bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biotin rescues manganese-induced Parkinson’s disease phenotypes and neurotoxicity
Authors: Lai Yunjia , Reina-Gonzalez Pablo , Maor Gali , Miller Gary W. , Sarkar Souvarish 
Published: November 2023

AbstractOccupational exposure to manganese (Mn) induces manganism and has been widely linked as a contributing environmental factor to Parkinson’s disease (PD), featuring dramatic signature overlaps between the two in motor symptoms and clinical hallmarks. However, the molecular mechanism underlying such link remains elusive, and for combating PD, effective mechanism-based therapies are lacking. Here, we developed an adultDrosophilamodel of Mn toxicity to recapitulate key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosome and mitochondria. We performed global metabolomics on flies at an early stage of toxicity and identified metabolism of the B vitamin, biotin (vitamin B7), as a master pathway underpinning Mn toxicity with systemic, body–brain increases in Mn-treated groups compared to the controls. Using BtndRNAimutant flies, we show that biotin depletion exacerbates Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction; while in Mn-exposed wild-type flies, biotin feeding dramatically ameliorates these pathophenotypes. We further show in human induced stem cells (iPSCs)- differentiated midbrain dopaminergic neurons that the supplemented biotin protects against Mn-induced neuronal loss, cytotoxicity, and mitochondrial dysregulation. Finally, human data profiling biotin-related proteins show for PD cases elevated circulating levels of biotin transporters but not of metabolic enzymes compared to healthy controls, suggesting humoral biotin transport as a key event involved in PD. Taken together, our findings identified compensatory biotin pathway as a convergent, systemic driver of Mn toxicity and parkinsonian pathology, providing new basis for devising effective countermeasures against manganism and PD.Significance StatementEnvironmental exposure to manganese (Mn) may increase the risk for Parkinson’s disease (PD); however, the mechanistic basis linking the two remains unclear. Our adult fruit fly (Drosophila) model of Mn toxicity recapitulated key Parkinson’s hallmarksin vivospanning behavioral deficits, neuronal loss, and mitochondrial dysfunction. Metabolomics identified the biotin (vitamin B7) pathway as a key mediator, featuring systemic biotin increases in the flies. Rescue trials leveraging biotin-deficient flies, wild-type flies, and human iPSC-derived dopaminergic neurons determined biotin as a driver of manganism, with the parkinsonian phenotypes dramatically reversed through biotin supplementation. Our findings, in line with overexpressed circulating biotin transporters observed in PD patients, suggest compensatory biotin pathway as a key to untangle the Mn-PD link for combating neurodegenerative disease.
An invariant C-terminal tryptophan in McdB mediates its interaction and positioning function with carboxysomes
Authors: Basalla Joseph L. , Ghalmi Maria , Hoang Y , Dow Rachel , Vecchiarelli Anthony G. 
Published: November 2023

ABSTRACTBacterial microcompartments (BMCs) are widespread, protein-based organelles that regulate metabolism. The model for studying BMCs is the carboxysome, which facilitates carbon-fixation in several autotrophic bacteria. Carboxysomes can be distinguished as type α or ß, which are structurally and phyletically distinct. We recently characterized the Maintenance of Carboxysome Distribution (Mcd) systems responsible for spatially regulating α- and ß-carboxysomes, consisting of the proteins McdA and McdB. McdA is an ATPase that drives carboxysome positioning, and McdB is the adaptor protein that directly interacts with carboxysomes to provide cargo specificity. The molecular features of McdB proteins that specify their interactions with carboxysomes, and whether these are similar between α- and ß-carboxysomes, remain unknown. Here, we identify C-terminal motifs containing an invariant tryptophan necessary for α- and ß-McdBs to associate with α- and ß-carboxysomes, respectively. Substituting this tryptophan with other aromatic residues reveals corresponding gradients of carboxysome colocalization and positioning by McdBin vivo. Intriguingly, these gradients also correlate with the ability of McdB to form condensatesin vitro. The results reveal a shared mechanism underlying McdB adaptor protein binding to carboxysomes, and potentially other BMCs. Our findings also implicate condensate formation as playing a key role in this association.SIGNIFICANCE STATEMENTMaintenance of carboxysome distribution protein B (McdB) is necessary for positioning a widespread class of protein-based organelles in bacteria that regulate metabolism. Without McdB, these organelles aggregate and lose functionality. How McdB interacts with and positions these organelles is unknown.We determine that an invariant tryptophan is necessary for McdB to interact with and position its organelle. A similar mechanism occurs in two diverse bacterial cell types, both relying on the invariant tryptophan.This class of bacterial organelle includes compartments involved in bacterial pathogenesis and carbon fixation. Our results therefore advance our understanding and applications of these organelles.
Identification of Promoter Activity in Gene-Less Cassettes fromVibrionaceaeSuperintegrons
Authors: Blanco Paula , Hipólito Alberto , García-Pastor Lucía , Trigo da Roza Filipa , Toribio-Celestino Laura , Ortega Alba Cristina , Vergara Ester , San Millán Álvaro , Escudero José Antonio 
Published: November 2023

