bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sigh breathing rhythm depends on intracellular calcium oscillations in a population of inspiratory rhythmogenic preBötzinger complex neurons in mice
Authors: Borrus Daniel S. , Grover Cameron J. , Smith Gregory D. Conradi , Del Negro Christopher A. 
Published: May 2022

ABSTRACTThe preBötzinger Complex (preBötC) of the lower brainstem generates two breathing-related rhythms: one for inspiration on a timescale of seconds and another that produces larger amplitude sighs on the order of minutes. Their underlying mechanisms and cellular origins remain incompletely understood. We resolve these problems via a joint experiment and modeling approach. Blocking purinergic gliotransmission does not perturb either rhythm and imaging experiments show that both rhythms emanate from the same glutamatergic neuron population. We hypothesized that these two disparate rhythms emerge in tandem wherein recurrent excitation gives rise to inspiratory rhythm while a calcium oscillator generates sighs; there is no obligatory role for gliotransmission, hyperpolarization activated mixed cationic current (Ih) in neurons, or synaptic inhibition-mediated coupling of separate populations. We developed a mathematical model that instantiates our working hypothesis. Tests of model predictions validate the single-population rhythmogenic framework, reproducing disparate breathing-related frequencies and the ability for inspiratory and sigh rhythms to be separately regulated in support of respiration under a wide array of conditions. Here we show how a single neuron population exploits two cellular tool-kits: one involving voltage-dependent membrane properties and synaptic excitation for inspiratory breathing (eupnea) and an intracellular biochemical oscillator for sighs, which ventilate and maintain optimal function in the compliant mammalian lung.SIGNIFICANCE STATEMENTBreathing consists of two vital rhythms: one for eupnea that serves periodic physiological gas exchange and the other for sighs, which are larger breaths that occur minutes apart and serve to optimize pulmonary function. These rhythms with disparate frequencies emerge via a mechanism that is simpler than previously envisaged: it results from one neuron population (not two as previously thought) without need for gliotransmission or synaptic inhibition-mediated coupling of neuronal populations. We show that a low-frequency intracellular calcium oscillation underlies sighs and functions in parallel with the higher-frequency voltage-dependent network oscillation that drives eupnea. Exploiting two separate cellular tool kits enables quasi-independent breathing rhythms, which are unique features of breathing in mammals with compliant lungs.
NPC1 confers metabolic flexibility in Triple Negative Breast Cancer
Authors: O’Neill KI , Kuo LW , Williams MM , Lind HE , Crump LS , Hammond NG , Spoelstra NS , Caino MC , Richer JK 
Published: May 2022

ABSTRACTTriple negative breast cancer (TNBC) often undergoes at least partial epithelial-to-mesenchymal transition (EMT) to facilitate metastasis. Identifying EMT-associated characteristics can reveal novel dependencies that may serve as therapeutic vulnerabilities in this aggressive breast cancer subtype. We find that NPC1, which encodes the lysosomal cholesterol transporter Niemann-Pick Type C1 is highly expressed in TNBC as compared to estrogen receptor-positive (ER+) breast cancer and is significantly elevated in high grade disease. We demonstrate that NPC1 is directly targeted by microRNA-200c (miR-200c) a potent suppressor of EMT, providing a mechanism for its differential expression in breast cancer subtypes. Silencing of NPC1 in TNBC causes an accumulation of cholesterol-filled lysosomes and drives decreased growth on soft agar and invasive capacity. Conversely, overexpression of NPC1 in an ER+ cell line increases invasion and growth on soft agar. We further identify TNBC cell lines as cholesterol auxotrophs, however, they do not solely depend on NPC1 for adequate cholesterol supply. Genetic inhibition of NPC1 in TNBC cell lines led to altered mitochondrial function and morphology, suppression of mTOR signaling, and accumulation of autophagosomes. A small-molecule inhibitor of NPC1, U18666A, decreased TNBC proliferation and synergized with the chemotherapeutic drug, paclitaxel. This work suggests that NPC1 promotes aggressive characteristics in TNBC and identifies NPC1 as a potential therapeutic target.
Rapid evolutionary change in trait correlations of a single protein
Authors: Dasmeh Pouria , Zheng Jia , Wagner Andreas 
Published: May 2022

