bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidermis Derived Lactate Promotes Sterile Inflammation by Inducing Metabolic Rewiring in Macrophages
Authors: Ayyangar Uttkarsh , Karkhanis Aneesh , Tay Heather , Afandi Aliya Farissa Binte , Bhattacharjee Oindrila , Han Lee Sze , Chan James , Raghavan Srikala 
Published: July 2022

AbstractDysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic, sterile inflammation. However, the metabolic cues that direct and support macrophage functions are poorly understood. Here, we show that during sterile inflammation in skin, the epidermis and macrophages uniquely depend on glycolysis and TCA cycle, respectively. This compartment separation is initiated by HIF1a stabilization and enhanced glycolysis in the epidermis. The end product of glycolysis, lactate is exported and utilized by the dermal macrophages to drive their effector functions. Notably, inhibition of lactate mediated crosstalk between the epidermis and macrophages leads to inhibition of sterile inflammation. Overall, our study identifies an essential role for the metabolite lactate in regulating macrophage response that can be effectively targeted to treat skin disorders such as psoriasis.One-Sentence SummaryEpidermis derived lactic acid drives sterile inflammation by augmenting pro-remodeling state in dermal macrophages.
Cloning, heterologous expression and characterization of o-phthalyl-CoA decarboxylase from phthalate degrading denitrifying bacterium
Authors: Junghare Madan 
Published: July 2022

AbstractPhthalic acid esters (phthalates) are used as additives in various plastics and industrial applications. They are produced worldwide in huge amounts causing major pollution in the environment. Biodegradation of phthalates from the environment is an important route for their removal. In our previous work, we showed that Azoarcus sp. strain PA01 catabolizes o-phthalate via the anaerobic benzoyl-CoA pathway that involved two putative enzymes: the succinyl-CoA:o-phthalate CoA-transferase activates o-phthalate to o-phthalyl-CoA which is subsequently decarboxylated to benzoyl-CoA by o-phthalyl-CoA decarboxylase. In this work, we provide the information on the enzymes involved in the promising step of anoxic decarboxylation of o-phthalate to benzoyl-CoA. We have identified that there are two proteins are involved in decarboxylation step, of which only one does the actual decarboxylation but other one is essential. o-Phthalyl-CoA decarboxylase (PhtDa and PhtDb) encoded by the two genes PA01_00217 and PA01_00218 which catalyses the decarboxylation of activated o-phthalate to benzoyl-CoA. Both genes are originally annotated as an UbiD-like/UbiX-like protein. The gene with locus tag PA01_00217 is 1584 bp long coding for protein PhtDa (60 kDa), whereas PA01_00218 is 600 bp long codes for protein PhtDb (22 kDa). Here, we demonstrate that PhtDb is a flavin mononucleotide (FMN)-binding protein which does not function as a decarboxylase alone. Rather, PhtDb is assumed to generate a modified FMN-containing cofactor that is required by the PhtDa for decarboxylase activity. Alone, PhtDa does not function as a decarboxylase either. Recombinantly expressed PhtDa and PhtDb together showed activity for decarboxylation of o-phthalyl-CoA to benzoyl-CoA, only if PhtDb was previously incubated with FMN and dimethylallyl monophosphate. Phylogenetically, the proteins PhtDa and PhtDb are closely related to UbiD-like/UbiX-like enzymes that catalyses the decarboxylation of 4-hydroxy-3-octaprenylbenzoic acid to 2-octaprenylphenol, an intermediate step in ubiquinone biosynthesis. Furthermore, multiple sequence alignment and structural modelling of both proteins suggested that only PthDb possesses the binding site for FMN. These results strongly indicate that the flavin-containing cofactor is essential for decarboxylation of o-phthalyl-CoA to benzoyl-CoA during anaerobic o-phthalate degradation by Azoarcus sp. strain PA01.
Dynamic states of eIF6 and SDS variants modulate interactions with uL14 of the 60S ribosomal subunit
Authors: Elliff Jonah , Biswas Aparna , Kuppa Sahiti , Roshan Poonam , Patterson Angela , Mattice Jenna , Chinnaraj Mathivanan , Burd Ryan , Walker Sarah E. , Pozzi Nicola , Antony Edwin , Bothner Brian , Origanti Sofia 
Published: July 2022

