Item-specific neural representations during human sleep support long-term memory.

Understanding how individual memories are reactivated during sleep is essential in theorizing memory consolidation. Here, we employed the targeted memory reactivation (TMR) paradigm to unobtrusively replaying auditory memory cues during human participants' slow-wave sleep (SWS). Using representational similarity analysis (RSA) on cue-elicited electroencephalogram (EEG), we found temporally segregated and functionally distinct item-specific neural representations: the early post-cue EEG activity (within 0 to 2,000 ms) contained comparable item-specific representations for memory cues and control cues, signifying effective processing of auditory cues. Critically, the later EEG activity (2,500 to 2,960 ms) showed greater item-specific representations for post-sleep remembered items than for forgotten and control cues, indicating memory reprocessing. Moreover, these later item-specific neural representations were supported by concurrently increased spindles, particularly for items that had not been tested prior to sleep. These findings elucidated how external memory cues triggered item-specific neural representations during SWS and how such representations were linked to successful long-term memory. These results will benefit future research aiming to perturb specific memory episodes during sleep.

Observing the suppression of individual aversive memories from conscious awareness.

When reminded of an unpleasant experience, people often try to exclude the unwanted memory from awareness, a process known as retrieval suppression. Here we used multivariate decoding (MVPA) and representational similarity analyses on EEG data to track how suppression unfolds in time and to reveal its impact on item-specific cortical patterns. We presented reminders to aversive scenes and asked people to either suppress or to retrieve the scene. During suppression, mid-frontal theta power within the first 500 ms distinguished suppression from passive viewing of the reminder, indicating that suppression rapidly recruited control. During retrieval, we could discern EEG cortical patterns relating to individual memories-initially, based on theta-driven visual perception of the reminders (0 to 500 ms) and later, based on alpha-driven reinstatement of the aversive scene (500 to 3000 ms). Critically, suppressing retrieval weakened (during 360 to 600 ms) and eventually abolished item-specific cortical patterns, a robust effect that persisted until the reminder disappeared (780 to 3000 ms). Representational similarity analyses provided converging evidence that retrieval suppression weakened the representation of target scenes during the 500 to 3000 ms reinstatement window. Together, rapid top-down control during retrieval suppression abolished cortical patterns of individual memories, and precipitated later forgetting. These findings reveal a precise chronometry on the voluntary suppression of individual memories.

Co-transcriptional R-loops-mediated epigenetic regulation drives growth retardation and docetaxel chemosensitivity enhancement in advanced prostate cancer.

R-loops are prevalent three-stranded nucleic acid structures, comprising a DNA-RNA hybrid and a displaced single-stranded DNA, that frequently form during transcription and may be attributed to genomic stability and gene expression regulation. It was recently discovered that RNA modification contributes to maintain the stability of R-loops such as N6-methyladenosine (m6A). Yet, m6A-modified R-loops in regulating gene transcription remains poorly understood. Here, we demonstrated that insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) recognize R-loops in an m6A-dependent way. Consequently, IGF2BPs overexpression leads to increased overall R-loop levels, cell migration inhibition, and cell growth retardation in prostate cancer (PCa) via precluding the binding of DNA methyltransferase 1(DNMT1) to semaphorin 3 F (SEMA3F) promoters. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A-containing R-loops and are required for tumor suppressor functions. Overexpression of SEMA3F markedly enhanced docetaxel chemosensitivity in prostate cancer via regulating Hippo pathway. Our findings point to a distinct R-loop resolution pathway mediated by IGF2BPs, emphasizing the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology.The manuscript summarizes the new role of N6-methyladenosine in epigenetic regulation, we introduce the distinct R-loop resolution mediated by IGF2BP proteins in an m6A-dependent way, which probably lead to the growth retardation and docetaxel chemotherapy resistance in prostate cancer. Moreover, our findings first emphasized the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology. In addition, our research provides a novel RBM15/IGF2BPs/DNMT1 trans-omics regulation m6A axis, indicating the new crosstalk between RNA m6A methylation and DNA methylation in prostate cancer.

Chemotherapeutic drug elemene induces pain and anxiety-like behaviors by activating GABAergic neurons in the lateral septum of mice.