AbstractMany organismal traits are genetically determined and covary in evolving populations. The resulting trait correlations can either help or hinder evolvability – the ability to bring forth new and adaptive phenotypes. The evolution of evolvability requires that trait correlations themselves must be able to evolve, but we know little about this ability. To learn more about it, we here study one of the simplest evolvable systems, a gene encoding a single protein, and two traits of this protein, namely the ability to emit yellow and green light. We show that correlations between these two traits can evolve rapidly through both mutation and selection on short evolutionary time scales. In addition, we show that these correlations are driven by a protein’s ability to fold, because single mutations that alter foldability can dramatically change trait correlations. Since foldability is important for most proteins and their traits, mutations affecting protein folding may alter trait correlations mediated by many other proteins. Thus, mutations that affect protein foldability may also help shape the correlations of complex traits that are affected by hundreds of proteins.
Parental care results in a greater mutation load, for which it is also a phenotypic antidote
Authors: Pascoal Sonia , Shimadzu Hideyasu , Mashoodh Rahia , Kilner Rebecca M. 
Published: May 2022

AbstractBenevolent social behaviours, such as parental care, are thought to enable mildly deleterious mutations to persist. We tested this prediction experimentally using the burying beetleNicrophorus vespilloides, an insect with biparental care. For 20 generations, we allowed replicate experimental burying beetle populations to evolve either with post-hatching care (‘Full Care’ populations) or without it (‘No Care’ populations). We then established new lineages, seeded from these experimental populations, which we inbred to assess their mutation load. Outbred lineages served as controls. We also tested whether the deleterious effects of a greater mutation load could be concealed by parental care by allowing half the lineages to receive post-hatching care, while half did not. We found that inbred lineages from the Full Care populations went extinct more quickly than inbred lineages from the No Care populations – but only when offspring received no post-hatching care. We infer that Full Care lineages carried a greater mutation load, but that the associated deleterious effects on fitness could be overcome if larvae received parental care. We suggest that the increased mutation load caused by parental care increases a population’s dependence upon care. This could explain why care is seldom lost once it has evolved.
A Self-Healing, Viscoelastic Hydrogel Promotes Healing of Brain Lesions
Authors: Hu Yan , Jia Yuanbo , Wang Siwei , Ma Yufei , Huang Guoyou , Ding Tan , Feng Dayun , Genin Guy M. , Wei Zhao , Xu Feng 
Published: May 2022

AbstractBrain lesions can arise from traumatic brain injury, infection, and craniotomy. Although injectable hydrogels show promise for promoting healing of lesions and health of surrounding tissue, enabling cellular ingrowth and restoring neural tissue continue to be challenging. We hypothesized that these challenges arise in part from viscoelastic mismatch between the hydrogel and the brain parenchyma, and tested this hypothesis by developing and evaluating a self-healing hydrogel that mimicked both the composition and viscoelasticity of native brain parenchyma. The hydrogel was crosslinked by dynamic boronate ester bonds between phenylboronic acid grafted hyaluronic acid (HA-PBA) and dopamine grafted gelatin (Gel-Dopa). This HA-PBA/Gel-Dopa hydrogel could be injected into a lesion cavity in a shear-thinning manner with rapid hemostasis, high tissue adhesion and efficient self-healing. We tested this in an in vivo mouse model of brain lesions and found the hydrogel to support neural cell infiltration, decrease astrogliosis and glial scars, and close the lesions. The results suggest a role for viscoelasticity in brain lesion healing, and motivate additional experimentation in larger animals as the technology progresses towards potential application in humans.
Mechanical forces impair antigen discrimination by reducing differences in T cell receptor off-rates
Authors: Pettmann Johannes , Awada Lama , Różycki Bartosz , Huhn Anna , Faour Sara , Kutuzov Mikhail , Limozin Laurent , Weikl Thomas R. , van der Merwe P. Anton , Robert Philippe , Dushek Omer 
Published: May 2022

