Miracle-dz/UniFAR-FTUs huggingface dataset:
FLEA PARASITISM AND HOST SURVIVAL IN A PLAGUE-RELEVANT SYSTEM: THEORETICAL AND CONSERVATION IMPLICATIONS

Abstract: Plague is a bacterial zoonosis of mammalian hosts and flea vectors. The disease is capable of ravaging rodent populations and transforming ecosystems. Because plague mortality is likely to be predicted by flea parasitism, it is critical to understand vector dynamics. It has been hypothesized that paltry precipitation and reduced vegetative production predispose herbivorous rodents to malnourishment and flea parasitism, and flea parasitism varies directly with plague mortality. We evaluated these hypotheses on five colonies of Utah prairie dogs (UPDs; Cynomys parvidens), on the Awapa Plateau, Utah, US, in 2013–16. Ten flea species were identified among 3,257 fleas from UPDs. These 10 flea species parasitize prairie dogs, mice, rats, voles, ground squirrels, chipmunks, and marmots, all known hosts of plague. The abundance of fleas on individual UPDs (1,198 observations) varied inversely with UPD body condition; fleas were most abundant on lightweight, malnourished UPDs. Flea abundance on UPDs was highest in dry years that were preceded by wet years. Increased precipitation and soil moisture in the prior year might generate humid microclimates in UPD burrows (that could facilitate flea survival and reproduction) and paltry precipitation in the current year could predispose UPDs to malnourishment and flea parasitism. Annual re-encounter rates for UPDs (1,072 observations) were reduced in wetter years preceded by drier years; reduced precipitation and vegetative production might kill UPDs, and increased flea densities in drier years could provide conditions for plague transmission (and UPD mortality) when moisture returns. Re-encounter rates were reduced for UPDs carrying at least one flea compared to UPDs with no detected fleas. These results support the hypothesis that reduced precipitation in the current year predisposes UPDs to flea parasitism. Our results also suggest a link between flea parasitism and UPD mortality. Given documented connections between flea parasitism and plague transmission, our results point toward an effect of flea parasitism on plague-related deaths for individual UPDs, a phenomenon rarely investigated in nature.
Vapor Selectivity of a Natural Photonic Crystal to Binary and Tertiary Mixtures Containing Chemical Warfare Agent Simulants

Vapor sensing via light reflected from photonic crystals has been increasingly studied as a means to rapidly identify analytes, though few studies have characterized vapor mixtures or chemical warfare agent simulants via this technique. In this work, light reflected from the natural photonic crystals found within the wing scales of the Morpho didius butterfly was analyzed after exposure to binary and tertiary mixtures containing dimethyl methylphosphonate, a nerve agent simulant, and dichloropentane, a mustard gas simulant. Distinguishable spectra were generated with concentrations tested as low as 30 ppm and 60 ppm for dimethyl methylphosphonate and dichloropentane, respectively. Individual vapors, as well as mixtures, yielded unique responses over a range of concentrations, though the response of binary and tertiary mixtures was not always found to be additive. Thus, while selective and sensitive to vapor mixtures containing chemical warfare agent simulants, this technique presents challenges to identifying these simulants at a sensitivity level appropriate for their toxicity.
Comparative efficacy of stents in endoscopic ultrasonography‐guided peripancreatic fluid collection drainage: A systematic review and network meta‐analysis

Although many studies have reported the efficacy of different stents for endoscopic ultrasonography (EUS)‐guided peripancreatic fluid collection (PFC) drainage, they have not completely determined which stent is superior. This network meta‐analysis comprehensively evaluated the comparative efficacy of stents used in EUS‐guided PFC.
Direct visualization of degradation microcompartments at the ER membrane

Significance Endoplasmic reticulum-associated degradation (ERAD) is an essential process that removes misfolded proteins from the ER, preventing cellular dysfunction and disease. While most of the key components of ERAD are known, their specific localization remains a mystery. This study uses in situ cryo-electron tomography to directly visualize the ERAD machinery within the native cellular environment. Proteasomes and Cdc48, the complexes that extract and degrade ER proteins, cluster together in non–membrane-bound cytosolic microcompartments that contact ribosome-free patches on the ER membrane. This discrete molecular organization may facilitate efficient ERAD. Structural analysis reveals that proteasomes directly engage ER-localized substrates, providing evidence for a noncanonical “direct ERAD” pathway. In addition, live-cell fluorescence microscopy suggests that these ER-associated proteasome clusters form by liquid–liquid phase separation. To promote the biochemical reactions of life, cells can compartmentalize molecular interaction partners together within separated non–membrane-bound regions. It is unknown whether this strategy is used to facilitate protein degradation at specific locations within the cell. Leveraging in situ cryo-electron tomography to image the native molecular landscape of the unicellular alga Chlamydomonas reinhardtii, we discovered that the cytosolic protein degradation machinery is concentrated within ∼200-nm foci that contact specialized patches of endoplasmic reticulum (ER) membrane away from the ER–Golgi interface. These non–membrane-bound microcompartments exclude ribosomes and consist of a core of densely clustered 26S proteasomes surrounded by a loose cloud of Cdc48. Active proteasomes in the microcompartments directly engage with putative substrate at the ER membrane, a function canonically assigned to Cdc48. Live-cell fluorescence microscopy revealed that the proteasome clusters are dynamic, with frequent assembly and fusion events. We propose that the microcompartments perform ER-associated degradation, colocalizing the degradation machinery at specific ER hot spots to enable efficient protein quality control.
Mitochondrial metabolic study guided by proteomics analysis in hepatocellular carcinoma cells surviving long-term incubation with the highest dose of sorafenib

