mir Santos Gerardo
Published: September 2022

Turcicum leaf blight (TLB) is a common foliar disease of maize in Mexico that is caused by the fungal pathogen Exserohilum turcicum. The most effective management strategy against TLB is monogenic race-specific resistance. Among the 140 E. turcicum isolates from symptomatic leaves collected from maize fields in Mexico, 100 were obtained from tropical (Veracruz) and temperate areas (Estado de México) between 2010 and 2019, and 40 isolates were obtained from tropical (Sinaloa, Tamaulipas, Veracruz, and Chiapas), subtropical (Nayarit, Jalisco, and Guanajuato), and temperate areas (Estado de Mexico, Hidalgo, and Puebla) collected in 2019. All the isolates caused TLB symptoms on the positive control (ht4), showing that they were all pathogenic. Six physiological races of E. turcicum (2, 3, 23, 3N, 23N, and 123N) were identified based on resistant or susceptible responses displayed by five maize differential genotypes (A619Ht1, A619Ht2, A619Ht3, B68HtN, and A619ht4). The most common was race 23, accounting for 68% of the isolates, followed by races 23N, 123N, 3, 2, and 3N at 15, 8, 6, 2, and 1%, respectively. Race 123N was able to infect the greatest number of maize differential genotypes used in the study. Race 123N was detected in Sinaloa and Estado de México. Race 3 was detected in Nayarit and Jalisco. Race 2 was detected in Jalisco, Estado de México, and Veracruz, and race 3N was detected in Tamaulipas. Race 23 was equally dominant in the tropical, subtropical, and temperate regions, while race 123N was more common in the tropical environment, and race 23N was more common in the tropical and temperate environments. There was no evidence for shifts in the races between 2010 and 2019.
Characterization of Soybean, Tomato, and Nicandra physalodes as Sources of Inoculum of Tomato Severe Rugose Virus to Tomato Crops
Authors: Favara Gabriel Madoglio , de Oliveira Felipe Franco , Chinelato Gressa Amanda , Bergamin Filho Armando , Rezende Jorge Alberto Marques
Published: September 2022

Tomato severe rugose virus (ToSRV) is one of Brazil’s main begomoviruses infecting tomato (Solanum lycopersicum). Recent studies indicate that soybean (Glycine max) crops harboring the whitefly Bemisia tabaci Middle East-Asia Minor 1 (MEAM1) may have epidemiological significance by acting as an asymptomatic amplifier host for the virus. In this study, we gathered experimental greenhouse and field evidence of the role of soybean in the epidemiology of the disease caused by ToSRV. Tomato and Nicandra physalodes, known as good sources of inoculum of this begomovirus, were used as references. The infection rates of soybean, tomato, and N. physalodes with ToSRV in greenhouse no-choice transmission tests with B. tabaci MEAM1 were 50, 71.4, and 64.2%, respectively. The transmission efficiencies of ToSRV to tomato when B. tabaci MEAM1 acquired the virus in ToSRV-infected soybean, tomato, and N. physalodes were 43, 33, and 20%, respectively. Leaves of ToSRV-infected soybean, tomato, and N. physalodes used as sources of inoculum had similar virus titers. In the host preference assay, viruliferous whiteflies preferred to land on tomato rather than soybean and N. physalodes, whereas aviruliferous whiteflies landed indistinctly on these plants. Under experimental field conditions, the transmission efficiency of ToSRV to tomato was higher when tomato was used as a source of inoculum, followed by N. physalodes and soybean. Considering that soybean is extensively cultivated in several Brazilian states that also grow tomato, it can serve as an efficient asymptomatic source of inoculum and support the recent hypothesis that it can also play, under certain conditions, a relevant role as an amplifier host in the epidemiology of the disease caused by ToSRV.
TrpR-Like Protein PXO_00831, Regulated by the Sigma Factor RpoD, Is Involved in Motility, Oxidative Stress Tolerance, and Virulence in Xanthomonas oryzae pv. oryzae
Authors: Xu Zhizhou , Wu Guichun , Wang Bo , Zhao Yancun , Liu Fengquan
Published: September 2022