T cells use their T cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity foreign peptide major-histocompatibility-complexes (pMHCs) based on the TCR/pMHC off-rate. It is now appreciated that T cells generate mechanical forces during this process but how force impacts the TCR/pMHC off-rate remains unclear. Here, we measured the effect of mechanical force on the off-rate of multiple TCR/pMHC interactions. Unexpectedly, we found that lower-affinity pMHCs with faster solution off-rates were more resistant to mechanical force (weak slip or catch bonds) than higher-affinity interactions (strong slip bonds), and this was confirmed by molecular dynamic simulations. Consistent with these findings, we show that the best characterized catch-bond, involving the OT-I TCR, has a low affinity and an exceptionally fast solution off-rate. Our findings imply that reducing forces on the TCR/pMHC interaction improves antigen discrimination and we suggest this new force-shielding role for the adhesion receptors CD2 and LFA-1.One sentence summaryMechanical forces disproportionately accelerate the off-rates of higher-affinity antigens reducing T cell antigen discrimination
SOPHIE: viral outbreak investigation and transmission history reconstruction in a joint phylogenetic and network theory framework
Authors: Skums Pavel , Mohebbi Fatemeh , Tsyvina Vyacheslav , Baykal Pelin Icer , Nemira Alina , Ramachandran Sumathi , Khudyakov Yury 
Published: May 2022

AbstractGenomic epidemiology is now widely used for viral outbreak investigations. Still, this methodology faces many challenges. First, few methods account for intra-host viral diversity. Second, maximum parsimony principle continues to be employed, even though maximum likelihood or Bayesian models are usually more consistent. Third, many methods utilize case-specific data, such as sampling times or infection exposure intervals. This impedes study of persistent infections in vulnerable groups, where such information has a limited use. Finally, most methods implicitly assume that transmission events are independent, while common source outbreaks violate this assumption.We propose a maximum likelihood framework SOPHIE (SOcial and PHilogenetic Investigation of Epidemics) based on integration of phylogenetic and random graph models. It infers transmission networks from viral phylogenies and expected properties of inter-host social networks modelled as random graphs with given expected degree distributions. SOPHIE is scalable, accounts for intra-host diversity and accurately infers transmissions without case-specific epidemiological data. SOPHIE code is freely available at https://github.com/compbel/SOPHIE/
Association of variants in ACE, ACTN3, AGT, IL6 and BDKRB2 genes with athlete status and playing position in Colombian amateur rugby athletes
Authors: Paz Garcia Efraín , Gonzalez Gerardo David , Barreto Guillermo 
Published: May 2022

SummaryGenetic polymorphisms are involved in different metabolic pathways that are manifested at the physiological level and have been associated with specific phenotypes in sport from anthropometric and functional characterizations that pose conditional and physiological demands for the rugby athlete. The identification of this type of polymorphisms in athletes represents a resource that contributes significantly to the processes of training, selection and sports orientation.The purpose of this study was to describe type and frequencies of allelic and genotypic variants in ACTN3, ACE, AGT, BDRKB2 and IL6 genes in sub elite rugby athletes in Colombia. Additionally, the polymorphisms found were compared with a control population, as well as contrasted according to playing position backs and forwards.In this research, 47 individuals from the Vallecaucana rugby league and 67 from a control group (non-athletes) were sampled. All were analyzed for polymorphisms in the ACE, AGT, ACTN3, IL6 and BDKRB2 genes, using the PCR RFLPs technique. The significance of the differences between the experimental and control groups was tested by the X2 test (p <0.05).In rugby athletes we found a higher frequency of allele D (0.883) ACE gene, allele R (0.63) ACTN3 gene, allele G (0.819) IL6 gene, all associated with strength and power sports. There are significant genotypic differences between athletes and the control population in all the genes analyzed and significant allelic differences in the ACE, ACTN3, BDRKB2 and IL6 genes. When comparing the playing positions (backs vs. forwards), significant genotypic differences were observed in the ACTN3, BDRKB2, AGT and IL6 genes. At the allelic level, the R and X alleles of the ACTN3 gene and the I allele of the ACE gene show significant differences.In conclusion, in the polymorphisms analyzed, an association with strength sports, explosive strength and rugby is observed. Significant genotypic and allelic differences were also recorded between the backs and forwards positions, as well as significant differences in the allelic and genotypic structure between the group of athletes and the control population.
Maintenance of neurotransmitter identity by Hox proteins through a homeostatic mechanism
Authors: Feng Weidong , Destain Honorine , Smith Jayson J , Kratsios Paschalis 
Published: May 2022