ABSTRACTIntegrons are genetic platforms that acquire new genes encoded in integron cassettes (ICs), building arrays of adaptive functions. ICs generally encode promoterless genes, whose expression relies on the platform-associated Pc promoter, with the cassette array functioning as an operon-like structure regulated by the distance to the Pc. This is relevant in large sedentary chromosomal integrons (SCIs) carrying hundreds of ICs, like those inVibriospecies. We selected 29 gene-less cassettes in fourVibrioSCIs, and explored whether their function could be related to the transcription regulation of adjacent ICs. We show that most gene-less cassettes have promoter activity on the sense strand, enhancing the expression of downstream cassettes. Additionally, we identified the transcription start sites of gene-less ICs through 5’-RACE. Accordingly, we found that most of the superintegron inVibrio choleraeis not silent. Thesepromoter cassettescan trigger the expression of a silentdfrB9cassette downstream, increasing trimethoprim resistance >512-fold inV. choleraeandEscherichia coli. Furthermore, one cassette with an antisense promoter can reduce trimethoprim resistance when cloned downstream. Our findings highlight the regulatory role of gene-less cassettes in the expression of adjacent cassettes, emphasizing their significance in SCIs and their clinical importance if captured by mobile integrons.
Beyond the Colony-Forming-Unit: Rapid Bacterial Evaluation in Osteomyelitis
Authors: Sun Qi , Huynh Kimberley , Muratovic Dzenita , Gunn Nicholas J. , Zelmer Anja R. , Solomon L. Bogdan , Atkins Gerald J. , Yang Dongqing 
Published: November 2023

AbstractExamination of bacteria/host cell interactions is important for understanding the aetiology of many infectious diseases. The colony-forming-unit (CFU) has been the standard for quantifying bacterial burden for the past century, however, this suffers from low sensitivity and is dependent on bacterial culturabilityin vitro. Our data demonstrate the discrepancy between the CFU and bacterial genome copy number in an osteomyelitis-relevant co-culture system and we confirm diagnosis and quantify bacterial load in clinical bone specimens. This study provides insight into improving the quantification of bacterial burden in such cases.
Bacillus velezensisHBXN2020 alleviatesSalmonellaTyphimurium infection in mice by improving intestinal barrier integrity and reducing inflammation
Authors: Wang Linkang , Wang Haiyan , Li Xinxin , Zhu Mengyuan , Gao Dongyang , Hu Dayue , Xiong Zhixuan , Li Xiangmin , Qian Ping 
Published: November 2023

