Single-Cell RNA Sequencing Reveals the Spatial Heterogeneity and Functional Alteration of Endothelial Cells in Chronic Hepatitis B Infection.

Chronic Hepatitis B virus (CHB) infection is a global health challenge, causing damage ranging from hepatitis to cirrhosis and hepatocellular carcinoma. In our study, single-cell RNA sequencing (scRNA-seq) analysis was performed in livers from mice models with chronic inflammation induced by CHB infection and we found that endothelial cells (ECs) exhibited the largest number of differentially expressed genes (DEGs) among all ten cell types. NF-κB signaling was activated in ECs to induce cell dysfunction and subsequent hepatic inflammation, which might be mediated by the interaction of macrophage-derived and cholangiocyte-derived VISFATIN/Nampt signaling. Moreover, we divided ECs into three subclusters, including periportal ECs (EC_Z1), midzonal ECs (EC_Z2), and pericentral ECs (EC_Z3) according to hepatic zonation. Functional analysis suggested that pericentral ECs and midzonal ECs, instead of periportal ECs, were more vulnerable to HBV infection, as the VISFATIN/Nampt- NF-κB axis was mainly altered in these two subpopulations. Interestingly, pericentral ECs showed increasing communication with macrophages and cholangiocytes via the Nampt-Insr and Nampt-Itga5/Itgb1 axis upon CHB infection, which contribute to angiogenesis and vascular capillarization. Additionally, ECs, especially pericentral ECs, showed a close connection with nature killer (NK) cells and T cells via the Cxcl6-Cxcr6 axis, which is involved in shaping the microenvironment in CHB mice livers. Thus, our study described the heterogeneity and functional alterations of three subclusters in ECs. We revealed the potential role of VISFATIN/Nampt signaling in modulating ECs characteristics and related hepatic inflammation, and EC-derived chemokine Cxcl16 in shaping NK and T cell recruitment, providing key insights into the multifunctionality of ECs in CHB-associated pathologies.

Comparability of JAK2 p.V617F allele burden in peripheral blood and that in bone marrow in patients with suspected myeloproliferative neoplasms: a single-center prospective study.

PURPOSE: To detect JAK2 p.V617F and measure allele burden in peripheral blood (PB) and bone marrow (BM) aspirates in patients with suspected myeloproliferative neoplasms (MPNs). METHODS: Patients with suspected MPNs were prospectively enrolled between August 2017 and May 2019, and their PB and BM were collected during the same period. Quantitative fluorescence polymerase chain reaction (PCR) was used to detect the copy number of JAK2 wild type and the V617F mutant; the JAK2 V617F proportion was also calculated. The JAK2 p.V617F proportion in PB was compared to that in BM by Chi-square test. RESULTS: Among 54 patients with suspected MPNs, 43 of them were eligible for analysis. The JAK2 p.V617F in PB had the same sensitivity and specificity as BM (all P>0.05). The Chi-square test suggested that the JAK2 p.V617F allele burden of PB was comparable to that of BM (Spearman Correlation =0.986; P=0.000). CONCLUSION: PB could be used as an alternative to BM for JAK2 p.V617F measurement in patients with suspected MPNs.

Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing.

The Ras GTPase-activating protein SYNGAP1 plays a central role in synaptic plasticity, and de novo SYNGAP1 mutations are among the most frequent causes of autism and intellectual disability. How SYNGAP1 is regulated during development and how to treat SYNGAP1-associated haploinsufficiency remain challenging questions. Here, we characterize an alternative 3' splice site (A3SS) of SYNGAP1 that induces nonsense-mediated mRNA decay (A3SS-NMD) in mouse and human neural development. We demonstrate that PTBP1/2 directly bind to and promote SYNGAP1 A3SS inclusion. Genetic deletion of the Syngap1 A3SS in mice upregulates Syngap1 protein and alleviates the long-term potentiation and membrane excitability deficits caused by a Syngap1 knockout allele. We further report a splice-switching oligonucleotide (SSO) that converts SYNGAP1 unproductive isoform to the functional form in human iPSC-derived neurons. This study describes the regulation and function of SYNGAP1 A3SS-NMD, the genetic rescue of heterozygous Syngap1 knockout mice, and the development of an SSO to potentially alleviate SYNGAP1-associated haploinsufficiency.