AbstractAssembly of ribosomal subunits into active ribosomal complexes is integral to protein synthesis. Release of eIF6 from the 60S ribosomal subunit primes 60S to associate with the 40S subunit and engage in translation. The dynamics of eIF6 interaction with the uL14 (RPL23) interface of 60S and its regulation by somatic mutations acquired in Shwachman-Diamond Syndrome (SDS) is yet to be clearly understood. Here, by using a modified strategy to obtain high yields of recombinant human eIF6 we have uncovered the critical interface entailing 8 key residues in the C-tail of RPL23 that is essential for physical interactions between 60S and eIF6. Disruption of the complementary binding interface by conformational changes in eIF6 disease variants provide a mechanism for weakened interactions of variants with the 60S. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) analyses uncovered dynamic configurational rearrangements in eIF6 induced by binding to RPL23 and exposed an allosteric interface regulated by the C-tail of eIF6. Disrupting a key residue in the eIF6-60S binding interface markedly limits proliferation of cancer cells, which highlights the significance of therapeutically targeting this interface. Establishing these key interfaces thus provide a therapeutic framework for targeting eIF6 in cancers and SDS.
Interspecies Killing Activity of Pseudomonas syringae Tailocins
Authors: Weaver Savannah L. , Zhu Libin , Ravishankar Sadhana , Clark Meara , Baltrus David A. 
Published: July 2022

AbstractTailocins are ribosomally synthesized bacteriocins, encoded by bacterial genomes, but originally derived from bacteriophage tails. As with both bacteriocins and phage, tailocins are largely thought to be species-specific with killing activity often assumed to be directed against closely-related strains. Previous investigations into interactions between tailocin host range and sensitivity across phylogenetically diverse isolates of the phytopathogen Pseudomonas syringae have demonstrated that many strains possess intraspecific tailocin activity and that this activity is highly precise and specific against subsets of strains. However, here we demonstrate that at least one strain of P. syringae, USA011R, defies both expectations and current overarching dogma because tailocins from this strain possess broad killing activity against other agriculturally significant phytopathogens such as Erwinia amylovora and Xanthomonas perforans as well as against the clinical human pathogen Salmonella choleraesuis. Moreover, we show that the full spectrum of this interspecific killing activity is not conserved across closely related strains with data suggesting that even if tailocins can target different species, they do so with different efficiencies. Our results reported herein highlight the potential for and phenotypic divergence of interspecific killing activity of P. syringae tailocins and establish a platform for further investigations into the evolution of tailocin host range and strain specificity.
A molecular mechanism for membrane chaperoning by a late embryogenesis abundant protein
Authors: Li Xiao-Han , Yu Conny W.H. , Gomez-Navarro Natalia , Stancheva Viktoriya , Zhu Hongni , Guibao Cristina , Murthy Andal , Xie Boer , Wozny Michael , Leslie Benjamin , Kaminski Marcin , Malhotra Ketan , Johnson Christopher M. , Blackledge Martin , Santhanam Balaji , Green Douglas R. , Peng Junmin , Liu Wei , Huang Jinqing , Miller Elizabeth A. , Freund Stefan M.V. , Babu M. Madan 
Published: July 2022

SummaryEnvironmental stress can result in substantial damage to proteins, membranes, and genetic material, impacting organismal survival1-3. Stress tolerance can be conferred by intrinsically disordered proteins (IDPs)4 that lack stable tertiary structure. IDPs from the large family of late embryogenesis abundant (LEA) proteins confer a fitness advantage when heterologously expressed5,6. Such protection suggests a general molecular function leading to stress tolerance, although the mechanisms remain unclear. Here, we report that a tardigrade LEA protein that confers stress tolerance in yeast acts as a molecular chaperone for the mitochondrial membrane. This protein, named HeLEA1, localizes to the mitochondrial matrix, and harbors conserved LEA sequence motifs that undergo dynamic disorder-to-helical transition upon binding to negatively charged membranes. Yeast expressing HeLEA1 show increased mitochondrial membrane fluidity, increased membrane potential, and enhanced tolerance to hyperosmotic stress under non-fermentative growth without significantly altering mitochondrial lipid composition or triggering a generic stress response. We demonstrate that membrane binding ameliorates excess surface tension, possibly by stabilizing lipid packing defects. Evolutionary analysis suggests that HeLEA1 homologs localize to different membrane-bound organelles and share similar sequence and biophysical features. We suggest that membrane chaperoning by LEA proteins represents a general biophysical solution that can operate across the domains of life.
Molecular basis for differential activation of p101 and p84 complexes of PI3Kγ by Ras and GPCRs
Authors: Rathinaswamy Manoj K , Jenkins Meredith L , Zhang Xuxiao , Stariha Jordan TB , Ranga-Prasad Harish , Dalwadi Udit , Fleming Kaelin D. , Yip Calvin K , Williams Roger L , Burke John E 
Published: July 2022

