bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secretory cells are the primary source of pIgR in small airways
Authors: Blackburn Jessica B. , Schaff Jacob A. , Gutor Sergey , Du Rui-Hong , Nichols David , Sherrill Taylor , Gutierrez Austin J. , Xin Matthew K. , Wickersham Nancy , Zhang Yong , Holtzman Michael J. , Ware Lorraine B , Banovich Nicholas E. , Kropski Jonathan A. , Blackwell Timothy S. , Richmond Bradley W. 
Published: November 2021

AbstractBackgroundLoss of secretory immunoglobulin A (SIgA) is common in COPD small airways and likely contributes to disease progression. We hypothesized loss of SIgA results from reduced expression of pIgR, a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium.MethodspIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in-situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice utilized immunostaining, primary murine tracheal epithelial cell (MTEC) culture, and transgenic mice with secretory or ciliated cell-specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from non-typeable Haemophilus influenzae (NTHi) was evaluated in vitro.ResultsWe found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and NTHi-secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD.InterpretationLoss of the SIgA immunobarrier in small airways of patients severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation.Key MessagesWhat is the key question? Localized SIgA deficiency in small airways is an established driver of COPD pathogenesis, but the mechanism of loss remains unclear. We hypothesized loss of SIgA is due to reduced numbers of pIgR-expressing cells in SIgA-deficient small airways.What is the bottom line? pIgR is primarily expressed by secretory cells in human and murine airways. Although numbers of secretory cells are similar between SIgA-deficient and SIgA-replete airways in COPD, there is reduced expression of pIgR protein, but not mRNA, in SIgA-deficient airways. Additionally, host and bacterial proteases degrade SIgA in vitro, suggesting loss of SIgA may relate to both impaired transcytosis and increased degradation.Why read on? This study highlights the complexity of SIgA immunobarrier maintenance and suggests that strategies aimed at restoring the SIgA immunobarrier will need to account for both impaired transcytosis and degradation by host and/or bacterial proteases.
8 Å structure of the cytoplasmic ring of the Xenopus laevis nuclear pore complex solved by cryo-EM and AI
Authors: Tai Linhua , Zhu Yun , Ren He , Huang Xiaojun , Zhang Chuanmao , Sun Fei 
Published: November 2021

ABSTRACTAs one of the largest protein complexes in eukaryotes, the nuclear pore complex (NPC) forms a conduit regulating nucleocytoplasmic transport. Here, we determined 8 Å resolution cryo-electron microscopic (cryo-EM) structure of the cytoplasmic ring (CR) from the Xenopus laevis NPC. With the aid of AlphaFold2, we managed to build a most comprehensive and accurate pseudoatomic model of the CR to date, including the Y complexes and flanking components of Nup358, Nup214 complexes, Nup205 and Nup93. Comparing with previously reported CR model, the Y complex structure in our model exhibits much tighter interactions in the hub region mediated by α-solenoid domain in Nup160 C-terminus. Five copies of Nup358 are identified in each CR subunit to provide rich interactions with other Nups in stem regions of Y complexes. Two copies of Nup214 complexes lay in a parallel pattern and attach to the short arm region of Y complexes towards the central channel of NPC. Besides, the structural details of two copies of Nup205 on the side of the short arm region and one copy of Nup93 on the stem region of Y complexes in each CR subunit are also revealed. These in-depth novel structural features represent a great advance in understanding the assembly of NPCs.
An essential role for a discrete parasubthalamic nucleus subpopulation in appetite suppression
Authors: Kim Jessica H. , Kromm Grace H. , Barnhill Olivia K. , Han Kenneth , Heuer Lauren B. , Loomis Sierra , Newman Matthew C. , Sperber Jacob , Legan Theresa B. , Gulamali Faris F. , Jensen Katharine E. , Funderburk Samuel C. , Krashes Michael J. , Carter Matthew E. 
Published: November 2021

AbstractFood intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTNTac1 neurons) and those that express corticotropin-releasing hormone (PSTNCRH neurons), and use a panel of genetically encoded tools in mice to show that PSTNTac1 neurons play an essential role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTNTac1, but not PSTNCRH neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTNTac1 neurons, but not PSTNCRH neurons, is sufficient to reduce food intake in hungry mice. PSTNTac1 and PSTNCRH neurons project to distinct downstream brain regions, and stimulation of PSTNTac1 projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an essential, anorexigenic role for PSTNTac1 neurons in the hormonal and central regulation of appetite.
Persistent CAD activity in memory CD8+ T cells supports rRNA synthesis and ribosomal biogenesis required at rechallenge
Authors: Claiborne Michael D. , Sengupta Srona , Zhao Liang , Arwood Matthew L. , Sun Im-Meng , Wen Jiayu , Thompson Elizabeth A. , Mitchell-Flack Marisa , Laiho Marikki , Powell Jonathan D. 
Published: November 2021