Evaluating the screening value of serum light chain ratio, ß2 microglobulin, lactic dehydrogenase and immunoglobulin in patients with multiple myeloma using ROC curves.

OBJECTIVE: Several laboratory and imaging assays are required to diagnose multiple myeloma (MM). Serum and urine immunofixation electrophoresis are two key assays to diagnose MM, while they have not been extensively utilized in Chinese hospitals. Serum light chain (sLC), ß2 microglobulin (ß2-MG), lactic dehydrogenase (LDH), and immunoglobulin (Ig) are routinely measured in the majority of Chinese hospitals. Imbalance of sLC ratio (involved light chain/uninvolved light chain) is frequently observed in MM patients. This study aimed to evaluate the screening value of sLC ratio, ß2-MG, LDH, and Ig in MM patients using receiver operating characteristic (ROC) curves. METHODS: Data of 303 suspected MM patients, who were admitted to the Taizhou Central Hospital between March 2015 and July 2021, were retrospectively analyzed. In total, 69 patients (MM arm) met the International Myeloma Working Group (IMWG) updated criteria for the diagnosis of MM, while 234 patients were non-MM (non-MM arm). All patients' sLC, ß2-MG, LDH, and Ig were measured using commercially available kits according to the manufacturer's instructions. The ROC curve analysis was employed to assess the screening value of sLC ratio, ß2-MG, LDH, creatinine (Cr) and Ig. The statistical analysis was carried out by SPSS 26.0 (IBM, Armonk, NY, USA) and MedCalc 19.0.4 (Ostend, Belgium) software. RESULTS: There was no significant difference between the MM and non-MM arms in terms of gender, age and Cr. The median sLC ratio in the MM arm was 11.5333, which was significantly higher than that of 1.9293 in the non-MM arm (P<0.001). The area under the curve (AUC) of sLC ratio was 0.875, which indicated a robust screening value. The optimal sensitivity and specificity were 81.16% and 94.87% respectively, when the sLC ratio was set as 3.2121. The serum levels of ß2-MG and Ig were higher in the MM arm than those in the non-MM arm (P<0.001). The AUC values of ß2-MG, LDH, and Ig were 0.843 (P<0.001), 0.547 (P = 0.2627), and 0.723 (P<0.001), respectively. The optimal cutoff values of ß2-MG, LDH, and Ig were 1.95 mg/L, 220 U/L, and 46.4 g/L respectively, in the context of screening value. The triple combination of sLC ratio (3.2121), ß2-MG (1.95 mg/L), and Ig (46.4 g/L) yielded a higher screening value compared with that of sLC ratio alone (AUC, 0.952; P<0.0001). The triple combination had a sensitivity of 94.20% and a specificity of 86.75%. The addition of LDH to the triple combination and formation of quadruple combination did not optimize the screening value, with AUC, sensitivity, and specificity of 0.952, 94.20%, and 85.47%, respectively. CONCLUSION: The triple combination strategy (sLC ratio, 3.2121; ß2-MG, 1.95 mg/L; Ig, 46.4 g/L) is accompanied by remarkable sensitivity and specificity for screening MM in Chinese hospitals.

Distinct inflammation-related proteins associated with T cell immune recovery during chronic HIV-1 infection.

