bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiometabolic side effects of androgen deprivation therapy in prostate cancer
Authors: Lafontaine Marie-Lyssa , Kokorovic Andrea 
Published: November 2022

Purpose of review
Androgen-deprivation therapy (ADT) is widely employed for treatment of advanced prostate cancer and it is considered the frontline therapy. However, the numerous adverse reactions associated with this treatment option are concerning and its potential association with cardiovascular diseases (CVD) should not be overlooked. In this review, we examine the literature on the cardiovascular side effects of ADT and the physiologic mechanisms underpinning the association with CVD. We will also specifically discuss the different findings regarding the interesting potential disparity in major cardiovascular events among GnRH agonist-treated patients compared with patients undergoing GnRH antagonist treatment.

Recent findings
Androgen-deprivation therapy increases the risk of developing CVD by altering the body composition, metabolism, vascular system, and cardiac physiology. GnRH agonists may pose a higher risk of cardiovascular mortality and morbidity than GnRH antagonists; however, this link remains to be determined. Furthermore, screening for cardiovascular risk factors before and during ADT treatment is a crucial step in preventing major adverse cardiac events in prostate cancer patients. Notably, preexisting CVD and comorbidities have been identified as major key elements predicting cardiovascular events. Early implementation of pharmacological and nonpharmacological treatment strategies is strongly suggested, and regular follow-up visits should be scheduled to continuously assess patients’ cardiovascular risk under ADT.

Summary
ADT is a very powerful treatment option for advanced prostate cancer that improves survival outcomes but has the potential of considerably impacting patients’ cardiovascular health. Medical optimization and close monitoring are crucial during treatment with ADT.
Association Between Polygenic Risk Score And Gut Microbiome Of Multiple Sclerosis
Authors: Elsayed Noha S. , Valenzuela Robert K. , Kitchner Terrie , Le Thao , Mayer John , Tang Zheng-Zheng , Bayanagari Vishnu R. , Lu Qiongshi , Aston Paula , Anantharaman Karthik , Shukla Sanjay K. 
Published: November 2022

AbstractBackgroundMultiple sclerosis (MS) is a complex autoimmune disease in which both the roles of genetic susceptibility and environmental/microbial factors have been investigated. More than 200 genetic susceptibility variants have been identified along with the dysbiosis of gut microbiota, both independently have been shown to be associated with MS. We hypothesize that MS patients harboring genetic susceptibility variants along with gut microbiome dysbiosis are at a greater risk of exhibiting the disease. We investigated the polygenic risk score for MS in conjunction with gut microbiota in the same cohort of 117 relapsing remitting MS (RRMS) and 26 healthy controls. DNA samples were genotyped using Illumina’s Infinium Immuno array-24 v2 chip followed by calculating polygenic risk score and the microbiota was determined by sequencing the V4 hypervariable region of the 16S rRNA gene.ResultsWe identified two clusters of MS patients, Cluster A and B both having a higher polygenic risk score than the control group. The Cluster B with the higher polygenic risk score had a distinct gut microbiota, different than the Cluster A. MS group whose microbiome was similar to that of the control group despite a higher genetic risk score than the control group. This could be due to i) the non-active state of the disease in that group of MS patients at the time of fecal sample collection and/or ii) the restoration of the gut microbiome post disease modifying therapy to treat the MS.ConclusionOur study showed that there seems to be association between polygenic risk score and gut microbiome dysbiosis in triggering the disease in a small cohort of MS patients. The MS Cluster A who have a higher polygenic risk score but microbiome profile similar to that of healthy controls could be due to the remitting phase of the disease or due to the effect of disease modifying therapies.
High-resolution temporal profiling of the gut microbiome through the whole life of mice
Authors: Takayasu Lena , Watanabe Eiichiro , Umeyama Taichi , Kurokawa Rina , Maskawa Rie , Basu Sumanta , Ogata Yusuke , Kiguchi Yuya , Masuoka Hiroaki , Umezaki Masahiro , Takayasu Hideki , Takayasu Misako , Hattori Masahira , Suda Wataru 
Published: November 2022

