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1دورية أكاديمية
المؤلفون: Xiaoting Jin (658188), Jingxu Zhang (4673482), Yanting Li (736120), Ze Zhang (47230), Tenglong Cui (11482446), Yuanyuan Wang (20181), Linlin Yao (8157678), Xiaoxi Yang (486981), Guangbo Qu (389834), Yuxin Zheng (621613), Guibin Jiang (343016)
مصطلحات موضوعية: Biochemistry, Microbiology, Genetics, Molecular Biology, Pharmacology, Ecology, Immunology, Mental Health, Infectious Diseases, Plant Biology, Virology, Computational Biology, Chemical Sciences not elsewhere classified, sufficient epidemiological data, similar regulatory mechanisms, multilayer biological responses, exogenous chemical exposure, emerging nongenetic factor, abovementioned finding suggested, pulmonary epithelial cells, chemical mixtures may, virus receptor abundance, numerous chemicals simultaneously, virus infection, may elevate, dominant receptor, structural characteristics, real scenario, protein expression, pathogen receptors
الوصف: Virus receptors are highly involved in mediating the entrance of infectious viruses into host cells. Here, we found that typical chemical exposure caused the upregulation of virus receptor mRNA levels. Chemicals with the same structural characteristics can affect the transcription of angiotensin-converting enzyme 2 ( ACE2 ), a dominant receptor of SARS-CoV-2. Some chemicals can also regulate the transcription of ACE2 by similar regulatory mechanisms, such as multilayer biological responses and the crucial role of TATA-box binding protein associated factor 6. The abovementioned finding suggested that chemical mixtures may have a joint effect on the ACE2 mRNA level in the real scenario, where humans are exposed to numerous chemicals simultaneously in daily life. Chemically regulated virus receptor transcription was in a tissue-dependent manner, with the highest sensitivity in pulmonary epithelial cells. Therefore, in addition to genetic factors, exogenous chemical exposure can be an emerging nongenetic factor that stimulates the transcription of virus receptor abundance and may elevate the protein expression. These alterations could ultimately give rise to the susceptibility to virus infection and disease severity. This finding highlights new requirements for sufficient epidemiological data about exposomes on pathogen receptors in the host.
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2دورية أكاديمية
المؤلفون: Hatim Thaker (7928519), Jie Zhang (64655), Shin-Ichiro Miyashita (6184568), Vivian Cristofaro (586878), SunHyun Park (11576924), Ali Hashemi Gheinani (11619876), Maryrose P. Sullivan (11576930), Rosalyn M. Adam (11576933), Min Dong (123378)
مصطلحات موضوعية: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Neuroscience, Physiology, Pharmacology, Biotechnology, Evolutionary Biology, Immunology, Cancer, Infectious Diseases, Chemical Sciences not elsewhere classified, wild type mice, target neurons determines, skeletal neuromuscular junctions, potent toxins known, dominant toxin receptor, bonts &# 8217, analyzing bont action, dominant receptor, injecting toxins, wide range, two sets, therapeutic efficacy, overactive bladder, leg muscle, findings establish
الوصف: (DOCX)
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3
المؤلفون: Xiaoting Jin (658188), Jingxu Zhang (4673482), Yanting Li (736120), Ze Zhang (47230), Tenglong Cui (11482446), Yuanyuan Wang (20181), Linlin Yao (8157678), Xiaoxi Yang (486981), Guangbo Qu (389834), Yuxin Zheng (621613), Guibin Jiang (343016)
مصطلحات موضوعية: Biochemistry, Microbiology, Genetics, Molecular Biology, Pharmacology, Ecology, Immunology, Mental Health, Infectious Diseases, Plant Biology, Virology, Computational Biology, Chemical Sciences not elsewhere classified, sufficient epidemiological data, similar regulatory mechanisms, multilayer biological responses, exogenous chemical exposure, emerging nongenetic factor, abovementioned finding suggested, pulmonary epithelial cells, chemical mixtures may, virus receptor abundance, numerous chemicals simultaneously, virus infection, may elevate, dominant receptor, structural characteristics, real scenario, protein expression, pathogen receptors
الوصف: Virus receptors are highly involved in mediating the entrance of infectious viruses into host cells. Here, we found that typical chemical exposure caused the upregulation of virus receptor mRNA levels. Chemicals with the same structural characteristics can affect the transcription of angiotensin-converting enzyme 2 ( ACE2 ), a dominant receptor of SARS-CoV-2. Some chemicals can also regulate the transcription of ACE2 by similar regulatory mechanisms, such as multilayer biological responses and the crucial role of TATA-box binding protein associated factor 6. The abovementioned finding suggested that chemical mixtures may have a joint effect on the ACE2 mRNA level in the real scenario, where humans are exposed to numerous chemicals simultaneously in daily life. Chemically regulated virus receptor transcription was in a tissue-dependent manner, with the highest sensitivity in pulmonary epithelial cells. Therefore, in addition to genetic factors, exogenous chemical exposure can be an emerging nongenetic factor that stimulates the transcription of virus receptor abundance and may elevate the protein expression. These alterations could ultimately give rise to the susceptibility to virus infection and disease severity. This finding highlights new requirements for sufficient epidemiological data about exposomes on pathogen receptors in the host.