Chronic inflammation and T cell dysregulation persist in individuals infected with human immunodeficiency virus type 1 (HIV-1), even after successful antiretroviral treatment. The mechanism involved is not fully understood. Here, we used Olink proteomics to comprehensively analyze the aberrant inflammation-related proteins (IRPs) in chronic HIV-1-infected individuals, including in 24 treatment-naïve individuals, 33 immunological responders, and 38 immunological non-responders. T cell dysfunction was evaluated as T cell exhaustion, activation, and differentiation using flow cytometry. We identified a cluster of IRPs (cluster 7), including CXCL11, CXCL9, TNF, CXCL10, and IL18, which was closely associated with T cell dysregulation during chronic HIV-1 infection. Interestingly, IRPs in cluster 5, including ST1A1, CASP8, SIRT2, AXIN1, STAMBP, CD40, and IL7, were negatively correlated with the HIV-1 reservoir size. We also identified a combination of CDCP1, CXCL11, CST5, SLAMF1, TRANCE, and CD5, which may be useful for distinguishing immunological responders and immunological non-responders. In conclusion, the distinct inflammatory milieu is closely associated with immune restoration of T cells, and our results provide insight into immune dysregulation during chronic HIV-1 infection.

Introduction of graphene oxide-supported multilayer-quantum dots nanofilm into multiplex lateral flow immunoassay: A rapid and ultrasensitive point-of-care testing technique for multiple respiratory viruses.

A lateral flow immunoassay (LFA) biosensor that allows the sensitive and accurate identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other common respiratory viruses remains highly desired in the face of the coronavirus disease 2019 pandemic. Here, we propose a multiplex LFA method for the on-site, rapid, and highly sensitive screening of multiple respiratory viruses, using a multilayered film-like fluorescent tag as the performance enhancement and signal amplification tool. This film-like three-dimensional (3D) tag was prepared through the layer-by-layer assembly of highly photostable CdSe@ZnS-COOH quantum dots (QDs) onto the surfaces of monolayer graphene oxide nanosheets, which can provide larger reaction interfaces and specific active surface areas, higher QD loads, and better luminescence and dispersibility than traditional spherical fluorescent microspheres for LFA applications. The constructed fluorescent LFA biosensor can simultaneously and sensitively quantify SARS-CoV-2, influenza A virus, and human adenovirus with low detection limits (8 pg/mL, 488 copies/mL, and 471 copies/mL), short assay time (15 min), good reproducibility, and high accuracy. Moreover, our proposed assay has great potential for the early diagnosis of respiratory virus infections given its robustness when validated in real saliva samples. Electronic Supplementary Material: Supplementary material (Section S1 Experimental section, Section S2 Calculation of the maximum number of QDs on the GO@TQD nanofilm, Section S3 Optimization of the LFA method, and Figs. S1-S17 mentioned in the main text) is available in the online version of this article at 10.1007/s12274-022-5043-6.

Value of plasma vitamin D level and nomogram model for predicting the prognosis of patients with small cell lung cancer treated with platinum plus etoposide as first-line chemotherapy.

BACKGROUND: To assess the value of plasma vitamin D level and nomogram model in predicting the prognosis of patients with small cell lung cancer (SCLC) treated with platinum plus etoposide (PPE) as first-line chemotherapy. METHODS: In this retrospective study, we included 178 patients with SCLC. The data of 25(OH)D level, basic clinical information, overall survival (OS) and progression-free survival (PFS) were collected. Moreover, a nomogram was constructed to predict the prognosis of the patients. RESULTS: The median OS value for patients with 25(OH)D < 10 ng/mL was 12.5 months. The median PFS value was 6.6 months. Sex, smoking status, clinical stage, and plasma vitamin D were independent prognostic predictors. Besides, the decision curve analysis and receiver operating characteristic curve indicated that the nomogram prediction models showed positive clinical benefit. CONCLUSIONS: The plasma vitamin D level is of great significance in prognosis of patients with SCLC. The construction of nomograms is beneficial in predicting the prognosis of patients with SCLC treated with PPE.

A study of gene variation in All-RAS wild-type metastatic colorectal cancer and its correlation with cetuximab.