Xanthomonas oryzae pv. oryzae ( Xoo) is a Gram-negative bacterium that causes bacterial leaf blight in rice. In this study, we identified a putative TrpR-like protein, PXO_TrpR (PXO_00831), in Xoo. This protein contains a tryptophan (Trp) repressor domain and is highly conserved in Xanthomonas. Auxotrophic assays and RT-qPCR confirmed that PXO_TrpR acts as a Trp repressor, negatively regulating the expression of Trp biosynthesis genes. Pathogenicity tests showed that PXO_trpR knockout in Xoo significantly reduced lesion development and disease symptoms in the leaves of susceptible rice. RNA-seq analysis and phenotypic tests revealed that the PXO_trpR mutant exhibited impaired cell motility and was more sensitive to H2O2 oxidative stress than the wild-type strain. Furthermore, we found that the sigma 70 factor RpoD controlled the transcription of PXO_trpR by directly binding to its promoter region. This study demonstrates the biological function and transcriptional mechanism of PXO_TrpR as a Trp repressor in Xoo and evaluates its novel pathogenic roles by regulating flagellar motility and the oxidative stress response.
“I've Never Been to a Doctor”
Authors: Narruhn Robin A. , Espina Christine R.
Published: September 2022

The Ri Majel (Marshallese) migrants of Washington State have endured health inequities and unique laws dictating their access to health care once they arrive to the United States. These health inequities can be seen to be a result of historical trauma and militarization of their islands. The research question was an inquiry regarding access to health care for the Ri Majel in Washington State. We first provide detailed historical data in the background to contextualize our research inquiry. We interviewed 12 people and using manifest content analysis found 2 main themes regarding the health of the Ri Majel: (1) health care access and inequity and (2) historical trauma and embodiment. Health care access was impeded by (1) ongoing effects of radiation, (2) repeated denial of services, (3) lack of health care and insurance, (4) lack of language interpretation during health care visits, and (5) poverty. Historical trauma and embodiment were evidenced by these findings: (1) illness and early mortality; (2) provider lack of knowledge and understanding of the Ri Majel; (3) structural discrimination; (4) feelings of sadness and despair; (5) shyness and humility; and (6) a sense of “cannot/will not” and fatalism. Our findings demonstrate the need to examine structural factors when assessing health inequities and a need to understand and mitigate the effects of historical trauma enacted by structural racism, violence, and colonialism. Strategies to mitigate the embodiment of historical trauma require further investigation.
Do Weightbearing Restrictions Cause Excess Weight Gain in Children With LEGG-Calvé-Perthes Disease?
Authors: Novotny Susan A. , Hailer Yasmin D. , Laine Jennifer C. , Wetzel Martha , Gillespie Scott E. , Gilbert Shawn R. , Goldstein Rachel Y. , Kim Harry K.W. , Schrader Tim ,   on behalf of the International Perthes Study Group
Published: September 2022

Background:

Restricted weight bearing is commonly prescribed in Legg-Calvé-Perthes Disease (LCPD), raising concerns of causing overweight or obesity. This study utilizes prospectively collected data to address the following questions: (1) does body mass index (BMI) Z-score increase over the course of LCPD follow-up; (2) is having a BMI category of normal, overweight, or obese at baseline associated with BMI Z-score changes over the course of follow-up; and (3) is the duration of weight bearing restrictions (no restrictions, <3, 3 to <6, 6 to 9, or >9 mo) associated with BMI Z-score changes.

Methods:

Data of 130 children aged 5 to 12 years with unilateral early-stage LCPD were extracted from an international database. Nation-specific BMI Z-scores and percentile-based weight categories were determined, and the duration of follow-up and weight bearing restrictions were calculated. Longitudinal changes in BMI Z-scores were evaluated for the 3 study questions using mixed effects linear regression models with surgery as a covariate. Sensitivity analyses were used to determine the influence of socio-cultural background (USA vs. India) for each study question.

Results:

During the 35.5±15.9 months of follow-up, no statistically significant increase in BMI Z-scores was observed across the entire cohort, or following stratification by baseline weight categories or the duration of the weight bearing restriction. Sensitivity analyses indicated that patients in the USA had no change in their BMI Z-score. When stratified by weight categories, the normal weight of US children had a small increase in their BMI Z-score (0.005 per mo, 95% confidence interval: 0.0002, 0.009), but this was not seen in other BMI categories. The cohort of Indian children had a small but significant decrease in their BMI Z-score (−0.005/mo, 95% CI: −0.009, −0.0002). After stratification by weight categories, a small decrease of the BMI Z-score was observed only in the Indian overweight children (−0.016 per mo, 95% CI: −0.027, −0.005) and no other BMI category.

Conclusions:

Weightbearing restrictions over the course of follow-up for our cohort of children with early-stage LCPD were not associated with clinically meaningful increases of BMI Z-scores. Weight gain is multi-factorial and probably not caused by weight bearing restrictions alone.

Level of Evidence:

III Diagnostic Study.