AbstractMemory CD8+ T cells are characterized by their ability to persist long after the initial antigen encounter and their ability to generate a rapid recall response. Recent studies have identified a role for metabolic reprogramming and mitochondrial function in promoting the longevity of memory T cells. However, detailed mechanisms involved in promoting the rapid recall response are incompletely understood. Here we identify a novel role for the initial and continued activation of the trifunctional rate-limiting enzyme of the de novo pyrimidine synthesis pathway CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as critical in promoting the rapid recall response of previously-activated CD8+ T cells. CAD is rapidly phosphorylated upon T cell activation in an mTORC1-dependent manner yet remains phosphorylated long after initial activation. Previously-activated CD8+ T cells display continued de novo pyrimidine synthesis in the absence of mitogenic signals and interfering with this pathway diminishes the speed and magnitude of cytokine production upon rechallenge. Inhibition of CAD does not affect cytokine transcript levels, but diminishes available pre-rRNA, the polycistronic rRNA precursor whose synthesis is the rate-limiting step in ribosomal biogenesis. CAD inhibition additionally decreases levels of detectable ribosomal proteins in previously-activated CD8+ T cells. Overexpression of CAD improves both the cytokine response and proliferation of memory T cells. Overall, our studies reveal a novel and critical role for CAD-induced pyrimidine synthesis and ribosomal biogenesis in promoting the rapid recall response characteristic of memory T cells.One Sentence SummaryPyrimidine synthesis fuels ribosomal biogenesis to facilitate rapid recall responses in CD8+ T cells
Divergent phenotypic plasticity of a convergent Mendelian trait in Drosophila
Authors: Francelle Pascaline , David Jean R. , Yassin Amir 
Published: November 2021

ABSTRACTIn Drosophila, comparisons of the thermal plasticity of pigmentation across serially homologous abdominal segments have been conducted in two species, namely Drosophila melanogaster and D. kikkawai. Pigmentation variation has different genetic architecture in the two species, being oligogenic in the former and monogenic in the later. Here, we analyze the thermal plasticity of abdominal pigmentation in a third species, D. erecta, which is phylogenetically close to D. melanogaster but like D. kikkawai has a monogenic basis for pigmentation variation. However, the underlying locus differs between D. erecta and D. kikkawai, being the X-linked melanin-synthesis gene tan in the former and the autosomal transcription factor pdm3 in the later. We found that in spite of a low overall plasticity in monogenic species compared to D. melanogaster, the two monogenic species showed divergent plasticity patterns in respect to the response to temperature and to the degree of dominance in heterozygotes. Those results provide new insights on the dependence of the degree of plasticity on the genetic architecture as well as on the extent of phenotypic convergence.
Sonic hedgehog is basolaterally sorted from the TGN and transcytosed to the apical domain involving Dispatched-1 at Rab11-ARE
Authors: Sandoval Lisette , Labarca Mariana , Retamal Claudio , Sanchez Paula , Larraín Juan , González Alfonso 
Published: November 2021

ABSTRACTHedgehog (Hh) secretion from apical and/or basolateral domains occurs in different epithelial cells impacting development and tissue homeostasis. Palmitoylation and cholestyrolation attach Hh proteins to membranes and Dispatched-1 (Disp-1) promotes their release. How these lipidated proteins are handled by the complex secretory and endocytic pathways of polarized epithelial cells remains unknown. We show that MDCK cells address newly synthesized sonic hedgehog (Shh) from the TGN to the basolateral cell surface and then to the apical domain through a transcytosis pathway that includes Rab11-apical recycling endosomes (Rab11-ARE). Both palmitoylation and cholestyrolation contribute to this sorting behavior, otherwise Shh lacking these lipid modifications is unpolarized. Disp-1 mediates first basolateral secretion from the TGN and then transcytosis from the Rab11-ARE. At steady state, Shh predominates apically and can be basolaterally transcytosed. This complex Shh trafficking provides several steps for regulation and variation in different epithelia, subordinating the apical to the basolateral secretion.
Timing of gene expression and recruitment in independent origins of CAM in the Agavoideae (Asparagaceae)
Authors: Heyduk Karolina , McAssey Edward V. , Leebens-Mack Jim 
Published: November 2021