Sorafenib is the standard first-line systemic therapy for hepatocellular carcinoma (HCC). However, the low objective response rates in clinical studies suggest the existence of certain HCC cells that are inherently insensitive to sorafenib. To understand the molecular basis of insensitivity of HCC cells to sorafenib, this study developed 3 kinds of insensitive HCC cells through exposure to various concentrations of sorafenib and performed a quantitative proteome analysis of the surviving HepG2 cells. 520 unique proteins were concentration-dependently upregulated by sorafenib. Bioinformatics-assisted analysis of 520 proteins revealed that the metabolic pathways involved in central carbon metabolism were significantly enriched, and 102 mitochondrial proteins, especially components of the electron transport chain (ETC), were incrementally upregulated in the 3 kinds of insensitive cells. Conversely, we identified a rapid holistic inhibitory effect of sorafenib on mitochondrial function by the direct targeting of the complex I-linked electron transport and the uncoupling of mitochondrial oxidative phosphorylation (OXHPOS) in HCC cells. Core metabolic reprogramming involved in a compensatory upregulation of OXHPOS combined with elevated glycolysis supports the survival of HCC cells under the highest dose of sorafenib treatment. Altogether, our work thus elaborates an ETC inhibitor and unveils the proteomic landscape of metabolic reprogramming in drug insensitivity.
De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction

Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1’s fundamental role within this pathway.
The evolution pathway from iron compounds to Fe1(II)-N4 sites through gas-phase iron during pyrolysis.

Pyrolysis is indispensable for synthesizing highly active Fe-N-C catalysts for the oxygen reduction reaction (ORR) in acid, but how Fe, N, and C precursors transform to ORR-active sites during pyrolysis remains unclear. This knowledge gap ob-scures the connections between the input precursors and output products, clouding the pathway toward Fe-N-C catalyst im-provement. Herein, we unravel the evolution pathway of precursors to ORR-active catalyst comprised exclusively of single atom Fe1(II)-N4 sites via in-temperature X-ray absorption spectroscopy. The Fe precursor transforms to Fe oxides below 300 ℃, and then to tetrahedral Fe1(II)-O4 via a crystal-to-melt-like transformation below 600 ℃. The Fe1(II)-O4 releases a single Fe atom that flows into the N-doped carbon defect forming Fe1(II)-N4 above 600 ℃. This vapor phase single Fe atom transport mechanism is verified by synthesizing Fe1(II)-N4 sites via "non-contact pyrolysis" wherein the Fe precursor is not in physical contact with the N and C precursors during pyrolysis.
Intrinsic and extrinsic factors associated with sputum characteristics of presumed tuberculosis patients

Background Sputum remains the most preferred specimen for detection of Mycobacterium tuberculosis due to its non-invasive method of production. Good quality sputum specimen is essential for accurate diagnosis of pulmonary tuberculosis (PTB). It is therefore imperative to assess factors that are related to the production of sputum that is of the best quality. Objective We assessed the intrinsic and extrinsic characteristics of presumed tuberculosis patients and the quality of sputum they produced. Methods This was a cross-sectional study in which consenting enrolled presumed tuberculosis patients were subjected to medical examination and a structured questionnaire administered to collect clinical history, demographic information, environmental and behavioral characteristics. The enrolled participants were instructed on how to collect spot and morning sputum specimens for macroscopic and microscopic assessment to determine any association. Results A total of 309 patients were enrolled into the study with an even distribution on gender (50.5% males). Of these, 202 (65.3%) submitted both a spot and a morning specimen for analysis. On macroscopic examination, 70% spot and 68% morning sputum were characterized as good quality (Purulent/mucoid). The factors associated (p<0.05) with quality specimen included both intrinsic and extrinsic factors. The intrinsic factors included: difficulty in breathing, presence of conjunctivitis and knowledge of the disease whereas the only extrinsic factor associated with production of good quality sputum for tuberculosis diagnosis was time taken by patient to seek tuberculosis treatment after occurrence of any of the TB symptoms. Conclusion Both intrinsic and extrinsic factors affected the quality of sputum produced by presumed tuberculosis patients. Clinical and behavioral characteristics including conjunctivitis, difficulty in breathing and delay in seeking treatment were important factors that determined the production of good quality sputum specimens, while knowledge of tuberculosis disease did not compel presumed tuberculosis patients to produce good quality sputum for diagnosis of the disease.
Midkine-a Is Required for Cell Cycle Progression of Müller Glia during Neuronal Regeneration in the Vertebrate Retina