Background: This study sought to explore the biological significance of genetic variation in RAS wild-type metastatic colorectal cancer (mCRC) in the real world, the difference in the efficacy of cetuximab in the treatment of mCRC with different genetic variants and identify clinical features and new predictors of efficacy. Methods: A retrospective analysis of the data of 60 patients with stage IV mCRC who received cetuximab at The First and Second Affiliated Hospital of Soochow University from 2016 to 2020 was conducted. The patients were divided into the following 3 groups according to the genetic test results: (I) group A (the all-RAS wild-type group); (II) group B (the all-RAS wild-type group with the tumor suppressor gene mutation); and (III) group C (the all-RAS wild-type group with the oncogenic driver gene mutation). A subgroup analysis was conducted to examine left CRC and local intervention, and the progression-free survival (PFS) and overall survival (OS) of the patients were observed. Results: The all-RAS wild-type mCRC patients were divided into group A (n=10), group B (including the TP53, APC, PTEN, BRCA2, and SMAD4 variants) (n=42), and group C (including the ERBB2, BRAF, PIK3CA, and RET variants) (n=8). The median PFS of groups A, B, and C were 15.0, 12.0, and 3.0 months, respectively (P=0.007). Fitting sex as a stratified variable to the Cox survival analysis model showed that only the PFS of groups B and C differed significantly (P=0.011). In the left-sided mCRC patients, the median PFS of groups A, B, C were 3.0, 13.0, and 3.0 months, respectively (P=0.009). Among the patients in group B, the median PFS of the metastatic local intervention subgroup was 14.0 months, and the non-local intervention subgroup was 12.0 months (P=0.55). Only the type of combined gene mutation was an independent factor affecting PFS. Conclusions: The PFS and OS of mCRC patients with all-RAS wild-type and no combined mutations treated with cetuximab were not better than those of patients with combined mutations. Compared to mCRC patients with all-RAS wild-type and oncogenic driver gene mutations, cetuximab significantly prolonged the PFS of all-RAS wild-type patients with the tumor suppressor gene mutations.

Survival analysis of patients with primary gallbladder cancer from 2010 to 2015: A retrospective study based on SEER data.

This study aims to assess the survival status of patients with Primary gallbladder cancer (PGC) and analyze the prognosis factors to facilitate the exploration of the prevention and therapeutic strategies of PGC.Data from 2433 PGC patients collected from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The SEER*Stat, SPSS 23.0 and GraphPad Prism 8 were used for statistical analyses. Kaplan Meier analysis was performed for the survival curve, log-rank test analyses were used to compare the survival rate difference and Cox regression analyses were performed to determine the prognosis factors.A total of 2433 PGC cases were reported from 2010 to 2015. The median age was 64.2 ±â€Š10.4 years old and the percentages of the white patients were 73.7% (1794/2433). The percentage of patients who received surgery treatment was 82.1% (1998/2433). The overall median survival time of all patients was 19 months and the 5-year survival rate was 28.8%. The 5-year survival rate of PGC patients in pN2 stage dropped to 0% and the 5-year survival rate for PGC patients with distant metastasis was only 2.7%. Age, tumor size, grade, pT stage, pM stage were risk factors for prognosis, surgery or not and radiation or not were protective factors for prognosis.Survival analysis of PGC patients based on the SEER database have provided an opportunity for understanding PGC prognosis and the basis for the exploration of viable PGC prevention and therapeutic strategies.

Essential Thrombocythaemia with Concomitant Waldenström Macroglobulinaemia: Case Report and Literature Review.

Essential thrombocythaemia (ET) and Waldenström macroglobulinaemia (WM) are two distinct disorders. Studies have reported several cases of myeloproliferative neoplasms (MPNs) with concomitant plasma cell dyscrasia. However, there were no reported cases of ET with concomitant WM to date. Here, we present a 55-year-old Chinese man with thrombocytosis and raised immunoglobulin level. Further investigations led to a diagnosis of ET and coexistent WM. Next-generation sequencing (NGS) of his bone marrow identified 3 mutated genes: JAK2 V617F, MYD88 L265P, and ATM F1036L. After being treated with pegylated interferon and low-dose aspirin, his platelet count normalized and immunoglobulin M (IgM) level reduced. To the best of our knowledge, this is the first reported case of dual pathology ET with WM.