AbstractBacillus velezensisis a species ofBacillusthat has been widely investigated because of its broad-spectrum antimicrobial activity. However, most studies onBacillus velezensishave focused on the biocontrol of plant diseases, with few reports on antagonizingSalmonellaTyphimurium infections. In this investigation, it was discovered thatBacillus velezensisHBXN2020, which was isolated from healthy black pigs, possessed strong anti-stress and broad-spectrum antibacterial activity. Importantly,Bacillus velezensisHBXN2020 did not cause any adverse side effects in mice when administered at various doses (1 × 107, 1 × 108, and 1 × 109CFU) for 14 d. SupplementingBacillus velezensisHBXN2020 spores, either as a curative or preventive measure, dramatically reduced the levels ofSalmonellaTyphimurium ATCC14028 in the mice’s feces, ileum, cecum, and colon, as well as the disease activity index (DAI), in a model of infection caused by this pathogen in mice. Additionally, supplementingBacillus velezensisHBXN2020 spores significantly regulated cytokine levels (TNF-α, IL-1β, IL-6, and IL-10) and maintained the expression of tight junction proteins and mucin protein. Most importantly, addingBacillus velezensisHBXN2020 spores to the colonic microbiota improved its stability and increased the amount of beneficial bacteria (LactobacillusandAkkermansia). All together,Bacillus velezensisHBXN2020 can improve intestinal microbiota stability and barrier integrity and reduce inflammation to help treat infection bySalmonellaTyphimurium.
A combination of physicochemical tropism and affinity moiety targeting of lipid nanoparticles enhances organ targeting
Authors: Zamora Marco E. , Omo-Lamai Serena , Patel Manthan N. , Wu Jichuan , Arguiri Evguenia , Muzykantov Vladmir , Myerson Jacob , Marcos-Contreras Oscar , Brenner Jacob S. 
Published: November 2023

AbstractTwo camps have emerged in the targeting of nanoparticles to specific organs and cell types: affinity moiety targeting, which conjugates nanoparticles to antibodies or similar molecules that bind to known surface markers on cells; and physicochemical tropism, which achieves specific organ uptake based on the nanoparticle’s physical or chemical features (e.g., binding to endogenous proteins). Because these camps are largely non-overlapping, the two targeting approaches have not been directly compared or combined. Here we do both, using intravenous (IV) lipid nanoparticles (LNPs) whose original design goal was targeting to the lungs’ endothelial cells. For an affinity moiety, we utilized PECAM antibodies, and for physicochemical tropism, we used cationic lipids, both having been heavily studied for lung targeting. Surprisingly, the two methods yield nearly identical levels of lung uptake. However, aPECAM LNPs display much greater specificity for endothelial cells. Intriguingly, LNPs that possess both targeting methods had >2-fold higher lung uptake than either method alone. The combined-targeting LNPs also achieved greater uptake in already inflamed lungs, and greater uptake in alveolar epithelial cells. To understand how the macro-scale route of delivery affects organ targeting, we compared IV injection vs. intra-arterial (IA) injection into the carotid artery. We found that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the brain, a level superior to any other reported targeting method. Thus, combining affinity moiety targeting and physicochemical tropism provides benefits that neither targeting method achieves alone.Graphical Abstract
Predicting Cortical Bone Resorption of Mouse Tibia in Disuse Condition Caused by Transient Muscle Paralysis
Authors: Shekhar Himanshu , Singh Sanjay , Prasad Jitendra 
Published: November 2023

AbstractLoad removal from the load-bearing bone, such as in the case of extended space travel and prolonged bed rest, harms bone health and leads to severe bone loss. However, the constitutive idea relating the quantity of bone loss to the absence of physiological loading is poorly understood. This work attempts to develop a mathematical model that predicts cortical bone loss at three sections: ‘distal,’ ‘mid-section,’ and ‘proximal’ along the length of a mouse tibia. Load-induced interstitial fluid flow-based dissipation energy density has been adopted as a stimulus to trigger mechanotransduction. The developed model takes the loss of stimulus due to the disuse of bone as an input and predicts the quantity of bone loss with spatial accuracy. We hypothesized that the bone loss site would be the site of maximum stimulus loss due to disuse.To test the hypothesis, we calculated stimulus loss, i.e., loss of dissipation energy density due to bone disuse, based on the poroelastic analysis of the bone using a finite element method. A novel mathematical model has been then developed that successfully relates this loss of stimulus to the in-vivo bone loss data in the literature. According to the developed model, the site-specific mineral rate is found to be proportional to the square root of the loss of dissipation energy density. To the author’s best knowledge, this model is the first of its kind to compute site-specific bone loss. The developed model can be extended to predict bone loss due to other disuse conditions such as long space travel, prolonged bed rest, etc.
Microbiome-based correction for random errors in nutrient profiles derived from self-reported dietary assessments
Authors: Wang Tong , Fu Yuanqing , Shuai Menglei , Zheng Ju-Sheng , Zhu Lu , Chan Andrew T. , Sun Qi , Hu Frank B. , Weiss Scott T. , Liu Yang-Yu 
Published: November 2023