Most chemotherapeutic drugs are potent and have a very narrow range of dose safety and efficacy, most of which can cause many side effects. Chemotherapy-induced peripheral neuropathy (CIPN) is the most common and serious side effect of chemotherapy for cancer treatment. However, its mechanism of action is yet to be fully elucidated. In the present study, we found that the treatment of the chemotherapy drug elemene induced hyperalgesia accompanied by anxiety-like emotions in mice based on several pain behavioral assays, such as mechanical allodynia and thermal hyperalgesia tests. Second, immunostaining for c-fos (a marker of activated neurons) further showed that elemene treatment activated several brain regions, including the lateral septum (LS), cingulate cortex (ACC), paraventricular nucleus of the thalamus (PVT), and dorsomedial hypothalamic nucleus (DMH), most notably in the GABAergic neurons of the lateral septum (LS). Finally, we found that both chemogenetic inhibition and apoptosis of LS neurons significantly reduced pain- and anxiety-like behaviors in mice treated with elemene. Taken together, these findings suggest that LS is involved in the regulation of elemene-induced chemotherapy pain and anxiety-like behaviors, providing a new target for the treatment of chemotherapy pain induced by elemene.

Guanine nucleotide exchange factor RABGEF1 facilitates TNF-induced necroptosis by targeting cIAP1.

Necroptosis is a form of regulated cell death that depends on the receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL). The molecular mechanisms underlying distinct instances of necroptosis have only recently begun to emerge. In the present study, we characterized RABGEF1 as a positive regulator of RIPK1/RIPK3 activation in vitro. Based on the overexpression and knockdown experiments, we determined that RABGEF1 accelerated the phosphorylation of RIPK1 and promoted necrosome formation in L929 cells. The pro-necrotic effect of RABGEF1 is associated with its E3 ubiquitin ligase activity and guanine nucleotide exchange factor (GEF) activity. We further confirmed that RABGEF1 interacts with cIAP1 protein by inhibiting its function and plays a regulatory role in necroptosis, which can be abolished by treatment with the antagonist Smac mimetic (SM)-164. In conclusion, our study highlights a potential and novel role of RABGEF1 in promoting TNF-induced cell necrosis.

Interaction between mental disorders and social disconnectedness on mortality: a population-based cohort study.

BACKGROUND: Despite the recognised importance of mental disorders and social disconnectedness for mortality, few studies have examined their co-occurrence. AIMS: To examine the interaction between mental disorders and three distinct aspects of social disconnectedness on mortality, while taking into account sex, age and characteristics of the mental disorder. METHOD: This cohort study included participants from the Danish National Health Survey in 2013 and 2017 who were followed until 2021. Survey data on social disconnectedness (loneliness, social isolation and low social support) were linked with register data on hospital-diagnosed mental disorders and mortality. Poisson regression was applied to estimate independent and joint associations with mortality, interaction contrasts and attributable proportions. RESULTS: A total of 162 497 individuals were followed for 886 614 person-years, and 9047 individuals (5.6%) died during follow-up. Among men, interaction between mental disorders and loneliness, social isolation and low social support, respectively, accounted for 47% (95% CI: 21-74%), 24% (95% CI: -15 to 63%) and 61% (95% CI: 35-86%) of the excess mortality after adjustment for demographics, country of birth, somatic morbidity, educational level, income and wealth. In contrast, among women, no excess mortality could be attributed to interaction. No clear trends were identified according to age or characteristics of the mental disorder. CONCLUSIONS: Mortality among men, but not women, with a co-occurring mental disorder and social disconnectedness was substantially elevated compared with what was expected. Awareness of elevated mortality rates among socially disconnected men with mental disorders could be of importance to qualify and guide prevention efforts in psychiatric services.

Study on the correlation between serum indole-3-propionic acid levels and the progression and prognosis of acute ischemic stroke.