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4صورة
المؤلفون: Hatim Thaker (7928519), Jie Zhang (64655), Shin-Ichiro Miyashita (6184568), Vivian Cristofaro (586878), SunHyun Park (11576924), Ali Hashemi Gheinani (11619876), Maryrose P. Sullivan (11576930), Rosalyn M. Adam (11576933), Min Dong (123378)
مصطلحات موضوعية: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Neuroscience, Physiology, Pharmacology, Biotechnology, Evolutionary Biology, Immunology, Cancer, Infectious Diseases, Chemical Sciences not elsewhere classified, wild type mice, target neurons determines, skeletal neuromuscular junctions, potent toxins known, dominant toxin receptor, bonts &# 8217, analyzing bont action, dominant receptor, injecting toxins, wide range, two sets, therapeutic efficacy, overactive bladder, leg muscle, findings establish
الوصف: The body weights of Syt1 M3 KI (TG/TG), Syt2 M3 KI, WT, and heterozygous (WT/TG) male and female mice were recorded and plotted over time. n = 3–10 mice. (TIF)
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5صورة
المؤلفون: Hatim Thaker (7928519), Jie Zhang (64655), Shin-Ichiro Miyashita (6184568), Vivian Cristofaro (586878), SunHyun Park (11576924), Ali Hashemi Gheinani (11619876), Maryrose P. Sullivan (11576930), Rosalyn M. Adam (11576933), Min Dong (123378)
مصطلحات موضوعية: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Neuroscience, Physiology, Pharmacology, Biotechnology, Evolutionary Biology, Immunology, Cancer, Infectious Diseases, Chemical Sciences not elsewhere classified, wild type mice, target neurons determines, skeletal neuromuscular junctions, potent toxins known, dominant toxin receptor, bonts &# 8217, analyzing bont action, dominant receptor, injecting toxins, wide range, two sets, therapeutic efficacy, overactive bladder, leg muscle, findings establish
الوصف: A. The indicated doses of BoNT/B were used in DAS assays and the scores over time were plotted. B. The indicated doses of BoNT/G were used in DAS assays and the scores over time were plotted. (TIF)
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6صورة
المؤلفون: Hatim Thaker (7928519), Jie Zhang (64655), Shin-Ichiro Miyashita (6184568), Vivian Cristofaro (586878), SunHyun Park (11576924), Ali Hashemi Gheinani (11619876), Maryrose P. Sullivan (11576930), Rosalyn M. Adam (11576933), Min Dong (123378)
مصطلحات موضوعية: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Neuroscience, Physiology, Pharmacology, Biotechnology, Evolutionary Biology, Immunology, Cancer, Infectious Diseases, Chemical Sciences not elsewhere classified, wild type mice, target neurons determines, skeletal neuromuscular junctions, potent toxins known, dominant toxin receptor, bonts &# 8217, analyzing bont action, dominant receptor, injecting toxins, wide range, two sets, therapeutic efficacy, overactive bladder, leg muscle, findings establish
الوصف: A. Immunohistochemistry analysis of human bladder sections, obtained from a commercial source with no underlying urologic pathology, showed Syt1 expression along nerve fibers (n.f.) within the detrusor (d.) layers, co-localized with synapsin. Syt2 expression is not detected. B. RNA sequencing of human post-mortem urinary bladder tissues showed higher levels of Syt1 transcripts than Syt2. pTPM: transcripts per kilobase million. Data obtained from Genotype-Tissue Expression (GTEx) project, accessed from www.proteinatlas.org . ****P<0.0001. C. The normalized and log 10 transformed transcriptional read counts for synaptic vesicle proteins (Syt1, Syt2, SYN1, and SV2A) and bladder markers (NRP2 and UPK2) in mouse bladders are represented as a heatmap. The data were extracted from GEO (Genome Expression Omnibus) series GSE144295 and GSE149569. The normalization was performed in R (R Core Team, 2021) based on the total read count per sample. The heatmap was generated with heatmap2 function in the Morpheus R package (Broad Institute). Relative expression level was used for the color coding. (TIF)