AbstractSince dietary intake is challenging to directly measure in large-scale cohort studies, we often rely on self-reported instruments (e.g., food frequency questionnaires, 24-hour recalls, and diet records) developed in nutritional epidemiology. Those self-reported instruments are prone to measurement errors, which can lead to inaccuracies in the calculation of nutrient profiles. Currently, few computational methods exist to address this problem. In the present study, we introduce a deep-learning approach ---Microbiome-based nutrient profilecorrector (METRIC), which leverages gut microbial compositions to correct random errors in self-reported dietary assessments using 24-hour recalls or diet records. We demonstrate the excellent performance of METRIC in minimizing the simulated random errors, particularly for nutrients metabolized by gut bacteria in both synthetic and three real-world datasets. Further research is warranted to examine the utility of METRIC to correct actual measurement errors in self-reported dietary assessment instruments.
Temporal gene expression changes and affected pathways in neurodevelopment of a mouse model of Smith-Lemli-Opitz syndrome
Authors: Li Amy , Tomita Hideaki , Xu Libin 
Published: November 2023

AbstractSmith-Lemli-Opitz syndrome is an autosomal recessive disorder that arises from mutations in the geneDHCR7, which encodes the terminal enzyme of cholesterol biosynthesis, leading to decreased production of cholesterol and accumulation of the cholesterol precursor, 7-dehydrocholesterol, and its oxysterol metabolites. The disorder displays a wide range of neurodevelopmental defects, intellectual disability, and behavioral problems. However, an in-depth study on the temporal changes of gene expression in the developing brains of SLOS mice has not been done before. In this work, we carried out the transcriptomic analysis of whole brains from WT andDhcr7-KO mice at four-time points through postnatal day 0. First, we observed the expected downregulation of theDhcr7gene in theDhcr7-KO mouse model, as well as gene expression changes of several other genes involved in cholesterol biosynthesis throughout all time points. Pathway and GO term enrichment analyses revealed affected signaling pathways and biological processes that were shared amongst time points and unique to individual time points. Specifically, the pathways important for embryonic development, including Hippo, Wnt, and TGF-β signaling pathways are the most significantly affected at the earliest time point, E12.5. Additionally, neurogenesis-related GO terms were enriched in earlier time points, consistent with the timing of development. Conversely, pathways related to synaptogenesis, which occurs later in development compared to neurogenesis, are significantly affected at the later time points, E16.5 and PND0, including the cholinergic, glutamatergic, and GABAergic synapses. The impact of these transcriptomic changes and enriched pathways is discussed in the context of known biological phenotypes of SLOS.
A Cortico-Striatal Circuit for Sound-Triggered Prediction of Reward Timing
Authors: Suri Harini , Salgado-Puga Karla , Wang Yixuan , Allen Nayomie , Lane Kaitlynn , Granroth Kyra , Olivei Alberto , Nass Nathanial , Rothschild Gideon 
Published: November 2023

AbstractA crucial aspect of auditory perception is the ability to use sound cues to predict future events and to time actions accordingly. For example, distinct smartphone notification sounds reflect a call that needs to be answered within a few seconds, or a text that can be read later; the sound of an approaching vehicle signals when it is safe to cross the street. Other animals similarly use sounds to plan, time and execute behaviors such as hunting, evading predation and tending to offspring. However, the neural mechanisms that underlie sound-guided prediction of upcoming salient event timing are not well understood. To address this gap, we employed an appetitive sound-triggered reward time prediction behavior in head-fixed mice. We find that mice trained on this task reliably estimate the time from a sound cue to upcoming reward on the scale of a few seconds, as demonstrated by learning-dependent well-timed increases in reward-predictive licking. Moreover, mice showed a dramatic impairment in their ability to use sound to predict delayed reward when the auditory cortex was inactivated, demonstrating its causal involvement. To identify the neurophysiological signatures of auditory cortical reward-timing prediction, we recorded local field potentials during learning and performance of this behavior and found that the magnitude of auditory cortical responses to the sound prospectively encoded the duration of the anticipated sound-reward time interval. Next, we explored how and where these sound-triggered time interval prediction signals propagate from the auditory cortex to time and initiate consequent action. We targeted the monosynaptic projections from the auditory cortex to the posterior striatum and found that chemogenetic inactivation of these projections impairs animal’s ability to predict sound-triggered delayed reward. Simultaneous neural recordings in the auditory cortex and posterior striatum during task performance revealed coordination of neural activity across these regions during the sound cue predicting the time interval to reward. Collectively, our findings identify an auditory cortical-striatal circuit supporting sound-triggered timing-prediction behaviors.
Winging it: Unveiling how hummingbirds alter their flying kinematics during molt
Authors: Díaz-Salazar Andrés F. , Garzón-Agudelo Felipe , Smiley Ashley , Cadena Carlos Daniel , Rico-Guevara Alejandro 
Published: November 2023

