242,270 research outputs found

    Data_Sheet_1_Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis.pdf

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    BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive impairment of spinal motor neurons. Continuous research endeavor is underway to fully understand the molecular mechanisms associating with this disorder. Although several studies have implied the involvement of inositol pyrophosphate IP7 in ALS, there is no direct experimental evidence proving this notion. In this study, we analyzed inositol pyrophosphate IP7 and its precursor IP6 in the mouse and human ALS biological samples to directly assess whether IP7 level and/or its metabolism are altered in ALS disease state.MethodsWe used a liquid chromatography-mass spectrometry (LC-MS) protocol originally-designed for mammalian IP6 and IP7 analysis. We measured the abundance of these molecules in the central nervous system (CNS) of ALS mouse model SOD1(G93A) transgenic (TG) mice as well as postmortem spinal cord of ALS patients. Cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) from ALS patients were also analyzed to assess if IP7 status in these biofluids is associated with ALS disease state.ResultsSOD1(G93A) TG mice showed significant increase of IP7 level in the spinal cord compared with control mice at the late stage of disease progression, while its level in cerebrum and cerebellum remains constant. We also observed significantly elevated IP7 level and its product-to-precursor ratio (IP7/IP6) in the postmortem spinal cord of ALS patients, suggesting enhanced enzymatic activity of IP7-synthesizing kinases in the human ALS spinal cord. In contrast, human CSF did not contain detectable level of IP6 and IP7, and neither the IP7 level nor the IP7/IP6 ratio in human PBMCs differentiated ALS patients from age-matched healthy individuals.ConclusionBy directly analyzing IP7 in the CNS of ALS mice and humans, the findings of this study provide direct evidence that IP7 level and/or the enzymatic activity of IP7-generating kinases IP6Ks are elevated in ALS spinal cord. On the other hand, this study also showed that IP7 is not suitable for biofluid-based ALS diagnosis. Further investigation is required to elucidate a role of IP7 in ALS pathology and utilize IP7 metabolism on the diagnostic application of ALS.</p

    Identified charged-hadron production in pp++Al, 3^3He++Au, and Cu++Au collisions at sNN=200\sqrt{s_{_{NN}}}=200 GeV and in U++U collisions at sNN=193\sqrt{s_{_{NN}}}=193 GeV

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    International audienceThe PHENIX experiment has performed a systematic study of identified charged-hadron (π±\pi^\pm, K±K^\pm, pp, pˉ\bar{p}) production at midrapidity in pp++Al, 3^3He++Au, Cu++Au collisions at sNN=200\sqrt{s_{_{NN}}}=200 GeV and U++U collisions at sNN=193\sqrt{s_{_{NN}}}=193 GeV. Identified charged-hadron invariant transverse-momentum (pTp_T) and transverse-mass (mTm_T) spectra are presented and interpreted in terms of radially expanding thermalized systems. The particle ratios of K/πK/\pi and p/πp/\pi have been measured in different centrality ranges of large (Cu++Au, U++U) and small (pp++Al, 3^3He++Au) collision systems. The values of K/πK/\pi ratios measured in all considered collision systems were found to be consistent with those measured in pp++pp collisions. However the values of p/πp/\pi ratios measured in large collision systems reach the values of 0.6\approx0.6, which is 2\approx2 times larger than in pp++pp collisions. These results can be qualitatively understood in terms of the baryon enhancement expected from hadronization by recombination. Identified charged-hadron nuclear-modification factors (RABR_{AB}) are also presented. Enhancement of proton RABR_{AB} values over meson RABR_{AB} values was observed in central 3^3He++Au, Cu++Au, and U++U collisions. The proton RABR_{AB} values measured in pp++Al collision system were found to be consistent with RABR_{AB} values of ϕ\phi, π±\pi^\pm, K±K^\pm, and π0\pi^0 mesons, which may indicate that the size of the system produced in pp++Al collisions is too small for recombination to cause a noticeable increase in proton production

    Antimicrobial Peptide Recognition Motif of the Substrate Binding Protein SapA from Nontypeable <i>Haemophilus influenzae</i>

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    Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen associated with respiratory diseases, including otitis media and exacerbations of chronic obstructive pulmonary disease. NTHi exhibits resistance to killing by host antimicrobial peptides (AMPs) mediated by SapA, the substrate binding protein of the sensitivity to antimicrobial peptides (Sap) transporter. However, the specific mechanisms by which SapA selectively binds various AMPs such as defensins and cathelicidin are unknown. In this study, we report mutational analyses of both defensin AMPs and the SapA binding pocket to define the specificity of AMP recognition. Bactericidal assays revealed that NTHi lacking SapA are more susceptible to human beta defensins and LL-37, while remaining highly resistant to a human alpha defensin. In contrast to homologues, our research underscores the distinct specificity of NTHi SapA, which selectively recognizes and binds to peptides containing the charged-hydrophobic motif PKE and RRY. These findings provide valuable insight into the divergence of SapA among bacterial species and NTHi SapA’s ability to selectively interact with specific AMPs to mediate resistance

    Table S1 from Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti–PD-1 Monotherapy: A Report from the International RRD Consortium

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    Baseline characteristics of patients with RRD high-grade gliomas treated with immune-checkpoint inhibition (ICI) (n=75)</p

    Prenatal features of congenital peribronchial myofibroblastic tumor

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    Here, we report a case of a congenital peribronchial myofibroblastic tumor (CPMT). A 34-year-old primigravida was referred to our hospital at 31 gestation weeks because of suspected congenital pulmonary airway malformation (CPAM). Fetal ultrasonography showed a mass measuring 4.6 × 4.0 × 3.9 cm with mixed high and low echogenicity in the left lung, which was associated with microvascular blood flow in the tumor. Fetal magnetic resonance imaging (MRI) revealed a low-intensity left lobe lung lesion on a T2-weighted image. These findings suggested that the mass was a CPAM with atypical hypointense findings on MRI T2-weighted images or a rare primary pulmonary tumor, such as a CPMT. Unfortunately, the fetus died in utero at 34 gestation weeks due to cardiovascular failure, which could have resulted from direct encasement of the great vessels or cardiac compression due to rapid tumor growth. The autopsy findings confirmed the diagnosis of CPMT. Primary pulmonary tumors, such as CPMT, are extremely rare lung diseases that develop in utero. These tumors often rapidly grow during pregnancy, resulting in intrauterine fetal death. However, if the patient survives surgical mass resection, the prognosis is good. Given the adverse outcomes observed in our case, careful fetal monitoring is required in case of suspected CPMT during the third trimester of pregnancy. Moreover, in case the well-being of the fetus cannot be assured, immediate delivery should be considered, even in the preterm period, followed by surgery