AbstractThe temporal changes of the gut microbiome are thought to be critical for understanding its interactions with host aging, but lifelong dynamics within the same individual remain largely unknown. Here we firstly report the high temporal resolution dynamics of gut microbiomes in mice sharing the same genetic background and environment from their birth to natural death, spanning >1,000 days. The 16S rRNA sequencing analysis revealed 9 patterns of OTU temporal dynamics and 38 common “life-core” bacterial species/operational taxonomic units (OTUs) in ≥80% of all samples across the lifespan of individual mice. The life-core OTUs are largely represented by the phylum Bacteroidota, whereas the transient bacterial group predominantly includes the phylum Firmicutes (Bacillota). Despite the shared genetic background and dietary habits, the gut microbiome structure significantly diversified with age and among individuals. A positive correlation existed between longevity and the microbiome α-diversity in middle age (200–500 days) followed by a negative correlation in old age (>700 days), likely influenced by the increase in diversity during the last days of life. The abundance of several “life-core” species also exhibited non-static correlation trends with lifespan. Overall, this research characterized the gut microbiomes based on its persistence over host’s lifetime and suggested a non-static host-microbiome relationship within individual mice.
High-throughput enzymology reveals mutations throughout a phosphatase that decouple catalysis and transition state analog affinity
Authors: Markin C.J. , Mokhtari D.A. , Du S. , Doukov T. , Sunden F. , Fordyce P.M. , Herschlag D. 
Published: November 2022

AbstractUsing High-Throughput Microfluidic Enzyme Kinetics (HT-MEK), we measured over 9,000 inhibition curves detailing impacts of 1,004 single-site mutations throughout the Alkaline Phosphatase PafA on binding affinity for two transition state analogs (TSAs), vanadate and tungstate. As predicted by catalytic models invoking transition state complementary, mutations to active site and active site-contacting residues had highly similar impacts on catalysis and TSA binding. Unexpectedly, most mutations to more distal residues which reduced catalysis had little or no impact on TSA binding and many even increased affinity for tungstate. These disparate effects are accounted for by a model in which distal mutations alter the enzyme’s conformational landscape and increase occupancy of microstates that are catalytically less effective but better able to accommodate larger transition state analogs. In support of this model, glycine substitutions (rather than valine) were more likely to increase tungstate affinity, presumably due to increased conformational flexibility and increased occupancy of previously disfavored microstates. These results indicate that residues throughout an enzyme provide specificity for the transition state and discriminate against analogs that are larger only by tenths of an Ångström. Thus, engineering enzymes that rival the most powerful natural enzymes will likely require consideration not just of residues in and around the active site, but also of more distal residues that shape the enzyme’s conformational landscape and finetune the active site. In addition, the extensive functional communication between the active site and remote residues may provide interconnections needed for allostery and make allostery a highly evolvable trait.Significance StatementTransition state analogs (TSAs) resemble fleeting high-energy transition states and have been used to inhibit enzymes in nature and medicine, to learn about enzyme active site features, and to design and select new enzymes. While TSAs mimic transition states, they differ from actual TSs, and we exploit these differences here. Systematic TSA affinity measurements for 1,004 mutants of PafA (a model phosphatase enzyme) revealed effects in and around the active site that mirror their effects on catalysis, but TSA-binding and catalytic effects diverge more distally. These observations suggest that residues throughout an enzyme adjust its conformational landscape on the tenth-Ångström scale to optimize the active site for catalysis, rendering allostery more evolvable in nature but likely complicating enzyme design.
Microtubule binding-induced allostery promotes LIS1 dissociation from dynein prior to cargo transport
Authors: Ton William D. , Wang Yue , Chai Pengxin , Beauchamp-Perez Cissloyny , Flint Nicholas T. , Lammers Lindsay G. , Xiong Hao , Zhang Kai , Markus Steven M. 
Published: November 2022