OBJECTIVE: This study aimed to explore the correlation between the serum level of indole-3-propionic acid (IPA) and the progression and prognosis of acute cerebral infarction (ACI). METHODS: This study enrolled 197 patients with ACI, and 53 participants from a community-based stroke screening program during the same period were included as the control group. The patients with ACI were divided into quartiles of serum IPA. A logistic regression model was used for comparison. Receiver operating characteristic (ROC) curves were drawn to evaluate the predictive value of the IPA. RESULTS: Compared with the healthy control group, the ACI group had lower serum IPA (P < 0.05). The serum IPA was an independent factor for acute ischemic stroke (OR=0.992, 95% CI: 0.984-0.999, P=0.035). The serum IPA was lower in patients with progressive stroke or poor prognosis than in patients with stable stroke or good prognosis (P < 0.05). Patients with ACI with low serum IPA are prone to progression and poor prognosis. The best cutoff value for predicting progression was 193.62 pg/mL (sensitivity, 67.5%; specificity 83.7%), and that for poor prognosis was 193.77 pg/mL (sensitivity, 71.1%; specificity, 72.5%). CONCLUSION: The serum level of IPA was an independent predictor of ACI and had certain clinical value for predicting stroke progression and prognosis in patients with ACI.

Motion screening of fiducial marker for improved localization precision and resolution in SMLM.

Single-molecule localization microscopy (SMLM) provides unmatched high resolution but relies on accurate drift correction due to the long acquisition time for each field of view. A popular drift correction is implemented via referencing to fiducial markers that are assumed to be firmly immobilized and remain stationary relative to the imaged sample. However, there is so far lack of efficient approaches for evaluating other motions except sample drifting of immobilized markers and for addressing their potential impacts on images. Here, we developed a new approach for quantitatively assessing the motions of fiducial markers relative to the sample via mean squared displacement (MSD) analysis. Our findings revealed that over 90% of immobilized fluorescent beads in the SMLM imaging buffer exhibited higher MSDs compared to stationary beads in dry samples and displayed varying degrees of wobbling relative to the imaged field. By excluding extremely high-MSD beads in each field from drift correction, we optimized drift correction and experimentally measured localization precision. In SMLM experiments of cellular microtubules, we also found that including only relatively low-MSD beads for drift correction significantly improved the image resolution and quality. Our study presents a simple and effective approach to assess the potential relative motions of fiducial markers and emphasizes the importance of pre-screening fiducial markers for improved image quality and resolution in SMLM imaging.

Ablation of Mto1 in zebrafish exhibited hypertrophic cardiomyopathy manifested by mitochondrion RNA maturation deficiency.

Deficient maturations of mitochondrial transcripts are linked to clinical abnormalities but their pathophysiology remains elusive. Previous investigations showed that pathogenic variants in MTO1 for the biosynthesis of τm5U of tRNAGlu, tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR) were associated with hypertrophic cardiomyopathy (HCM). Using mto1 knock-out(KO) zebrafish generated by CRISPR/Cas9 system, we demonstrated the pleiotropic effects of Mto1 deficiency on mitochondrial RNA maturations. The perturbed structure and stability of tRNAs caused by mto1 deletion were evidenced by conformation changes and sensitivity to S1-mediated digestion of tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR). Notably, mto1KO zebrafish exhibited the global decreases in the aminoacylation of mitochondrial tRNAs with the taurine modification. Strikingly, ablated mto1 mediated the expression of MTPAP and caused the altered polyadenylation of cox1, cox3, and nd1 mRNAs. Immunoprecipitation assay indicated the interaction of MTO1 with MTPAP related to mRNA polyadenylation. These alterations impaired mitochondrial translation and reduced activities of oxidative phosphorylation complexes. These mitochondria dysfunctions caused heart development defects and hypertrophy of cardiomyocytes and myocardial fiber disarray in ventricles. These cardiac defects in the mto1KO zebrafish recapitulated the clinical phenotypes in HCM patients carrying the MTO1 mutation(s). Our findings highlighted the critical role of MTO1 in mitochondrial transcript maturation and their pathological consequences in hypertrophic cardiomyopathy.

Gamma-band neural coupling during conceptual alignment.