AbstractCAM photosynthesis has evolved repeatedly across the plant tree of life, yet our understanding of the genetic convergence across independent origins remains hampered by the lack of comparative studies. CAM is furthermore thought to be closely linked to the circadian clock in order to achieve temporal separation of carboxylation and sugar production. Here, we explore gene expression profiles in eight species from the Agavoideae (Asparagaceae) encompassing three independent origins of CAM. Using comparative physiology and transcriptomics, we examined the variable modes of CAM in this subfamily and the changes in gene expression across time of day and between well-watered and drought-stressed treatments. We further assessed gene expression and molecular evolution of genes encoding phosphoenolpyruvate carboxylase (PPC), an enzyme required for primary carbon fixation in CAM. Most time-of-day expression profiles are largely conserved across all eight species and suggest that large perturbations to the central clock are not required for CAM evolution. In contrast, transcriptional response to drought is highly lineage specific. Yucca and Beschorneria have CAM-like expression of PPC2, a copy of PPC that has never been shown to be recruited for CAM in angiosperms, and evidence of positive selection in PPC genes implicates mutations that may have facilitated the recruitment for CAM function early in the evolutionary history of the Agavoideae. Together the physiological and transcriptomic comparison of closely related C3 and CAM species reveals similar gene expression profiles, with the notable exception of differential recruitment of carboxylase enzymes for CAM function.
The hexokinase “HKDC1” interaction with the mitochondria is essential for hepatocellular carcinoma progression
Authors: Khan Md. Wasim , Terry Alexander R. , Priyadarshini Medha , Guzman Grace , Cordoba-Chacon Jose , Ben-Sahra Issam , Wicksteed Barton , Layden Brian T. 
Published: November 2021

AbstractHepatocellular carcinoma (HCC) is a leading cause of death from cancer malignancies. Recently, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in HCC compared to healthy tissue. Using in vitro and in vivo tools, we examined the role of HKDC1 in HCC progression. Importantly, HKDC1 ablation stops HCC progression by promoting metabolic reprogramming by shifting glucose flux away from the TCA cycle. Next, HKDC1 ablation leads to mitochondrial dysfunction resulting in less cellular energy which cannot be compensated by enhanced glucose uptake. And finally, we show that the interaction of HKDC1 with the mitochondria is essential for its role in HCC progression, and without this mitochondrial interaction mitochondrial dysfunction occurs. In sum, HKDC1 is highly expressed in HCC cells compared to normal hepatocytes, therefore targeting HKDC1, specifically its interaction with the mitochondria, reveals a highly selective approach to target cancer cells in HCC.
Going through phages: A Computational approach to Revealing the role of prophage in Staphylococcus aureus
Authors: Sweet Tyrome , Sindi Suzanne , Sistrom Mark 
Published: November 2021

AbstractProphages have important roles in virulence, antibiotic resistance and genome evolution in Staphylococcus aureus. Rapid growth in the number of sequenced S. aureus genomes allows for an investigation of prophage sequences in S. aureus at an unprecedented scale. We developed a computational pipeline to detect and analyze prophage sequences in nearly 10,011 S. aureus genomes, discovering thousands of putative prophage sequences with genes encoding virulence factors and antibiotic resistance.ImportanceBacteriophages (phages) play key roles in bacterial evolution, governing abundance, adaptation and diversity of bacterial communities. Temperate phage can facilitate bacterial adaptation via transduction of novel genes. This study takes advantage of the unprecedented quantity of genomic sequencing in public repositories to analyze viral genes in 10,000 Staphylococcus aureus genomes. We found 196,727 prophage sequences, with an estimated total of 129,935 genes. We determined the function of these genes, identifying a large quantity of novel genes that benefit the host such as beta-lactamase, enterotoxins and cytotoxins. These results will inform studies of bacterial evolution and adaptation, by identifying the mechanism of horizontal transfer of genes that confer adaptive traits to bacteria, especially in the context of antibiotic resistance.
EBV LMP1-activated mTORC1 and mTORC2 Coordinately Promote Nasopharyngeal Cancer Stem Cell Formation
Authors: Zhu Nannan , Wang Qian , Wu Zhidong , Wang Yan , Zeng Mu-Sheng , Yuan Yan 
Published: November 2021