In the retina of zebrafish, Müller glia have the ability to reprogram into stem cells capable of regenerating all classes of retinal neurons and restoring visual function. Understanding the cellular and molecular mechanisms controlling the stem cell properties of Müller glia in zebrafish may provide cues to unlock the regenerative potential in the mammalian nervous system. Midkine is a cytokine/growth factor with multiple roles in neural development, tissue repair, and disease. In the retina of zebrafish, Müller glia have the ability to reprogram into stem cells capable of regenerating all classes of retinal neurons and restoring visual function. Understanding the cellular and molecular mechanisms controlling the stem cell properties of Müller glia in zebrafish may provide cues to unlock the regenerative potential in the mammalian nervous system. Midkine is a cytokine/growth factor with multiple roles in neural development, tissue repair, and disease. In midkine-a loss-of-function mutants of both sexes, Müller glia initiate the appropriate reprogramming response to photoreceptor death by increasing expression of stem cell-associated genes, and entering the G1 phase of the cell cycle. However, transition from G1 to S phase is blocked in the absence of Midkine-a, resulting in significantly reduced proliferation and selective failure to regenerate cone photoreceptors. Failing to progress through the cell cycle, Müller glia undergo reactive gliosis, a pathological hallmark in the injured CNS of mammals. Finally, we determined that the Midkine-a receptor, anaplastic lymphoma kinase, is upstream of the HLH regulatory protein, Id2a, and of the retinoblastoma gene, p130, which regulates progression through the cell cycle. These results demonstrate that Midkine-a functions as a core component of the mechanisms that regulate proliferation of stem cells in the injured CNS. SIGNIFICANCE STATEMENT The death of retinal neurons and photoreceptors is a leading cause of vision loss. Regenerating retinal neurons is a therapeutic goal. Zebrafish can regenerate retinal neurons from intrinsic stem cells, Müller glia, and are a powerful model to understand how stem cells might be used therapeutically. Midkine-a, an injury-induced growth factor/cytokine that is expressed by Müller glia following neuronal death, is required for Müller glia to progress through the cell cycle. The absence of Midkine-a suspends proliferation and neuronal regeneration. With cell cycle progression stalled, Müller glia undergo reactive gliosis, a pathological hallmark of the mammalian retina. This work provides a unique insight into mechanisms that control the cell cycle during neuronal regeneration.
Mating-Type-Specific Ribosomal Proteins Control Aspects of Sexual Reproduction in Cryptococcus neoformans

This study demonstrated that the ribosomal proteins Rpl22 and Rpl39 encoded by the MAT locus of Cryptococcus neoformans are essential. Focusing on the RPL22a and RPL22α alleles, Ianiri et al. found differential expression of the two RPL22. The MAT locus of Cryptococcus neoformans has a bipolar organization characterized by an unusually large structure, spanning over 100 kb. MAT genes have been characterized by functional genetics as being involved in sexual reproduction and virulence. However, classical gene replacement failed to achieve mutants for five MAT genes (RPL22, RPO41, MYO2, PRT1, and RPL39), indicating that they are likely essential. In the present study, targeted gene replacement was performed in a diploid strain for both the α and a alleles of the ribosomal genes RPL22 and RPL39. Mendelian analysis of the progeny confirmed that both RPL22 and RPL39 are essential for viability. Ectopic integration of the RPL22 allele of opposite MAT identity in the heterozygous RPL22a/rpl22αΔ or RPL22α/rpl22aΔ mutant strains failed to complement their essential phenotype. Evidence suggests that this is due to differential expression of the RPL22 genes, and an RNAi-dependent mechanism that contributes to control RPL22a expression. Furthermore, via CRISPR/Cas9 technology, the RPL22 alleles were exchanged in haploid MATα and MATa strains of C. neoformans. These RPL22 exchange strains displayed morphological and genetic defects during bilateral mating. These results contribute to elucidating functions of C. neoformans essential mating type genes that may constitute a type of imprinting system to promote inheritance of nuclei of both mating types.
Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy

Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy. Currently, the only option available to attenuate chemotherapy-induced neuropathy is to limit or discontinue this treatment. Sphingosine 1-phosphate (S1P) is a lipid-based signaling molecule involved in neuroinflammatory processes by interacting with its five cognate receptors: S1P1–5. In this study, using a combination of drug pharmacodynamic analysis in human study participants, disease modeling in rodents, and cell-based assays, we examined whether S1P signaling may represent a potential target in the treatment of chemotherapy-induced neuropathy. To this end, we first investigated the effects of platinum-based drugs on plasma S1P levels in human cancer patients. Our analysis revealed that oxaliplatin treatment specifically increases one S1P species, d16:1 S1P, in these patients. Although d16:1 S1P is an S1P2 agonist, it has lower potency than the most abundant S1P species (d18:1 S1P). Therefore, as d16:1 S1P concentration increases, it is likely to disproportionately activate proinflammatory S1P1 signaling, shifting the balance away from S1P2. We further show that a selective S1P2 agonist, CYM-5478, reduces allodynia in a rat model of cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia, likely by activating stress-response proteins, including ATF3 and HO-1. Cumulatively, the findings of our study suggest that the development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.
The Best of All Worlds: Streptococcus pneumoniae Conjunctivitis through the Lens of Community Ecology and Microbial Biogeography

The study of the forces which govern the geographical distributions of life is known as biogeography, a subject which has fascinated zoologists, botanists and ecologists for centuries. Advances in our understanding of community ecology and biogeography—supported by rapid improvements in next generation sequencing technology—have now made it possible to identify and explain where and why life exists as it does, including within the microbial world. In this review, we highlight how a unified model of microbial biogeography, one which incorporates the classic ecological principles of selection, diversification, dispersion and ecological drift, can be used to explain community dynamics in the settings of both health and disease. These concepts operate on a multiplicity of temporal and spatial scales, and together form a powerful lens through which to study microbial population structures even at the finest anatomical resolutions. When applied specifically to curious strains of conjunctivitis-causing, nonencapsulated Streptococcus pneumoniae, we show how this conceptual framework can be used to explain the possible evolutionary and disease-causing mechanisms which allowed these lineages to colonize and invade a separate biogeography. An intimate knowledge of this radical bifurcation in phylogeny, still the only known niche subspecialization for S. pneumoniae to date, is critical to understanding the pathogenesis of ocular surface infections, nature of host-pathogen interactions, and developing strategies to curb disease transmission.
Semi-purified rhamnolipid mixes protect Brassica napus against Leptosphaeria maculans early infections.

The rapeseed crop (Brassica napus L.) has to cope with fungal diseases that significantly impacts yields. In particular, the fungal pathogen Leptosphaeria maculans, the causal agent of blackleg disease (also named phoma stem canker), is a worldwide issue to this crop. Considering environmental concerns, it is essential to propose alternative natural compounds for rapeseed crop protection to reduce chemical fungicide use. Here we report data showing the efficacy of semi-purified rhamnolipid (RL) mixes from bacterial origin to protect rapeseed against L. maculans at early stages of infection in controlled conditions. In addition, we show that RL solutions have excellent adhesion properties when sprayed onto rapeseed leaves, without adding any adjuvant. We demonstrate that RL mixes display direct antimycelial properties against the pathogen and stimulate plant defense responses in rapeseed. Our results validate, a preventive action of low RL concentrations to protect rapeseed against L. maculans and a curative effect in specific conditions when applied after the inoculation of the pathogen spores. Semi-purified RL mixes therefore appear to be real cost-effective compounds that could be used in field as biocontrol products to fight L. maculans early infections of rapeseed.
Inhibition of Haspin kinase promotes cell-intrinsic and extrinsic anti-tumor activity.

Melanoma patients resistant to RAF/MEK-inhibitors (RMi) are frequently resistant to other therapies, such as immune checkpoint inhibitors (ICI), and individuals succumb to their disease. New drugs that control tumor growth and favorably modulate the immune environment are therefore needed. We report that the small molecule CX-6258 has potent activity against both RMi sensitive (RMS) and resistant (RMR) melanoma cell lines. Haspin Kinase (HASPIN) was identified as a target of CX-6258. HASPIN inhibition resulted in reduced proliferation, frequent formation of micronuclei (MN), recruitment of cGAS and activation of the cGAS-STING-pathway. In murine models, CX-6258 induced a potent cGAS-dependent type-I-interferon response in tumor cells, increased IFNγ-producing CD8+ T-cells and reduced Treg frequency in vivo. HASPIN was more strongly expressed in malignant compared to healthy tissue and its inhibition by CX-6258 had minimal toxicity in ex vivo expanded human tumor-infiltrating lymphocytes (TILs), proliferating TILs and in vitro differentiated neurons, suggesting a potential therapeutic index for anti-cancer therapy. Furthermore, the activity of CX-6258 was validated in several Ewing sarcoma and multiple myeloma cell lines. Thus, HASPIN inhibition may overcome drug resistance in melanoma, modulate the immune environment and target a vulnerability in different cancer lineages.