Conceptual alignment is a prerequisite for mutual understanding. However, little is known about the neurophysiological brain-to-brain underpinning during conceptual alignment for mutual understanding. Here, we recorded multi-channel electroencephalogram (EEG) simultaneously from two participants in Experiment 1 and adopted the dual-tACS techniques in Experiment 2 to investigate the underlying brain-to-brain EEG coupling during conceptual alignment and the possible enhancement effect. Our results showed that 1) higher phase-locking value (PLV), a sensitive measure for quantifying neural coupling strength between EEG signals, at the gamma frequency band (28-40 Hz), was observed in the left temporoparietal site (left TP) area between successful versus unsuccessful conceptual alignment. The left TP gamma coupling strength correlated with the accuracy of conceptual alignment and differentiated whether subjects belonged to the SUCCESS or FAILURE groups in our study. 2) In-phase gamma-band transcranial alternating current stimulation (tACS) over the left TP area increased the accuracy of subjects in the SUCCESS group but not the FAILURE group. 3) The effect of perspective-taking on the accuracy was mediated by the gamma coupling strength within the left TP area. Our results support the role of gamma-band coupling between brains for interpersonal conceptual alignment. We provide dynamic interpersonal neurophysiological insights into the formation of successful communication.

Spinal microglia-derived TNF promotes the astrocytic JNK/CXCL1 pathway activation in a mouse model of burn pain.

Burn injury-induced pain (BIP) is an extremely complicated condition usually resistant to analgesic drugs, while its pathogenesis remains unknown. Considerable attention has been attracted to elucidate the glial mechanisms in chronic pain. In this study, we initiatively used a mouse model of second-degree BIP to investigate the underlying non-neuronal mechanisms at the spinal cord level. Our behavioral results showed that hind-paw burn injury caused persistent allodynia and hyperalgesia for 2 weeks in mice. Further studies revealed that both microglia and astrocytes activated in a spatially- and temporally-dependent manner in spinal cord after burn injury. In addition, the phosphorylated p38 mitogen-activated protein kinase (MAPK)-mediated tumor necrosis factor (TNF) release in spinal microglia is essentially attributed to the early stage of BIP, while the c-Jun N-terminal kinase (JNK) MAPK-dependent chemokine CXCL1 expression is mainly involved in the maintenance of pain hypersensitivity. Most strikingly, burn injury-induced pain symptoms and the activation of astrocytes were significantly suppressed by TNF inhibitor Thalidomide. On the contrary, intrathecal injection of TNF caused apparent pain hypersensitivity, accompanied by the activation of astrocytes and the upregulation of CXCL1 via the JNK MAPK signaling pathway, indicating that TNF is the key cytokine in the interaction between microglia and astrocytes at the spinal level. Moreover, treatment with the CXCR2 receptor antagonist SB225002 to block the biological activities of CXCL1 significantly attenuated the mechanical allodynia and thermal hyperalgesia in this BIP model. Taken together, this study indicates that intervention of glial pathways provides a new perspective in the management of BIP.

Groundwater antibiotics and microplastics in a drinking-water source area, northern China: Occurrence, spatial distribution, risk assessment, and correlation.

In recent years, antibiotics and microplastics have both received increasing attention. However, the contamination and correlation between the two pollutants in the groundwater of drinking-water source areas has not yet been considered. In this study, eight antibiotics were detected in 81 groundwater samples from a drinking-water source area. These were trimethoprim (TMP), sulfadimidine (SDD), sulfadiazine (SDZ), sulfamethoxazole (SMX), sulfachloropyridazine (SCP), norfloxacin (NOR), ciprofloxacin (CIP) and enrofloxacin (ENRO). Detection rates ranged from 1.23% to 95.06% and the maximum concentration ranged from 0.44 ng/L to 45.40 ng/L. Antibiotics in the groundwater pose no threat to human health, while only ENRO, CIP, NOR, SMX, and SDZ posed medium to low risks to the aquatic ecosystem. In contrast, the detection rate of microplastics was 100% with abundance values ranging from 4 n/L to 72 n/L, with an average of 29 n/L. Microplastic polymers were identified as polyamide, polyethylene, polypropylene, polyvinyl chloride and polystyrene. These also occurred in surface water but the particle sizes in groundwater were lower than those in the surface water. Through correlation analysis, it was found that NOR, ENRO and total antibiotic concentrations were significantly correlated with microplastic abundances. This study revealed the contamination and potential risks of antibiotics and microplastics in the groundwater of a drinking-water source area and found a correlation between them, indicating that risk management of antibiotics and microplastics in groundwater should be highly concerned.

