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Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.

Research and development in the field of micro/nano-robots have made significant progress in the past, especially in the field of clinical medicine, where further research may lead to many revolutionary achievements. Through the research and experiment of microrobots, a controllable drug delivery system will be realized, which will solve many problems in drug treatment. In this work, we design and study the ability of magnetic-driven hydrogel microrobots to carry Lycorine hydrochloride (LH) to inhibit colorectal cancer (CRC) cells. We have successfully designed a magnetic field driven, biocompatible drug carrying hydrogel microsphere robot with Fe3O4 particles inside, which can achieve magnetic field response, and confirmed that it can transport drug through fluorescence microscope. We have successfully demonstrated the motion mode of hydrogel microrobots driven by a rotating external magnetic field. This driving method allows the microrobots to move in a precise and controllable manner, providing tremendous potential for their use in various applications. Finally, we selected drug LH and loaded it into the hydrogel microrobot for a series of experiments. LH significantly inhibited CRC cells proliferation in a dose- and time-dependent manner. LH inhibited the proliferation, mobility of CRC cells and induced apoptosis. This delivery system can significantly improve the therapeutic effect of drugs on tumors.

Abstract Background Hypothalamic hamartoma (HH) is a congenital non-progressive lesion of hypothalamus during fetal development. Mass-like lesions in different anatomical locations often develop a variously disabling course presenting with cognitive decline, psychiatric symptoms, as well as multiple seizure types. As a rare disease, HH is relatively common in infants and children, but it is extremely rare in adults. Case presentation We reported a case of adult-onset hypothalamic hamartoma, and summarized and analyzed relevant reports and studies of HH worldwide. The patient had clinical manifestations characterized by multiple seizure forms. After stereotactic radiofrequency thermocoagulation and drug treatment, the condition was effectively controlled. The patient was followed up till October 2022, with no recurrence of seizures. Conclusions Epilepsy caused by HH can resemble that of temporal lobe seizures, as HH forms a complex epileptogenic network with other regions of the brain through anatomical and functional connections. Early treatment of HH can provide better control of the symptoms of epilepsy, and patients with longer disease courses may have more complications.

IntroductionHospital is a stressful place of employment, and a high proportion of healthcare workers, especially the ICU (Intensive Care Unit) nurses were found to be at risk of PTSD. Previous studies showed that taxing working memory through visuospatial tasks during the reconsolidation process of aversive memories can reduce the number of intrusions afterwards. However, the finds could not be replicated by some researches, indicating there may be some boundary conditions that are subtle and complex.MethodsWe performed a randomized controlled trial (ChiCTR2200055921; URL: www.chictr.org.cn). In our study, a series of ICU nurses or probationers who performed a cardiopulmonary resuscitation (CPR) were enrolled and instructed to play a visuospatial music tapping game (“Ceaseless Music Note”, CMN; Beijing Muyuan Technology Co., Ltd., Beijing, China) at the fourth day after CPR. The numbers of intrusions each day were recorded from the first to the seventh days (24 h×6 day), and the vividness and emotionality of CPR memories were rated at the 4th and 7th days. These parameters were compared between different groups (game with background sound; game with sound off; sound only; none).ResultsThe game-matching background music can have an add-on effect for single tapping game with no sound in reducing the emotionality of previous aversive memories.DiscussionWe proposed that flow experience (the subjective experience of effortless attention, reduced self-awareness, and enjoyment, and may be induced by optimal skill-demands compatibility in challenging tasks) as a key boundary condition for successful reconsolidation intervention.Clinical trial registrationwww.chictr.org.cn, identifier: ChiCTR2200055921.

ObjectiveThe objective of this study was to explore the relation between interictal epileptiform discharge (IED) source connectivity and cortical structural couplings (SCs) in temporal lobe epilepsy (TLE).MethodsHigh-resolution 3D-MRI and 32-sensor EEG data from 59 patients with TLE were collected. Principal component analysis was performed on the morphological data on MRI to obtain the cortical SCs. IEDs were labeled from EEG data and averaged. The standard low-resolution electromagnetic tomography analysis was performed to locate the source of the average IEDs. Phase-locked value was used to evaluate the IED source connectivity. Finally, correlation analysis was used to compare the IED source connectivity and the cortical SCs.ResultsThe features of the cortical morphology in left and right TLE were similar across four cortical SCs, which could be mainly described as the default mode network, limbic regions, connections bilateral medial temporal, and connections through the ipsilateral insula. The IED source connectivity at the regions of interest was negatively correlated with the corresponding cortical SCs.SignificanceThe cortical SCs were confirmed to be negatively related to IED source connectivity in patients with TLE as detected with MRI and EEG coregistered data. These findings suggest the important role of intervening IEDs in treating TLE.