SUMMARYHox transcription factors play fundamental roles during early patterning, but they are also expressed continuously – from embryo through adulthood – in the nervous system. The functional significance of their sustained expression remains unclear. In C. elegans motor neurons (MNs), we find that LIN-39 (Scr/Dfd/Hox4-5) is continuously required during post-embryonic life to maintain neurotransmitter identity, a core element of neuronal function. LIN-39 acts directly to co-regulate genes that define cholinergic identity (e.g., unc-17/VAChT, cho-1/ChT). We further show that LIN-39, MAB-5 (Antp/Hox6-8) and the transcription factor UNC-3 (Collier/Ebf) operate in a positive feedforward loop to ensure continuous and robust expression of cholinergic identity genes. Finally, we identify a two-component, design principle (Hox transcriptional autoregulation counterbalanced by negative UNC-3 feedback) for homeostatic control of Hox gene expression in adult MNs. These findings uncover a noncanonical role for Hox proteins during post-embryonic life, critically broadening their functional repertoire from early patterning to the control of neurotransmitter identity.
A new, Critically Endangered species of Impatiens (Balsaminaceae) from the coastal plain of the Republic of Congo
Authors: Cheek Martin 
Published: May 2022

AbstractImpatiens moutsambotei is described from a herbarium specimen collected at a waterfall in forest on the coastal plain, below the Mayombe Mts of the Republic of Congo. Sharing many distinctive characters with Impatiens floretii of the Doudou Mts of Gabon, it is abundantly distinguished inter alia by the leaf-blades which are lanceolate or narrowly elliptic, not ovate, their bases acute, not obtuse or broadly rounded to truncate; the reduced, peduncular bracts bearing long, filiform setae, and not entire; the proximal (upper) of the lateral united petals are entire, not bifid; the spur is curved at the base and overlaps the lower sepal, not curved through its length to describe a semi-circle and held below the lower sepal. Both species are placed in the Impatiens macroptera species aggregate. Impatiens moutsambotei is known from a single site, where it was collected nearly 30 years ago and not seen since. The new species is assessed as Critically Endangered due to threats of habitat clearance from mining and road widening, and may be already be extinct.
Multicomponent Pseudomonas aeruginosa vaccines eliciting Th17 cells and functional antibody responses confer enhanced protection against experimental acute pneumonia in mice
Authors: Shaikh Mohammad Omar Faruk , Schaefers Matthew M. , Merakou Christina , DiBlasi Marco , Bonney Sarah , Liao Tiffany , Zurakowski David , Kehl Margaret , Tabor David E. , DiGiandomenico Antonio , Priebe Gregory P. 
Published: May 2022

AbstractThe Gram-negative pathogen Pseudomonas aeruginosa is a common cause of pneumonia in hospitalized patients. Its increasing antibiotic resistance and widespread occurrence present a pressing need for vaccines. We previously showed that a P. aeruginosa type III secretion system protein, PopB elicits a strong Th17 response in mice after intranasal (IN) immunization and confers antibody-independent protection against pneumonia in mice. In the current study, we evaluated the immunogenicity and protective efficacy in mice of the combination of PopB (purified with its chaperone protein PcrH) and OprF/I, an outer membrane hybrid fusion protein, compared to immunization with the proteins individually either by the intranasal (IN) or subcutaneous (SC) routes. Our results show that after vaccination, a Th17 recall response from splenocytes was detected only in mice vaccinated with PopB/PcrH, either alone or in combination with OprF/I. Mice that were immunized with the combination of PopB/PcrH and OprF/I had enhanced protection in an acute lethal P. aeruginosa pneumonia model, regardless of vaccine route, compared to the mice vaccinated the with either alone or adjuvant control. Immunization generated IgG titers against the vaccine proteins and whole P. aeruginosa cells. Interestingly, none of these antisera had opsonophagocytic killing activity, but antisera from mice immunized with vaccines containing OprF/I had the ability to block IFN-γ binding to OprF/I, a known virulence mechanism. Hence, vaccines combining PopB/PcrH with OprF/I that elicit functional antibodies lead to a broadly and potently protective vaccine against P. aeruginosa pulmonary infections.
Spermine inhibits pathogen-associated molecular pattern (PAMP) ROS and Ca2+ burst and reshapes the transcriptional landscape of PAMP-triggered immunity in Arabidopsis thaliana
Authors: Zhang Chi , Atanasov Kostadin E. , Alcázar Rubén 
Published: May 2022