Longitudinal change in components of astigmatism and its association with axial length-corneal radius ratio in Chinese young children: the Nanjing Eye Study.

PURPOSE: To assess the longitudinal change in components of astigmatism from age 4 to 7 years and its association with axial length-corneal radius ratio (AL/CR). METHODS: Children born between September 2011 and August 2012 in Yuhuatai District of Nanjing were invited to participate in the Nanjing Eye Study for a comprehensive eye examination annually since 2015. The data presented in this paper were obtained in 2016, 2017, and 2019. At each study encounter, noncycloplegic autorefraction and ocular biometric parameters were measured. Changes of total astigmatism (TA), corneal astigmatism (CA), anterior corneal astigmatism (ACA), residual astigmatism (RA), and internal astigmatism (IA) were analyzed in clinical notation (Cyl) and vector notation (J0, J45). RESULTS: Nine hundred fifty-four children (mean ± standard deviation of baseline age: 4.63 ± 0.29 years, 53.7% boys) had complete data and were included in this study. Mean slopes of longitudinal changes in Cyl notation were significantly negative for TA, CA, and ACA, but positive for IA. TA, CA, ACA, and RA of J0 notation had a shift toward increasing with-the-rule (WTR) astigmatism and/or decreasing against-the-rule (ATR) astigmatism. TA of J45 notation showed an increase in astigmatism at axis 135° and/or a decrease in astigmatism at axis 45°, while CA and ACA of J45 notation showed an opposite change. Longitudinal changes in ACA and IA were negatively correlated in J0 notation, but not in J45 notation. Based on compensation factor (CF, defined as the minus ratio of IA and ACA), the compensation proportions for J0 in varying degrees (CF: 0.1-2) in 2016, 2017, and 2019 were 91.3%, 93.5%, and 90.0%, respectively, while these for J45 were 74.9%, 76.5%, and 34.6%, respectively. Higher AL/CR increase was associated with less decrease or more increase in CA and ACA of Cyl notation, and a shift toward increasing WTR and/or decreasing ATR in these of J0 notation. CONCLUSIONS: The compensatory role of IA was persistent and prominent from 4 to 7 years old for J0 notation in Chinese young children. The progression of AL/CR was correlated with astigmatism originated from the cornea.

Comparison of alternate part-time patching and pencil push-up training for patients with intermittent exotropia.

BACKGROUND: To compare the effect of alternate part-time patching and pencil push-up training on control ability in patients with intermittent exotropia. METHODS: Patients (3-7 years old) with previously untreated intermittent exotropia were randomly assigned to receive alternate part-time patching, pencil push-up training, or observation. Control ability was assessed using the Office Control Score. Stereoacuity at 40 cm was evaluated with Titmus. Results were compared after a 12-week follow-up. RESULTS: Ninety-two patients (28 in patching, 30 in pencil push-ups, and 34 in observation group) completed 12-week follow-up assessments. Based on 6-point scale, the mean deviation control was significantly better in patching and pencil push-up group after 12 weeks at distance (P = 0.002 and 0.026, respectively). Furthermore, there were greater control changes in patching and pencil push-up groups in comparison with observation group from baseline to 12 weeks (P<0.001; P = 0.003, respectively). After 12 weeks of treatment, stereoacuity and stereoacuity changes were not significantly different between either the intervention group or control group (P = 0.140 and 0.393, respectively). CONCLUSIONS: Based on the common office control scale, alternate part-time patching and pencil push-up training were effective treatment strategies for intermittent exotropia.

Altered retinal nerve fiber layer thickness in children with allergic conjunctivitis: the Nanjing eye study.