ABSTRACTThe lissencephaly-related protein LIS1 is a critical regulator of cytoplasmic dynein that governs motor function and intracellular localization (e.g., to microtubule plus-ends). Although LIS1 binding is required for dynein activity, its unbinding prior to initiation of cargo transport is equally important, since preventing dissociation leads to dynein dysfunction. To understand whether and how dynein-LIS1 binding is modulated, we engineered dynein mutants locked in a microtubule-bound (MT-B) or -unbound (MT-U) state. Whereas the MT-B mutant exhibits low LIS1 affinity, the MT-U mutant binds LIS1 with high affinity, and as a consequence remains almost irreversibly bound to microtubule plus-ends. We find that a monomeric motor domain is sufficient to exhibit these opposing LIS1 affinities, and that this is an evolutionarily conserved phenomenon. Three cryo-EM structures of dynein with and without LIS1 reveal microtubule-binding induced conformational changes responsible for this regulation. Our work reveals key biochemical and structural insight into LIS1-mediated dynein activation.
Molecular diversity and connectivity of accessory olfactory system neurons
Authors: Prakash Nandkishore , Matos Heidi Y , Sebaoui Sonia , Tsai Luke , Tran Tuyen , Aromolaran Adejimi , Atrachji Isabella , Campbell Nya , Goodrich Meredith , Hernandez-Pineda David , Herrero Maria , Hirata Tsutomu , Lischinsky Julieta , Martinez Wendolin , Torii Shisui , Yamashita Satoshi , Sokolowski Katie , Esumi Shigeyuki , Kawasawa Yuka Imamura , Hashimoto-Torii Kazue , Jones Kevin S , Corbin Joshua G 
Published: November 2022

AbstractOlfaction is the primary sensory modality by which most vertebrate species interpret environmental cues for appropriate behavioral outputs. The olfactory system is subdivided into main (MOS) and accessory (AOS) components which process volatile and non-volatile cues. While much is known regarding the molecular diversity of neurons that comprise the MOS, less is known about the AOS. Here, focusing on the AOS which is largely comprised of the peripheral vomeronasal organ (VNO), the accessory olfactory bulb (AOB) and the medial subnucleus of the amygdala (MeA), we studied the molecular diversity and neuronal subtype connectivity of this interconnected circuit. We show that populations of neurons of the AOS can be molecularly subdivided based on their current or prior expression of the transcription factorsFoxp2orDbx1. We show that the majority of AOB neurons that project directly to the MeA are of theFoxp2-lineage. Using single cell patch clamp electrophysiology, we further reveal that in addition to sex-specific differences across lineage, the relative contributions of excitatory and inhibitory inputs to MeAFoxp2-lineage neurons differ between sexes. Together, this work uncovers a novel molecular diversity of AOS neurons and lineage- and sex-differences in patterns of connectivity.
SIRT6 is a key regulator of mitochondrial function in the brain
Authors: Smirnov Dmitrii , Eremenko Ekaterina , Stein Daniel , Kaluski Shai , Jasinska Weronika , Consentino Claudia , Martinez-Pastor Barbara , Brotman Yariv , Mostoslavsky Raul , Khrameeva Ekaterina , Toiber Debra 
Published: November 2022

AbstractSIRT6 is implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. In this work, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mice brains. Our analysis revealed that SIRT6 is a critical regulator of mitochondrial activity in the brain. In its absence, there is a mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolites content. We predict that SIRT6 can affect mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and 4 levels. Importantly, the changes observed in SIRT6 deficient brains are observed in brains of aging people, but the overlapping is greater in patients with Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that reduced levels of SIRT6 in the aging brain and neurodegeneration could initiate mitochondrial dysfunction by altering gene expression, ROS production and mitochondrial decay.
Systems-level transcriptional regulation ofCaenorhabditis elegansmetabolism
Authors: Nanda Shivani , Jacques Marc-Antoine , Wang Wen , Myers Chad L , Yilmaz L. Safak , Walhout Albertha JM 
Published: November 2022