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7صورة
المؤلفون: Hatim Thaker (7928519), Jie Zhang (64655), Shin-Ichiro Miyashita (6184568), Vivian Cristofaro (586878), SunHyun Park (11576924), Ali Hashemi Gheinani (11619876), Maryrose P. Sullivan (11576930), Rosalyn M. Adam (11576933), Min Dong (123378)
مصطلحات موضوعية: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Neuroscience, Physiology, Pharmacology, Biotechnology, Evolutionary Biology, Immunology, Cancer, Infectious Diseases, Chemical Sciences not elsewhere classified, wild type mice, target neurons determines, skeletal neuromuscular junctions, potent toxins known, dominant toxin receptor, bonts &# 8217, analyzing bont action, dominant receptor, injecting toxins, wide range, two sets, therapeutic efficacy, overactive bladder, leg muscle, findings establish
الوصف: A. Contractile responses to electrical field stimulation of WT and KI mice, in the setting of high dose (1 nM) of BoNT/B. WT and Syt2 M3 bladder strips have decreased contractile capability, while Syt1 M3 bladders are largely resistant to the effect of BoNT/B. Only under long duration (300 mins) of 1 nM BoNT/B do Syt1 M3 bladders begin to become slightly paralyzed. B. Carbachol treatment validates that bladder muscle viability and contractility remain unchanged after incubation with high dose BoNT/B. C. Survival curve for direct bladder wall injection of BoNT/B revealed the highest tolerable dose injected into the bladder is 3.25 pg. Systemic toxicity and death resulted from 4.25 pg bladder injection. WT 1 nM BoNT/B (n = 2); Syt1 M3 1 nM BoNT/B (n = 5); Syt2 M3 1 nM BoNT/B (n = 5). (TIF)
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8صورة
المؤلفون: Hatim Thaker (7928519), Jie Zhang (64655), Shin-Ichiro Miyashita (6184568), Vivian Cristofaro (586878), SunHyun Park (11576924), Ali Hashemi Gheinani (11619876), Maryrose P. Sullivan (11576930), Rosalyn M. Adam (11576933), Min Dong (123378)
مصطلحات موضوعية: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Neuroscience, Physiology, Pharmacology, Biotechnology, Evolutionary Biology, Immunology, Cancer, Infectious Diseases, Chemical Sciences not elsewhere classified, wild type mice, target neurons determines, skeletal neuromuscular junctions, potent toxins known, dominant toxin receptor, bonts &# 8217, analyzing bont action, dominant receptor, injecting toxins, wide range, two sets, therapeutic efficacy, overactive bladder, leg muscle, findings establish
الوصف: A. Immunohistochemistry analysis detected expression of Syt2, but not Syt1, in motor nerve terminals at WT mouse diaphragm neuromuscular junctions (NMJs). SMI-312 antibody detects neurofilament and marks the phrenic nerve. α-Bungarotoxin (a-btx) labels post-synaptic acetylcholine receptors and serves as a marker for NMJs. Scale bar, 20 μm. B. Immunohistochemistry analysis of bladder sections from WT mice detected expression of Syt1, but not Syt2 in neurons. β-3 tubulin marks nerve fibers and synapsin marks the pre-synaptic site of neuronal varicosities in bladder tissues. Scale bar, 20 μm. C. Diaphragms isolated from WT, Syt1 M3 KI, or Syt2 M3 KI mice were incubated with BoNT/B (100 nM, 90 min) in high K + buffer. Tissues were washed, and immunohistochemistry analysis was performed on whole mount tissues. BoNT/B binding and entry was detected on both WT and Syt1 M3 , but not Syt2 M3 diaphragms. D. Bladder tissues isolated from WT, Syt1 M3 , or Syt2 M3 mice were incubated with BoNT/B (100 nM, 90 min) in high K + buffer. Tissues were washed, and immunohistochemistry analysis was performed. BoNT/B binding and entry was detected on both WT and Syt2 M3 , but not Syt1 M3 bladders. Representative images were selected from n = 3–4 biological replicates.