BACKGROUND: So far, few data are available on the relationship between allergic conjunctivitis (AC) and ocular fundus. Whether retinal parameters change in patients with AC remains unknown. In this study, we investigated the influence of AC on retinal thickness and vessel density among 7-years-old school-age children. METHODS: This large population-based study is part of the Nanjing Eye Study (NES). Comprehensive examinations including anthropometric parameters, refraction, ocular biometric parameters, intraocular pressure and retinal parameters were conducted on each child. Retinal thickness and vessel density were assessed using the optical coherence tomography angiography. Information on AC was obtained from a comprehensive questionnaire. RESULTS: A total of 739 children (mean age ± SD: 7.40 ± 0.29 years) had complete eye examination and questionnaire data we needed. Ninety-four children (12.7%) had AC, among which, 5 children had the history of corticosteroid use and were excluded from the final analysis. Spherical equivalent, axial length, body mass index and birth weight were correlated with retinal parameters. After adjusting for sex, age, spherical equivalent, axial length, body mass index, birth weight and premature history, children with AC had thinner retinal nerve fiber layer thickness for average (117.39 versus 120.97 µm, p = 0.007), temporal (80.73 versus 84.34 µm, p = 0.001), nasal (98.82 versus 102.18 µm, p = 0.049) and inferior (152.68 versus 157.06 µm, p = 0.034) quadrants than the control group. CONCLUSIONS: Children with AC tended to have thinner retinal nerve fiber layer thickness. More attention is needed to fundus condition of children with AC.

Corneal endothelial cell density and its correlation with birth weight, anthropometric parameters, and ocular biometric parameters in Chinese school children.

BACKGROUND: To describe the distribution of corneal endothelial cell density (ECD), and to explore its correlation with birth weight (BW), anthropometric parameters, and ocular biometric parameters in Chinese school children. METHODS: In the population-based cross-sectional Nanjing Eye Study, children were measured for anthropometric information, for ECD by the noncontact specular microscope and for ocular biometric parameters by the optic low-coherent reflectometer. Data from right eyes were analyzed to illustrate the distribution of ECD and for determining correlated factors with ECD using univariate and multiple linear regression analysis. Comparisons among three different BW groups were performed using a one-way ANOVA analysis followed by the Bonferroni correction for pairwise comparisons. RESULTS: Of 1171 children, the mean (± standard deviation) ECD was 2875.34 ± 195.00 cells/mm2. In the Multiple Linear Regression analysis, BW, gender and central corneal thickness were significantly associated with ECD. The ECD increased by 36.16 cells/mm2 with BW increasing by 1 kg (P = 0.001) and increased by 0.44 cells/mm2 for every additional 1 mm in central corneal thickness (P = 0.01). The ECD of girls was 54.41 cells/mm2 higher than boys (P < 0.001). Children born with low BW presented significantly lower ECD than those born with normal BW (P < 0.05) and high BW (P < 0.05). Age and axial length were not significantly associated with ECD (P = 0.06 and P = 0.21, respectively). CONCLUSIONS: In Chinese school children aged 82 to 94 months, the ECD is positively correlated with BW and central corneal thickness, in which BW is a newly identified associated factor. It is like that gender plays an important role in ECD distribution while girls have relatively greater ECD than boys.

Cell density detection based on a microfluidic chip with two electrode pairs.

Cell density detection is usually the counting of cells in certain volume of liquid, which is an important process in biological and medical fields. The Coulter counting method is an important method for biological cell detection and counting. In this paper, a microfluidic chip based on two electrode pairs is designed, which uses the Coulter principle to detect the flow rate of liquid and count the cells, and then calculate the cell density. When the cell passes through the sensor channel formed by the electrode pair on the chip, the impedance will change between the electrodes. This phenomenon has been proved by experiments. The designed chip has the advantages of simple structure, small size and low manufacturing cost. The cell density detection method proposed in this article is of great significance to the research in the field of biological cell detection and development of related medical devices.

Regulation of survivin protein stability by USP35 is evolutionarily conserved.