Familial hypercholesterolemia (FH; OMIM: # 143890) is a common inherited autosomal dominant disease, characterized by high-level low-density lipoprotein cholesterol (LDL-C) in plasma. Elevated LDL-C levels is closely related with atherosclerotic plaques and premature cardiovascular disease if not treated in time. Here we generated an induced pluripotent stem cell (iPSC) line using urine cells (UCs) derived from an 8-year-old male FH patient who carrying two coding and pathogenic mutations of low-density lipoprotein receptor (LDLR) gene (exon12:c.C1747T and exon13: c. 1948 del G). This induced pluripotent stem cell line named SMBCi009-A can be used to understand more cellular details about FH.

Objective. To characterize the cerebral imaging and electroclinical features and investigate their etiological contributions to seizures in pseudoparathyroidism (PHP). Methods. The clinical symptoms, biochemical imaging by magnetic resonance imaging (MRI) and computed tomography (CT) tests, and electroencephalogram (EEG) manifestations of five PHP patients with seizures were retrospectively collected and analyzed. Results. Physical examination showed an average stature in cases 2~4 and short stature in cases 1 and 5. X-ray tests suggested ectopic calcification in four patients. The seizures in four cases were effectively controlled with antiseizure medicines (ASMs). Cerebral CT scans showed extensive brain calcifications in the bilateral basal ganglia (all five cases), cerebellum (cases 1, 3, and 5), thalamus (case 4), and cerebral cortex. Cerebral MRI showed short T1 signals mainly in the basal ganglia. EEG records revealed focal EEG abnormalities, including abnormal slow waves and epileptiform discharges, mainly over the temporal and frontal lobes. The brain areas with focal EEG abnormalities and calcification did not always coincide. Conclusion. The seizures in PHP can be focal to bilateral tonic–clonic. ASMs are effective in epilepsy combined with PHP. Intracranial calcification is not a reliable etiological cause of epilepsy in PHP patients.

A human induced pluripotent stem cell (iPSC) line was generated from the urine cells of a 8-year-old female with Gaucher disease with the homozygous changes c.1448 T>C in the GBA gene. Reprogramming factors OCT4, SOX2, KLF4, and miR-302–367 were delivered using a non-integrative plasmid. Our iPSCs showed complete pluripotency, normal genetic stability, and the ability to differentiate into three germ layers.

Mutations in the neurofibromin (NF1) gene cause neurofibromatosis type 1 (NF1), a complex tumour predisposition syndrome. Here, we generated two induced pluripotent stem cell (iPSC) lines using urine cells (UCs) derived from a 21-year-old female NF1 patient carrying c.496_497delGT mutation in the NF1 gene (p.Val166LeufsTer7). The newly derived SMBCi003-A and SMBCi003-B iPSC lines used as a cellular model to unravel pathogenesis of NF1.

The cytidine deaminase APOBEC3B (A3B) is an endogenous inducer of somatic mutations and causes chromosomal instability by converting cytosine to uracil in single-stranded DNA. Therefore, identification of factors and mechanisms that mediate A3B expression will be helpful for developing therapeutic approaches to decrease DNA mutagenesis. Arsenic (As) is one well-known mutagen and carcinogen, but the mechanisms by which it induces mutations have not been fully elucidated. Herein, we show that A3B is upregulated and required for As-induced DNA damage and mutagenesis. We found that As treatment causes a decrease of N6-methyladenosine (m6A) modification near the stop codon of A3B, consequently increasing the stability of A3B mRNA. We further reveal that the demethylase FTO is responsible for As-reduced m6A modification of A3B, leading to increased A3B expression and DNA mutation rates in a manner dependent on the m6A reader YTHDF2. Our in vivo data also confirm that A3B is a downstream target of FTO in As-exposed lung tissues. In addition, FTO protein is highly expressed and positively correlates with the protein levels of A3B in tumor samples from human non-small cell lung cancer patients. These findings indicate a previously unrecognized role of A3B in As-triggered somatic mutation and might open new avenues to reduce DNA mutagenesis by targeting the FTO/m6A axis. [ABSTRACT FROM AUTHOR]