AbstractMetabolism is precisely controlled to ensure organismal development and homeostasis. Several mechanisms regulate metabolism, including allosteric control and transcriptional regulation of metabolic enzymes and transporters. So far, metabolism regulation has mostly been described for individual genes and pathways, and the extent of transcriptional regulation of the entire metabolic network remains largely unknown. Here, we find that more than three-quarters of all metabolic genes are transcriptionally regulated in the nematodeCaenorhabditis elegans. We find that many annotated metabolic pathways are coexpressed, and we use gene expression data and the iCEL1314 metabolic network model to define coregulated sub-pathways in an unbiased manner. Using a large gene expression compendium, we determine the conditions where sub-pathways exhibit strong coexpression. Finally, we develop ‘WormClust’, a web application that enables a gene-by-gene query of genes to view their association with metabolic (sub)-pathways. Overall, this study sheds light on the ubiquity of transcriptional regulation of metabolism and provides a blueprint for similar studies in other organisms, including humans.
Directed evolution of mesophilic HNA polymerases providing insight into DNA polymerase mechanisms
Authors: Handal-Marquez Paola , Torres Leticia L. , Pinheiro Vitor B. 
Published: November 2022

AbstractDetailed biochemical characterization of natural and mutant enzymes provides essential clues to understand their mechanisms. There are, however, limits to the throughput of such approaches and they are not without errors. DNA polymerases have benefited from over 50 years of detailed study and remain not fully understood. As such, methods that allow high-throughput interrogation of variants, and viable analysis pipelines to identify relevant variants, become an important tool to accelerate research. Using the DNA polymerase fromB. subtilisPhi29 bacteriophage as a model, we demonstrate how coupling focused libraries, selection and deep sequencing can be combined to identify variants of interest for characterization. As selection parameters can be controlled, different areas of an enzyme’s mechanism can be explored. Focusing selection on faster HNA (1,5-anhydrohexitol nucleic acid) synthesis, we identified P562del as a variant of interest, enriching significantly between rounds. Characterization confirmed its faster HNA synthesis initiation but lower processivity and fidelity. P562 is a non-conserved residue, unlikely to be selected by more traditional approaches, but its deletion recapitulates knowledge on how Phi29 exonuclease, thumb and TPR2 subdomains regulate polymerase function. Our data further support the hypothesis that Phi29 shows a two-state binding to its template: a fast non-replicative complex that transitions to a replication-competent state.
FIRST INSIGHTS IN A NON-RODENT MODEL SPECIES OF THE OLFACTORY LIMBUS. THE RED FOX (Vulpes vulpes) AS A CASE IN POINT
Authors: Ortiz-Leal Irene , Torres Mateo V. , Vargas-Barroso Víctor , Fidalgo Luis Eusebio , López-Beceiro Ana , Larriva-Sahd Jorge , Sanchez-Quinteiro Pablo 
Published: November 2022

ABSTRACTThe mammalian olfactory systems can be divided into several subsystems based on the anatomical location of their neuroreceptor cells and the family of receptors they express. The more in depth studied systems are the main olfactory system and the vomeronasal system, whose first integrative enters are the main and the accessory olfactory bulb, respectively. In addition, there is a range of olfactory subsystems which converge to the transition zone located between the main olfactory bulb and the accessory olfactory bulb., which has been termed as olfactory limbus (OL) and includes specialized glomeruli which receive uncanonical sensory afferences and interact with the MOB and AOB. Beyond the laboratory rodents, there is a lack of information regarding the olfactory subsystems of carnivores. We have focused on the specific study of the olfactory limbus of the fox, performing serial histological sections, general and specific histological stainings, including both double and simple immunohistochemical and lectin-histochemical labeling techniques. As a result, we have been able to determine that the OL of the fox shows an uncommon development with a high degree of development and complexity. This makes this species a novel mammalian model that could provide a wider understanding of non-canonical pathways involved in the processing of chemosensory cues.
Cerebellar granule neurons induce Cyclin D1 in an early stage of Huntington’s disease
Authors: Bauer Susanne , Chen Chwen-Yu , Jonson Maria , Kaczmarczyk Lech , Magadi Srivathsa , Jackson Walker S. 
Published: November 2022

