Neurologic Abnormalities in Workers of a 1-Bromopropane Factory

We reported recently that 1-bromopropane (1-BP; n-propylbromide, CAS Registry no. 106-94-5), an alternative to ozone-depleting solvents, is neurotoxic and exhibits reproductive toxicity in rats. The four most recent case reports suggested possible neurotoxicity of 1-BP in workers. The aim of the present study was to establish the neurologic effects of 1-BP in workers and examine the relationship with exposure levels. We surveyed 27 female workers in a 1-BP production factory and compared 23 of them with 23 age-matched workers in a beer factory as controls. The workers were interviewed and examined by neurologic, electrophysiologic, hematologic, biochemical, neurobehavioral, and postural sway tests. 1-BP exposure levels were estimated with passive samplers. Tests with a tuning fork showed diminished vibration sensation of the foot in 15 workers exposed to 1-BP but in none of the controls. 1-BP factory workers showed significantly longer distal latency in the tibial nerve than did the controls but no significant changes in motor nerve conduction velocity. Workers also displayed lower values in sensory nerve conduction velocity in the sural nerve, backward recalled digits, Benton visual memory test scores, pursuit aiming test scores, and five items of the Profile of Mood States (POMS) test (tension, depression, anxiety, fatigue, and confusion) compared with controls matched for age and education. Workers hired after May 1999, who were exposed to 1-BP only (workers hired before 1999 could have also been exposed to 2-BP), showed similar changes in vibration sense, distal latency, Benton test scores, and depression and fatigue in the POMS test. Time-weighted average exposure levels in the workers were 0.34–49.19 ppm. Exposure to 1-BP could adversely affect peripheral nerves or/and the central nervous system

Spatio-Temporal Modeling for Flash Memory Channels Using Conditional Generative Nets

We propose a data-driven approach to modeling the spatio-temporal characteristics of NAND flash memory read voltages using conditional generative networks. The learned model reconstructs read voltages from an individual memory cell based on the program levels of the cell and its surrounding cells, as well as the specified program/erase (P/E) cycling time stamp. We evaluate the model over a range of time stamps using the cell read voltage distributions, the cell level error rates, and the relative frequency of errors for patterns most susceptible to inter-cell interference (ICI) effects. We conclude that the model accurately captures the spatial and temporal features of the flash memory channel

Self‐Assembly of Therapeutic Peptide into Stimuli‐Responsive Clustered Nanohybrids for Cancer‐Targeted Therapy

Clinical translation of therapeutic peptides, particularly those targeting intracellular protein–protein interactions (PPIs), has been hampered by their inefficacious cellular internalization in diseased tissue. Therapeutic peptides engineered into nanostructures with stable spatial architectures and smart disease targeting ability may provide a viable strategy to overcome the pharmaceutical obstacles of peptides. This study describes a strategy to assemble therapeutic peptides into a stable peptide–Au nanohybrid, followed by further self‐assembling into higher‐order nanoclusters with responsiveness to tumor microenvironment. As a proof of concept, an anticancer peptide termed β‐catenin/Bcl9 inhibitors is copolymerized with gold ion and assembled into a cluster of nanohybrids (pCluster). Through a battery of in vitro and in vivo tests, it is demonstrated that pClusters potently inhibit tumor growth and metastasis in several animal models through the impairment of the Wnt/β‐catenin pathway, while maintaining a highly favorable biosafety profile. In addition, it is also found that pClusters synergize with the PD1/PD‐L1 checkpoint blockade immunotherapy. This new strategy of peptide delivery will likely have a broad impact on the development of peptide‐derived therapeutic nanomedicine and reinvigorate efforts to discover peptide drugs that target intracellular PPIs in a great variety of human diseases, including cancer.A strategy for clinical translation of therapeutic peptides by assembling them into a stable peptide–Au nanohybrid, followed by further self‐assembling into higher‐order nanoclusters with responsiveness to the tumor microenvironment, is presented. An anticancer peptide termed β‐catenin/Bcl9 inhibitor is assembled into a cluster of nanohybrids termed pCluster, which potently inhibits tumor growth as well as metastasis, and synergizes with immunotherapy, while maintaining a highly favorable biosafety profile.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148246/1/adfm201807736.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148246/2/adfm201807736-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148246/3/adfm201807736_am.pd

Alpha-tocopherol enhances spermatogonial stem cell proliferation and restores mouse spermatogenesis by up-regulating BMI1