AbstractClass IB phosphoinositide 3-kinase (PI3Kγ) is activated in immune cells by diverse stimuli and can form two distinct complexes, with the p110γ catalytic subunit binding to either p101 or p84 regulatory subunits. These two complexes are differentially activated by G-protein coupled receptors (GPCRs) and Ras, but the molecular details of this activation are still unclear. Using a combination of X-ray crystallography, HDX-MS, EM, molecular modeling, and biochemical assays we reveal molecular differences between the two p110γ-p84 and p110γ-p101 complexes that explain their differential activation. The structure of p110γ-p84 shows a similar assembly to p110γ-p101 at the p110γ interface, however the interface in p110γ-p84 is dynamic and is evolutionarily conserved to be less stable compared to p110γ-p101. The p110γ-p84 complex is only weakly recruited to membranes by Gβγ subunits alone and requires recruitment by Ras to allow for Gβγ activation through an interaction with the p110γ helical domain. The interfaces of the p101 GBD with Gβγ, and the p110γ helical domain with Gβγ were determined using computational alphafold2 modeling and HDX-MS. There are distinct differences in the C-terminal domain of p84 and p101, which allows p101 to bind Gβγ subunits, while p84 does not. The two Gβγ interfaces in p110γ and p101 are distinct, revealing how unique mutants of Gβγ cause differential disruption of PI3Kγ complex activation. Overall, our work provides key insight into the molecular basis for how different PI3Kγ complexes are activated.
TERRA increases at short telomeres in yeast survivors and regulates survivor associated senescence (SAS)
Authors: Misino Stefano , Busch Anke , Wagner Carolin B. , Luke Brian 
Published: July 2022

AbstractCancer cells achieve immortality by employing either homology-directed repair (HDR) or the telomerase enzyme to maintain telomeres. ALT (alternative lengthening of telomeres) refers to the subset of cancer cells that employ HDR. ALT mechanisms are strongly conserved from yeast to human cells, with the yeast equivalent being referred to as survivors. The non-coding RNA, TERRA and its ability to form RNA-DNA hybrids have been implicated in ALT/survivor maintenance by promoting HDR. It is not understood which telomeres in ALT/survivors engage in HDR, nor is it clear which telomeres upregulate TERRA. Using yeast survivors as a model for ALT, we demonstrate that HDR only occurs at telomeres when they become critically short. Moreover, TERRA levels steadily increase as telomeres shorten and decrease again following HDR-mediated recombination. Surprisingly, we observe that survivors undergo cycles of senescence, in a similar manner to non-survivors following telomerase loss, which we refer to as survivor associated senescence (SAS). Similar to “normal” senescence, we observe that RNA-DNA hybrids slow the rate of SAS by decreasing the rate of telomere shortening. In summary, TERRA RNA-DNA hybrids regulate telomere dysfunction-induced senescence in both pre- and post-crisis cells.
Advancing Spectrally-Resolved Single Molecule Localization Microscopy using Deep Learning
Authors: Manko Hanna , Mély Yves , Godet Julien 
Published: July 2022