Survivin is the key component of the chromosomal passenger complex and plays important roles in the regulation of cell division. Survivin has also been implicated in the regulation of apoptosis and tumorigenesis. Although the survivin protein has been reported to be degraded by a ubiquitin/proteasome-dependent mechanism, whether there is a DUB that is involved in the regulation of its protein stability is largely unknown. Using an expression library containing 68 deubiquitinating enzymes, we found that ubiquitin-specific-processing protease 35 (USP35) regulates survivin protein stability in an enzymatic activity-dependent manner. USP35 interacted with and promoted the deubiquitination of the survivin protein. USP38, an ortholog of USP35 encoded by the human genome, is also able to regulate survivin protein stability. Moreover, we found that the deubiquitinating enzyme DUBAI, the Drosophila homolog of human USP35, is able to regulate the protein stability of Deterin, the Drosophila homolog of survivin. Interestingly, USP35 also regulated the protein stability of Aurora B and Borealin which are also the component of the chromosomal passenger complex. By regulating protein stabilities of chromosomal passenger complex components, USP35 regulated cancer cell proliferation. Taken together, our work uncovered an evolutionarily conserved relationship between USP35 and survivin that might play an important role in cell proliferation.

Deletion of Gtpbp3 in zebrafish revealed the hypertrophic cardiomyopathy manifested by aberrant mitochondrial tRNA metabolism.

GTPBP3 is a highly conserved tRNA modifying enzyme for the biosynthesis of τm5U at the wobble position of mitochondrial tRNAGlu, tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR). The previous investigations showed that GTPBP3 mutations were associated with hypertrophic cardiomyopathy (HCM). However, the pathophysiology of GTPBP3 deficiency remains elusively. Using the gtpbp3 knockout zebrafish generated by CRISPR/Cas9 system, we demonstrated the aberrant mitochondrial tRNA metabolism in gtpbp3 knock-out zebrafish. The deletion of gtpbp3 may alter functional folding of tRNA, indicated by conformation changes and sensitivity to S1-mediated digestion of tRNAGlu, tRNALys, tRNATrp and tRNALeu(UUR). Strikingly, gtpbp3 knock-out zebrafish displayed the global increases in the aminoacylated efficiencies of mitochondrial tRNAs. The aberrant mitochondrial tRNA metabolisms impaired mitochondrial translation, produced proteostasis stress and altered activities of respiratory chain complexes. These mitochondria dysfunctions caused the alterations in the embryonic heart development and reduced fractional shortening of ventricles in mutant zebrafish. Notably, the gtpbp3 knock-out zebrafish exhibited hypertrophy of cardiomyocytes and myocardial fiber disarray in ventricles. These cardiac defects in the gtpbp3 knock-out zebrafish recapitulated the clinical phenotypes in HCM patients carrying the GTPBP3 mutation(s). Our findings highlight the fundamental role of defective nucleotide modifications of tRNAs in mitochondrial biogenesis and their pathological consequences in hypertrophic cardiomyopathy.

Geographical distribution and prevalence of mental disorders among healthcare workers in China: A cross-sectional country-wide survey: A cross-sectional study to assess mental disorders of healthcare workers in China.

BACKGROUND: Reliable and detailed nationwide data on the prevalence and distribution of mental disorders among healthcare workers in China during the coronavirus disease 2019 (COVID-19) outbreak are scarce. METHODS: We did a cross-sectional online survey from March 2 to 2 April 2020 and a total of 19,379 healthcare workers from 25 provinces participated. Depression, anxiety and post-traumatic stress disorder (PTSD) were assessed by the Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Scale (GAD-7) and PTSD Checklist for DSM-5 (PCL-5), respectively. RESULTS: The age-standardized prevalence of depression, anxiety and PTSD was 15.5%, 12.7% and 5.2%, respectively. Frontline workers had higher prevalence estimates than non-frontline workers (depression: 18.2% vs. 13.9%; anxiety: 14.7% vs. 11.6%; PTSD: 6.1% vs. 4.6%). Subgroups who were nurses, were married or had dependent children reported higher prevalence of depression, anxiety and PTSD. Despite of the large variations, the prevalence of mental disorders was lowest in East China, followed by Middle China, and highest in West China. CONCLUSION: Healthcare workers faced enormous stress not only from the direct risk presented by the COVID-19 outbreak, but also from the profound changes in their professional practice. Prevalence of adverse psychological outcomes has a significant association with geographically distribution of health resources and regional economic level. Sufficient medical resource may be a protective factor to mental health condition of healthcare personnel when such a public health emergency happened.