ABSTRACTAlthough Huntington’s disease (HD) is predominantly defined by selective vulnerability of striatal projection neurons, there is increasing evidence that cerebellar degeneration modulates clinical symptoms. However, little is known about cell type-specific responses of cerebellar neurons in HD. To dissect early disease mechanisms in the cerebellum and cerebrum, we analyzed translatomes of neuronal cell types from both regions in a new HD mouse model. For this, HdhQ200 knock-in mice were backcrossed with the calm, 129S4 strain, to constrain experimental noise caused by variable hyperactivity of mice in a C57BL/6 background. Behavioral and neuropathological characterization showed that these S4-HdhQ200 mice had very mild behavioral abnormalities starting around 12 months of age that remained mild up to 18 months. By 9 months, we observed abundant Huntingtin-positive neuronal intranuclear inclusions (NIIs) in the striatum and cerebellum. The translatome analysis of GABAergic cells of the cerebrum further confirmed changes typical of HD-induced striatal pathology. Surprisingly, we observed the strongest response with 626 differentially expressed genes in glutamatergic neurons of the cerebellum, a population consisting predominantly of granule cells, a cell type commonly considered disease-resistant. Our findings suggest vesicular fusion and exocytosis, as well as differentiation-related pathways are affected. Furthermore, increased expression of cyclin D1 (Ccnd1) in the granular layer and upregulated expression of polycomb group complex protein genes and cell cycle regulatorsCbx2, Cbx4andCbx8point to a putative role of aberrant cell cycle regulation in cerebellar granule cells in early disease.
Shigellaserotypes associated with carriage in humans establish persistent infection in zebrafish
Authors: Torraca Vincenzo , Brokatzky Dominik , Miles Sydney L. , Chong Charlotte E. , De Silva P. Malaka , Baker Stephen , Jenkins Claire , Holt Kathryn E. , Baker Kate S. , Mostowy Serge 
Published: November 2022

SummaryShigellarepresents a paraphyletic group of human-adaptedEscherichia colilineages that converged towards the same enteropathogenic pathovar. In low-income countries,Shigellais typically transmitted by ingestion of contaminated water and food, while in high-income countries sexual transmission among men who have sex with men (MSM) is the dominant route of transmission. Although more than 40 different serotypes ofShigellahave been reported globally, within the MSM community the majority of reported cases are attributed to threeShigellaserotypes: theShigella sonneiunique serotype (Ss) and theShigella flexneriserotypes 2a and 3a. Here, using a zebrafish infection model, we demonstrate thatShigellacan establish persistent infectionin vivo. In this case, bacteria are not cleared by the host immune system and become tolerant to therapeutic doses of antibiotics. We show that persistence is dependent on theShigellaO-Antigen, a key constituent of the bacterial cell surface and determinant of serotype classification. Representative isolates of threeShigellaserotypes associated with global dissemination and MSM transmission (S. sonneiSs,S. flexneri2a and 3a) all persist in zebrafish, while a serotype not associated with MSM transmission (S. flexneri5a) does not. Strikingly,Shigellaserotypes which establish persistent infection fail to promote macrophage cell deathin vivo. We conclude that zebrafish can be a valuable platform to illuminate host and pathogen factors underlying the establishment of persistent infection withShigellain humans.HighlightsShigellacan establish persistent infection in zebrafishEstablishment of persistent infectionin vivodepends onShigellaserotypeThe same serotypes establishing persistent infection in zebrafish are prevalent in a patient group in whom persistent infection is observedShigellaserotypes which establish persistent infection fail to promote macrophage cell deathin vivoIn BriefIn high-income countries, sexual transmission among men who have sex with men (MSM) is the dominant cause of domesticShigellatransmission. Torracaet al. discover that three serotypes ofShigellaassociated with MSM transmission also persist in zebrafish. These results indicate thatShigellaserotypes associated with MSM transmission can establish carriage in the host, and highlight the use of zebrafish infection to studyShigellapersistent infection in humans.