Spectrally-Resolved Single Molecule Localization Microscopy (srSMLM) is a recent multidimensional technique enriching single molecule localization imaging by the simultaneous recording of single emitters spectra. As for SMLM, the localization precision is fundamentally limited by the number of photons collected per emitters. But srSMLM is more impacted because splitting the emission light from single emitters into a spatial and a spectral channel further reduces the number of photons available for each channel and impairs both spatial and spectral precision - or forces the sacrifice of one or the other. Here, we explored the potential of deep learning to overcome this limitation. We report srUnet - a Unet-based image processing that enhances the spectral and spatial signals and compensates for the signal loss inherent in recording the spectral component. We showed that localization and spectral precision of low-emitting species remain as good as those obtained with a high photons budget together with improving the fraction of localizations whose signal is both spatially and spectrally interpretable. srUnet is able to deal with spectral shift and its application to multicolour imaging in biological sample is straight-forward.srUnet advances spectrally resolved single molecule localization microscopy to achieve performance close to conventional SMLM without complicating its use.
Molecular phylogenetic analysis for Ovis aries with whole mitochondrial genome sequencing
Authors: Pal Aruna , Banerjee Samiddha , Pathak Kanai , Das Manas Kumar , Chatterjee P.N. 
Published: July 2022

AbstractDomestication of Ovis aries has taken place time immorial across the different geographical regions across the globe. Biodiversity among the sheep population has been interesting to study by a group of researchers based on mitochondrial genes like Cytochrome B, D loop. The current study is a novel attempt to understand the molecular phylogenomics among Ovis aries through all the 37 genes of mitochondria. We have analyzed complete mitochondrial genome sequencing for sheep breeds for West Bengal as Garole, Chotanagpuri, Bonpala and Birbhum sheep. Phylogenetic analysis reveals genetic similarity between Garole and Chotanagpuri brred of sheep, where as Birbhum and Bonpala were found to be genetically distinct. Phylogenomics in a global prospect reveal three lineages, Lineage A comprise of sheep from West Bengal grouped with Tibetan sheep. Lineage B consists of sheep population across the other parts including Europe (France, Denmark), Africa and Syro-Arabian desert, whereas Lineage C emerged as smaller outgroup.
Rescue Stenting in Mechanical Thrombectomy Refractory Occlusions: A Single Center Multiethnic Cohort
Authors: Imam Yahia Z , Akhtar Naveed , Kamran Saadat , Bermejo Pablo , Jerdi Salman Al , Zakaria Ayman , Own Ahmed , Patro Satya 
Published: July 2022

AbstractIntroductionRefractory large vessel occlusion in acute ischemic stroke carries high morbidity and mortality. Rescue stenting is an emerging modality that is increasingly utilized especially in East Asia. We aim to investigate the safety and efficacy of performing rescue stenting in acute stroke patients who had failed mechanical thrombectomy.MethodsThis is a retrospective, all-inclusive, observational, descriptive review of the prospectively collected stroke database. Post stenting, an aggressive antiplatelet protocol was followed with glycoprotein IIb/IIIa infusion. Incidence of intracerebral hemorrhage (ICH), recanalization score and favorable prognosis (modified Rankin Score ≤3) at 90 days was used to determine primary outcome. Additionally, comparison was made between patients from the Middle East and North Africa (MENA) region and others.ResultsIn total, 55 patients were included with 87.3% being male. Mean age was 51.3±11.8 years. This included 32 patients (58.3%) from South Asia, 12 (21.8%) from the MENA region, 9 (16.4%) from Southeast Asia and 2 (3.6%) from other parts of the world. Optimal recanalization (Thrombolysis in cerebral infarction (TICI) scale=2b-3) was achieved in 43 (78.2%); the incidence of symptomatic ICH was 2 (3.6%) and favorable outcome at 90 days was seen in 23 (41.8%). Apart from significantly older age, mean 62.8±13 years (median 69) vs. 48.1±9.3 (mean 49) and coronary artery disease burden 4 (33.3%) vs.1 (2.3%) (p<0.05). Patients from the MENA cohort had similar risk factor profiles, stroke severity, recanalization rates, ICH rates and 90-day outcomes compared to patients from South and Southeast Asia.ConclusionRescue stenting showed comparably good outcomes and low risk of clinically significant bleeding in a multiethnic cohort of patients from MENA and South and Southeast Asia.
Modelling the role of quarantine escapees on COVID-19 dynamics
Authors: Mushanyu Josiah , Madubueze Chinwendu Emilian , Chukwu Williams , Chazuka Zviiteyi , Mudzingwa Frenick , Ogbogbo Chisara 
Published: July 2022