ABSTRACTHummingbirds are well known for their hovering flight, one of the most energetically expensive modes of locomotion among animals. Molt is a costly event in the annual cycle, in which birds replace their feathers, including all their primary feathers which, in hummingbirds, comprise most of the area of the wing. Despite this, the effects of molt on hovering flight are not well known. Here, we examined high-speed videos (14 individuals of three species from the Colombian Andes recorded at 1200 FPS) comparing molting and non-molting hummingbirds’ wing kinematics and wingtip trajectories. We found that molting hummingbirds extended their wings in sharper angles during both downstroke and upstroke compared to non-molting individuals (10° vs 20°, and 15° vs 29°, respectively), while other flight parameters remained unchanged. Our findings show that hummingbirds are capable of sustaining hovering flight kinematics even under impressive wing area reductions by adjusting their wing flapping behavior.
Novel Alphaproteobacteria transcribe genes for nitric oxide transformation at high levels in a marine oxygen deficient zone
Authors: Elbon Claire E. , Stewart Frank J. , Glass Jennifer B. 
Published: November 2023

AbstractMarine oxygen deficient zones (ODZs) are portions of the ocean where intense nitrogen loss occurs primarily via denitrification and anammox. Despite many decades of study, the identity of the microbes that catalyze nitrogen loss in ODZs are still being elucidated. Intriguingly, high transcription of genes in the same family as the nitric oxide dismutase (nod) gene fromMethylomirabilotahas been reported in the anoxic core of ODZs. Here, we show that the most abundantly transcribednodgenes in the Eastern Tropical North Pacific ODZ belong to a new order (UBA11136) of Alphaproteobacteria, rather thanMethylomirabilotaas previously assumed. Gammaproteobacteria and Planctomycetia also transcribenod, but at lower relative abundance than UBA11136 in the upper ODZ. Thenod-transcribing Alphaproteobacteria likely use formaldehyde and formate as a source of electrons for aerobic respiration, with additional electrons possibly from sulfide oxidation. They also transcribe multiheme cytochrome (here namedptd) genes for a putative porin-cytochrome protein complex of unknown function, potentially involved in extracellular electron transfer. Molecular oxygen for aerobic respiration may originate from nitric oxide dismutation via cryptic oxygen cycling. Our results implicate Alphaproteobacteria order UBA11136 as a significant player in marine nitrogen loss and highlight their potential in one-carbon, nitrogen, and sulfur metabolism in ODZs.Significance statementIn marine oxygen deficient zones, microbes transform bioavailable nitrogen to gaseous nitrogen, with nitric oxide as a key intermediate. The Eastern Tropical North Pacific contains the world’s largest oxygen deficient zone, but the identity of the microbes transforming nitric oxide remain unknown. Here, we show that highly transcribed nitric oxide dismutase(nod) genes belong to Alphaproteobacteria of the novel order UBA11136, which lacks cultivated isolates. These Alphaproteobacteria show evidence for aerobic respiration, using oxygen potentially sourced from nitric oxide dismutase, and possess a novel porin-cytochrome protein complex with unknown function. Gammaproteobacteria and Planctomycetia transcribenodat lower levels. Our results pinpoint the microbes mediating a key step in marine nitrogen loss and reveal an unexpected predicted metabolism for marine Alphaproteobacteria.