PurposeSpermatogonial stem cells (SSCs) are essential for maintaining reproductive function in males. B-lymphoma Mo-MLV insertion region 1 (BMI1) is a vital transcription repressor that regulates cell proliferation and differentiation. However, little is known about the role of BMI1 in mediating the fate of mammalian SSCs and in male reproduction. This study investigated whether BMI1 is essential for male reproduction and the role of alpha-tocopherol (α-tocopherol), a protective agent for male fertility, as a modulator of BMI1 both in vitro and in vivo.MethodsMethyl thiazolyl tetrazolium (MTT) and 5-ethynyl-2′-deoxyuridine (EDU) assays were used to assess the effect of BMI1 on the proliferative ability of the mouse SSC line C18-4. Real-time polymerase chain reaction (PCR), western blotting, and immunofluorescence were applied to investigate changes in the mRNA and protein expression levels of BMI1. Male mice were used to investigate the effect of α-tocopherol and a BMI1 inhibitor on reproduction-associated functionality in vivo.ResultsAnalysis revealed that BMI1 was expressed at high levels in testicular tissues and spermatogonia in mice. The silencing of BMI1 inhibited the proliferation of SSCs and DNA synthesis and enhanced the levels of γ-H2AX. α-tocopherol enhanced the proliferation and DNA synthesis of C18-4 cells, and increased the levels of BMI1. Notably, α-tocopherol rescued the inhibition of cell proliferation and DNA damage in C18-4 cells caused by the silencing of BMI1. Furthermore, α-tocopherol restored sperm count (Ctrl vs. PTC-209, p = 0.0034; Ctrl vs. PTC-209 + α-tocopherol, p = 0.7293) and normalized sperm malformation such as broken heads, irregular heads, lost and curled tails in vivo, as demonstrated by its antagonism with the BMI1 inhibitor PTC-209.ConclusionAnalysis demonstrated that α-tocopherol is a potent in vitro and in vivo modulator of BMI1, a transcription factor that plays an important role in in SSC proliferation and spermatogenesis. Our findings identify a new target and strategy for treating male infertility that deserves further pre-clinical investigation

Personalized anesthesia and precision medicine: a comprehensive review of genetic factors, artificial intelligence, and patient-specific factors

Precision medicine, characterized by the personalized integration of a patient’s genetic blueprint and clinical history, represents a dynamic paradigm in healthcare evolution. The emerging field of personalized anesthesia is at the intersection of genetics and anesthesiology, where anesthetic care will be tailored to an individual’s genetic make-up, comorbidities and patient-specific factors. Genomics and biomarkers can provide more accurate anesthetic protocols, while artificial intelligence can simplify anesthetic procedures and reduce anesthetic risks, and real-time monitoring tools can improve perioperative safety and efficacy. The aim of this paper is to present and summarize the applications of these related fields in anesthesiology by reviewing them, exploring the potential of advanced technologies in the implementation and development of personalized anesthesia, realizing the future integration of new technologies into clinical practice, and promoting multidisciplinary collaboration between anesthesiology and disciplines such as genomics and artificial intelligence

Modulation of cardiac resident macrophages immunometabolism upon high-fat-diet feeding in mice

BackgroundA high-fat diet (HFD) contributes to various metabolic disorders and obesity, which are major contributors to cardiovascular disease. As an essential regulator for heart homeostasis, cardiac resident macrophages may go awry and contribute to cardiac pathophysiology upon HFD. Thus, to better understand how HFD induced cardiac dysfunction, this study intends to explore the transcriptional and functional changes in cardiac resident macrophages of HFD mice.MethodsC57BL/6J female mice that were 6 weeks old were fed with HFD or normal chow diet (NCD) for 16 weeks. After an evaluation of cardiac functions by echocardiography, mouse hearts were harvested and cardiac resident CCR2- macrophages were sorted, followed by Smart sequencing. Bioinformatics analysis including GO, KEGG, and GSEA analyses were employed to elucidate transcriptional and functional changes.ResultsHyperlipidemia and obesity were observed easily upon HFD. The mouse hearts also displayed more severe fibrosis and diastolic dysfunction in HFD mice. Smart sequencing and functional analysis revealed metabolic dysfunctions, especially lipid-related genes and pathways. Besides this, antigen-presentation-related gene such as Ctsf and inflammation, particularly for NF-κB signaling and complement cascades, underwent drastic changes in cardiac resident macrophages. GO cellular compartment analysis was also performed and showed specific organelle enrichment trends of the involved genes.ConclusionDysregulated metabolism intertwines with inflammation in cardiac resident macrophages upon HFD feeding in mice, and further research on crosstalk among organelles could shed more light on potential mechanisms

Fault Extension Characteristics of the Middle Section of Shanxi Graben System and the Seismogenic Environments of the Hongdong and Linfen Earthquakes

The Shanxi Graben System exhibits high seismic activity and significant destructive potential. Previous studies in this region have primarily focused on geological methods such as seismology, geological surveys, and trench excavations, with limited research in the field of geophysics. In this study, we collected two magnetotelluric profiles crossing the central segment of the Shanxi Graben System, including the fault system and the Hongdong–Linfen seismic zone. Through qualitative analysis and inversion calculations, we constructed a three-dimensional electrical model of the study area. The seismogenic environment was studied by integrating the deformation field, recent seismic geological data, and geophysical survey results of the study area and its surroundings. The Luoyunshan Piedmont Fault and the Huoshan Piedmont Fault are likely two main faults in the central segment of the Shanxi Graben System. These faults span the entire crustal scale and serve as basement faults separating the Ordos Block and the Taihangshan Block. They exhibit patterns of activity. The western side of the Shanxi Graben System, represented by the Ordos Block, exhibits a stable tectonic environment, while the eastern side, represented by the Taihangshan Block, experiences severe lithospheric destruction and thinning. The results of the magnetotelluric (MT) survey support the 1303 Hongdong earthquake as an event that occurred on the Huoshan Piedmont Fault and provide geophysical evidence for the possible dominance of the Luoyunshan Piedmont Fault in the 1695 Linfen earthquake. Multiple factors controlled the seismogenic environments of these two earthquakes. The continuous upwelling of asthenospheric material in the lower-middle crust on the eastern side of the Linfen Basin possibly leads to the regional extension of the North China Block. This, in turn, triggers inclined sliding along the Huoshan Piedmont Fault and the Luoyunshan Piedmont Fault, which may be the main controlling factors for major earthquakes in the region