AbstractThe recent outbreak of the novel coronavirus (COVID-19) pandemic which originated from the Wuhan City of China has devastated many parts of the globe. At present, non-pharmaceutical interventions are the widely available measures being used in combating and controlling this disease. There is great concern over the rampant unaccounted cases of individuals skipping the border during this critical period in time. We develop a deterministic compartmental model to investigate the impact of escapees on the transmission dynamics of COVID-19 in Zimbabwe. A suitable Lyapunov function has been used to show that the disease-free equilibrium is globally asymptotically stable provided ℛ0< 1. We performed global sensitivity analysis using the Latin-hyper cube sampling method and partial rank correlation coefficients to determine the most influential model parameters on the short and long term dynamics of the pandemic, so as to minimize uncertainties associated with our variables and parameters. Results confirm that there is a positive correlation between the number of escapees and the reported number of COVID-19 cases. It is shown that escapees are largely responsible for the rapid increase in local transmissions. Also, the results from sensitivity analysis show that an increase in the governmental role actions and a reduction in immigration rate will help to control and contain the disease spread.
Native language leaves distinctive traces in brain connections
Authors: Goucha T. , Anwander A. , Adamson H. , Friederici A. D. 
Published: July 2022

AbstractThe world’s languages differ substantially in their sounds, grammatical rules, and expression of semantic relations. While starting from a shared neural substrate, the developing brain must therefore have the plasticity to accommodate to the specific processing needs of each language. However, there is little research on how language-specific differences impacts brain function and structure. Here, we show that speaking typologically different languages leaves unique traces in the brain’s white matter connections of monolingual speakers of English (fixed word order language), German (with grammatical marking), and Chinese (tonal language). Using machine learning, we classified with high accuracy the mother tongue based on the participants’ patterns of structural connectivity obtained with probabilistic tractography. More importantly, connectivity differences between groups could be traced back to relevant processing characteristics of each native tongue. Our results show that the life-long use of a certain language leaves distinct traces in a speaker’s neural network.
Single Cell Cortical Bone Transcriptomics Defines Novel Osteolineage Gene Sets Altered in Chronic Kidney Disease
Authors: Agoro Rafiou , Nookaew Intawat , Noonan Megan L. , Marambio Yamil G. , Liu Sheng , Chang Wennan , Gao Hongyu , Hibbard Lainey M. , Metzger Corinne E. , Horan Daniel , Thompson William R. , Xuei Xiaoling , Liu Yunlong , Zhang Chi , Robling Alexander G. , Bonewald Lynda F. , Wan Jun , White Kenneth E. 
Published: July 2022

AbstractDue to a lack of spatial-temporal resolution at the single cell level, the etiologies of the bone dysfunction caused by diseases such as normal aging, osteoporosis, and the metabolic bone disease associated with chronic kidney disease (CKD) remain largely unknown. To this end, flow cytometry and scRNAseq were performed on long bone cells from Sost-cre/Ai9+mice, and pure osteolineage transcriptomes were identified, including novel osteocyte-specific gene sets. Clustering analysis isolated osteoblast precursors that expressedTnc,Mmp13,andSpp1,and a mature osteoblast population defined bySmpd3,Col1a1, andCol11a1. Osteocytes were demarcated byCd109,Ptprz1, Ramp1, Bambi, Adamts14,Spns2, Bmp2,WasI,andPhex. We validated ourin vivoscRNAseq using integrativein vitropromoter occupancy via ATACseq coupled with transcriptomic analyses of a conditional, temporally differentiated MSC cell line. Further, trajectory analyses predicted osteoblast-to-osteocyte transitions via defined pathways associated with a distinct metabolic shift as determined by single-cell flux estimation analysis (scFEA). Using the adenine mouse model of CKD, at a time point prior to major skeletal alterations, we found that gene expression within all stages of the osteolineage was disturbed. In sum, distinct populations of osteoblasts/osteocytes were defined at the single cell level. Using this roadmap of gene assembly, we demonstrated unrealized molecular defects across multiple bone cell populations in a mouse model of CKD, and our collective results suggest a potentially earlier and more broad bone pathology in this disease than previously recognized.