ABSTRACTPolyamines are small polycationic amines which levels increase during defense. Previous studies support the contribution of the polyamine spermine (Spm) to the establishment of the hypersensitive response (HR) during incompatible plant-pathogen interactions. However, the potential contribution of Spm to other layers of defense, and pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) in particular, was not completely established. Here we compared the contribution of Spm and putrescine (Put) to early and late PTI responses. We find that Put and Spm show opposite effects on PAMP-elicited reactive oxygen species (ROS) production, with Put increasing whereas Spm lowering flg22-stimulated ROS burst. Through genetic and pharmacological approaches, we find that the inhibitory effect of Spm on flg22-elicited ROS is independent of polyamine oxidation and EDS1 (ENHANCED DISEASE SUSCEPTIBILITY 1), PAD4 (PHYTOALEXIN DEFICIENT 4), salicylic acid and NPR1 (NONEXPRESSER OF PR GENES 1) defense components but resembles chemical inhibition of RBOHD (RESPIRATORY BURST OXIDASE HOMOLOG D) function. Remarkably, Spm can also suppress ROS elicited by FLS2-independent but RBOHD-dependent pathways, thus pointing to compromised RBOHD function. Consistent with this, we find that Spm dampens flg22-stimulated cytosolic Ca2+ influx necessary for RBOHD function and reshapes the transcriptional landscape of PTI and defense responses against Pseudomonas syringae pv. tomato DC3000. Overall, we provide molecular evidence for the differential contribution of Put and Spm to PTI with an impact on plant defense.
Feature-space selection with banded ridge regression
Authors: la Tour Tom Dupré , Eickenberg Michael , Nunez-Elizalde Anwar O. , Gallant Jack L. 
Published: May 2022

AbstractEncoding models provide a powerful framework to identify the information represented in brain recordings. In this framework, a stimulus representation is expressed within a feature space and is used in a regularized linear regression to predict brain activity. To account for a potential complementarity of different feature spaces, a joint model is fit on multiple feature spaces simultaneously. To adapt regularization strength to each feature space, ridge regression is extended to banded ridge regression, which optimizes a different regularization hyperparameter per feature space. The present paper proposes a method to decompose over feature spaces the variance explained by a banded ridge regression model. It also describes how banded ridge regression performs a feature-space selection, effectively ignoring non-predictive and redundant feature spaces. This feature-space selection leads to better prediction accuracy and to better interpretability. Banded ridge regression is then mathematically linked to a number of other regression methods with similar feature-space selection mechanisms. Finally, several methods are proposed to address the computational challenge of fitting banded ridge regressions on large numbers of voxels and feature spaces. All implementations are released in an open-source Python package called Himalaya.
SWEET13 transport of sucrose, but not gibberellin, restores male fertility in Arabidopsis sweet13;14
Authors: Isoda Reika , Palmai Zoltan , Yoshinari Akira , Chen Li Qing , Tama Florence , Frommer Wolf B. , Nakamura Masayoshi 
Published: May 2022

AbstractSWEET sucrose transporters play important roles in the allocation of sucrose in plants. Some SWEETs were shown to also mediate transport of the plant growth regulator gibberellin (GA). The close physiological relationship between sucrose and GA raised the questions of if there is a functional connection, and whether one or both of the substrates are physiologically relevant. To dissect these two activities, molecular dynamics were used to map the binding sites of sucrose and GA in the pore of SWEET13 and predicted binding interactions that might be selective for sucrose or GA. Transport assays confirmed these predictions. In transport assays, the N76Q mutant had 7x higher relative GA3 activity, and the S142N mutant only transported sucrose. The impaired pollen viability and germination in sweet13;14 double mutants were complemented by the sucrose-selective SWEET13S142N but not by the SWEET13N76Q mutant, indicating that sucrose is the physiologically relevant substrate and that GA transport capacity is dispensable in the context of male fertility. Therefore, GA supplementation to counter male sterility may act indirectly via stimulating sucrose supply in male sterile mutants. These findings are also relevant in the context of the role of SWEETs in pathogen susceptibility.