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9صورة
المؤلفون: Hatim Thaker (7928519), Jie Zhang (64655), Shin-Ichiro Miyashita (6184568), Vivian Cristofaro (586878), SunHyun Park (11576924), Ali Hashemi Gheinani (11619876), Maryrose P. Sullivan (11576930), Rosalyn M. Adam (11576933), Min Dong (123378)
مصطلحات موضوعية: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Neuroscience, Physiology, Pharmacology, Biotechnology, Evolutionary Biology, Immunology, Cancer, Infectious Diseases, Chemical Sciences not elsewhere classified, wild type mice, target neurons determines, skeletal neuromuscular junctions, potent toxins known, dominant toxin receptor, bonts &# 8217, analyzing bont action, dominant receptor, injecting toxins, wide range, two sets, therapeutic efficacy, overactive bladder, leg muscle, findings establish
الوصف: A. Sequence alignment of the BoNT-binding region in Syt1 and Syt2 (residues 32 to 52 in Syt1 and 40 to 60 in Syt2). Residues highlighted in red mark the designed triple mutations (Syt1 M3 and Syt2 M3 ) that abolish BoNT-binding. B. Co-crystal structure of the BoNT/B-Syt2 complex (PDB:4KBB) with the triple mutation sites (F54A, F55A, E57K) highlighted. C-E. Miniature inhibitory postsynaptic currents (mIPSC) were monitored and analyzed by whole-cell patch-clamp recording in cultured rat cortical neurons, with representative traces shown in C, frequency (freq) in D, and amplitude (amp) in E. WT: wild type neurons; Syt1 KD: neurons with their endogenous Syt1 knocked down by shRNA expressed via lentiviral transduction; Syt1 WT : WT Syt1 is expressed in Syt1 KD neurons via lentiviral transduction; Syt1 M3 : Syt1 M3 mutant was expressed in Syt1 KD neurons via lentiviral transduction. Syt1 KD increased mIPSC frequency, which is restored by expression of either Syt1 WT or Syt1 M3 . For each condition, we recorded from 12–15 neurons from a total of four coverslips. Data shown are means ± SEM. Statistical analysis was performed with Student’s t-test (***P < 0.001). F-H. Spontaneous inhibitory postsynaptic currents (sIPSC) were monitored and analyzed by whole-cell patch-clamp recording in cultured rat cortical neurons, with representative traces shown in F, frequency in G, and amplitude in H. The amplitude and frequency of sIPSC were greatly deceased in Syt1 KD, and both Syt1 WT and Syt1 M3 restored normal levels of sIPSC. Data shown are means ± SEM. Statistical analysis was performed with Student’s t-test (***P < 0.001). I-K. Evoked inhibitory postsynaptic currents (IPSC) were monitored and analyzed by whole-cell patch-clamp recording in cultured rat cortical neurons, with representative traces shown in I, amplitude in J, and total charge transfer in K. The amplitude and charge of IPSC were greatly deceased in Syt1 KD, and both Syt1 WT and Syt1 M3 restored normal levels of IPSC. L. Schematic drawing of generating ...
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10صورة
المؤلفون: Hatim Thaker (7928519), Jie Zhang (64655), Shin-Ichiro Miyashita (6184568), Vivian Cristofaro (586878), SunHyun Park (11576924), Ali Hashemi Gheinani (11619876), Maryrose P. Sullivan (11576930), Rosalyn M. Adam (11576933), Min Dong (123378)
مصطلحات موضوعية: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Neuroscience, Physiology, Pharmacology, Biotechnology, Evolutionary Biology, Immunology, Cancer, Infectious Diseases, Chemical Sciences not elsewhere classified, wild type mice, target neurons determines, skeletal neuromuscular junctions, potent toxins known, dominant toxin receptor, bonts &# 8217, analyzing bont action, dominant receptor, injecting toxins, wide range, two sets, therapeutic efficacy, overactive bladder, leg muscle, findings establish
الوصف: A. Schematic diagram of ex vivo bladder strip contraction assay. Bladder strips were immersed in aerated Krebs solution. Exogenous pharmacologic agents (i.e., carbachol, BoNT/B) were added directly to the solution. Trains of voltage delivered over a range of frequencies were generated by the electrical field stimulator to trigger bladder contraction, which is detected and measured by the force transducer. B. Bladder weights across WT and KI mice were similar prior to ex vivo contraction assay. ns = not significant (ANOVA). C-D. The nerve-evoked contraction forces of WT (n = 3), Syt1 M3 (n = 5), and Syt2 M3 (n = 4) bladder strips were recorded, with the representative force trace shown in C. A set of frequency-dependent stimulations (enclosed by brackets above tracing) were delivered every 100 min. After a baseline frequency-response, evoked responses at constant frequency (16 Hz) were produced every 15 min. BoNT/B (0.3 nM) was administered at red arrow. The time dependent effects of BoNT/B on nerve evoked responses are shown in frequency-response curves that were plotted in 100 min intervals, shown in D. Incubation with BoNT/B reduced contractions of WT and Syt2 M3 bladders, but did not affect Syt1 M3 bladders. *p<0.05, repeated measures ANOVA. E. Carbachol induces direct muscle contraction independent of neurotransmission. Carbachol does-response curves were generated at the beginning and end of the experiment as a control showing that bladder strips maintained their viability and contractility after incubation with BoNT/B for 300 min. p>0.05, RM ANOVA.