AbstractEpstein-Barr Virus (EBV) is associated with several malignant diseases, including Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC), certain types of lymphomas, and a portion of gastric cancers. Virus-encoded oncoprotein LMP1 induces the epithelial-to-mesenchymal transition (EMT), leading to cancer stem cell formation. In the current study, we investigated how LMP1 contributes to cancer stem cell development in NPC. We found that LMP1 plays an essential role in acquiring CSC characteristics, including tumor initiation, metastasis, and therapeutic resistance by activating the PI3K/mTOR/Akt signaling pathway. We dissected the functions of distinct signaling (mTORC1 and mTORC2) in the acquisition of different CSC characteristics. Side population (SP) formation, which represents the chemotherapy resistance feature of CSC, requires mTORC1 signaling. Tumor initiation capability is mainly attributed to mTORC2, which confers on NPC the capabilities of proliferation and survival by activating mTORC2 downstream genes c-Myc. Both mTORC1 and mTORC2 enhance cell migration and invasion of NPC cells, suggesting that mTORC1/2 co-regulate metastasis of NPC. The revelation of the roles of the mTOR signaling pathways in distinct tumorigenic features provides a guideline for designing efficient therapies by choosing specific mTOR inhibitors targeting mTORC1, mTORC2, or both to achieve durable remission of NPC in patients.SignificanceLMP1 endows NPC to gain cancer stem cell characteristics through activating mTORC1 and mTORC2 pathways. The different mTOR pathways are responsible for distinct tumorigenic features. Rapamycin-insensitive mTORC1 is essential for CSC drug resistance. NPC tumor initiation capacity is mainly attributed to mTORC2 signaling. mTORC1 and mTORC2 co-regulate NPC cell migration and invasion. The revelation of the roles of mTOR signaling in NPC CSC establishment has implications for novel therapeutic strategies to treat relapsed and metastatic NPC and achieve durable remission.
Serum methylation of GALNT9, UPF3A, WARS, and LDB2 as non-invasive biomarkers for the early detection of colorectal cancer and premalignant adenomas
Authors: Gallardo-Gómez María , Rodríguez-Girondo Mar , Planell Núria , Moran Sebastian , Bujanda Luis , Etxart Ane , Castells Antoni , Balaguer Francesc , Jover Rodrigo , Esteller Manel , Cubiella Joaquín , Gómez-Cabrero David , Chiara Loretta De 
Published: November 2021

ABSTRACTBackgroundEarly detection through screening programs has proven to be the most effective strategy to reduce the incidence and mortality of colorectal cancer. The most widely implemented non-invasive screening test is the fecal immunochemical test, which presents an inadequate sensitivity for the detection of precancerous advanced adenomas. This fact, together with the modest participation rates in screening programs, highlights the need for a blood test that could improve both the adherence to screening and the selection to colonoscopy.MethodsIn this study, we conducted a serum-based discovery and validation of circulating cell-free DNA (cfDNA) methylation biomarkers for colorectal cancer screening in a multicentre cohort of 433 serum samples including healthy controls, benign pathologies, advanced adenomas, and colorectal cancer. First, we performed an epigenome-wide methylation analysis with the MethylationEPIC array in 280 cfDNA samples using a pooling approach, followed by a robust prioritization of candidate biomarkers for the joint detection of advanced adenomas and colorectal cancer (advanced neoplasia). Then, candidate biomarkers were validated by pyrosequencing in independent individual 153 cfDNA samples.ResultsWe report GALNT9, UPF3A, WARS, and LDB2 as new non-invasive methylation biomarkers for the early detection of colorectal advanced neoplasia. A model composed of GALNT9, UPF3A, WARS, and LDB2 reported a sensitivity of 62.1% and a specificity of 97.4% for the detection of advanced neoplasia. On the other hand, the combination of GALNT9 and UPF3A by logistic regression discriminated advanced neoplasia with 78.8% sensitivity and 100% specificity, outperforming the commonly used fecal immunochemical test and the methylated SEPT9 blood test.ConclusionsSerum methylation levels of GALNT9, UPF3A, WARS, and LDB2 represent highly specific and sensitive novel blood-based biomarkers for the detection of colorectal cancer and premalignant advanced adenomas of both distal and proximal locations. The reported results show the feasibility of DNA sample pooling strategies for biomarker discovery. Overall, this study highlights the utility of cfDNA methylation for the early detection of colorectal neoplasia, with the potential to be implemented as a non-invasive test for colorectal cancer screening.
Tenofovir Disoproxil Fumarate and severity of COVID-19 in people with HIV infection
Authors: Del Amo J , Polo R , Moreno S , Martínez E , Cabello A , Iribarren JA , Curran A , Macías J , Montero M , Dueñas C , Mariño AI , Pérez de la Cámara S , Díaz A , Arribas JR , Jarrín I , Hernán MA 
Published: November 2021

AbstractBackgroundEffective, safe, and affordable antivirals are needed for COVID-19. Tenofovir has not been studied in randomized trials despite evidence consistent with its effectiveness against COVID-19.MethodsWe studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4-cell count, HIV-RNA viral load, comorbidities and the following outcomes: laboratory-confirmed SARS-CoV-2 infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/ FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting.ResultsOf 51,558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2,402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% CI) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88-6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals ≥50 years and 1.15 (0.59, 1.93) in younger individuals.ConclusionOur findings suggest that, compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.