Follicular Lymphoma Presenting With Monoclonal IgM And MYD88 Mutation: A Case Report And Review Of The Literature.

MYD88 mutation has been reported in various lymphomas, specifically in lymphoplasmacytic lymphoma. Yet, the mutation has not been reported in primary follicular lymphoma. Here, we present a 62-year-old male with follicular lymphoma who had an MYD88 L265P somatic mutation and monoclonal IgM gammopathy. He received four cycles of R-CHOP immunochemotherapy. Interim PET/CT evaluation indicated a state of stable disease (SD). Neither did serum IgM remarkably drop. He was then given a bortezomib-contained regimen which significantly reduced the level of serum IgM. To the best of our knowledge, this is the first report of follicular lymphoma with monoclonal IgM and MYD88 L265P mutation. The present case indicated bortezomib may benefit these patients.

Combining ctnnb1 genetic variability with epidemiologic factors to predict lung cancer susceptibility.

OBJECTIVE: Early detection and diagnosis of lung cancer remain challenging but would improve patient prognosis. The goal of this study is to develop a model to estimate the risk of lung cancer for a given individual. METHODS: We conducted a case-control study to develop a predictive model to identify individuals at high risk for lung cancer. Clinical data from 500 lung cancer patients and 500 population-based age- and gender-matched controls were used to develop and evaluate the model. Associations between environmental variants together with single nucleotide polymorphisms (SNPs) of beta-catenin (ctnnb1) and lung cancer risk were analyzed using a logistic regression model. The predictive accuracy of the model was determined by calculating the area under the receiver operating characteristic (ROC) curve. RESULTS: Prior diagnosis of chronic obstructive pulmonary disease (COPD), pulmonary tuberculosis, family history of cancer, and smoking are lung cancer risk factors. The area under the curve (AUC) was 0.740, and the sensitivity, specificity, and Youden index were 0.718, 0.660, and 0.378, respectively. CONCLUSION: Our risk prediction model for lung cancer is useful for distinguishing high-risk individuals.

China's Efforts on Management, Surveillance, and Research of Noncommunicable Diseases: NCD Scorecard Project.

BACKGROUND: The incidence of noncommunicable diseases (NCDs) is rising dramatically throughout the world. Aspects of researches concerned with the improvement and development of prevention and control of NCDs have been conducted. Furthermore, the influence of most determinants of the major NCDs has showed that a broad and deep response involving stakeholders in different sectors is required in the prevention and control of NCDs. OBJECTIVE: China has experienced an increase in NCDs in a short period compared with many countries. To address the burden of NCDs in China, it is important to learn about the progress that has been made in prevention and control of NCDs in China and worldwide, informed by opinions of stakeholders in different areas. METHODS: In 2014, GRAND South developed the NCD Scorecard instrument to evaluate progress of NCD prevention and control in 23 countries through a 2-round Delphi process. The scorecard included 51 indicators in 4 domains: governance, surveillance and research, prevention and risk factors, and health system response. Stakeholders were then selected in the areas of government, nongovernmental organizations, private sectors, and academia to join the NCD Scorecard survey. Indicators of progress were scored by stakeholders from 0 (no activity), 1 (present but not adequate), and 2 (adequate) to 3 (highly adequate) and then the percentage of progress in each domain was calculated, representing the current situation in each country. FINDINGS: There were 14 indicators in the domains of governance and surveillance and research. Of 429 stakeholders worldwide, 41 in China participated in the survey. China scored in the top 5 out of all participating countries in those 2 domains, scoring 67% in governance and 64% in surveillance and research. Indicators on which China scored particularly well included having a well-resourced unit or department responsible for NCDs, having a strong national system for recording the cause of all deaths, and having a system of NCD surveillance. Areas where China had the greatest need for improvement included increasing taxes on tobacco and addressing the needs of the population older than age 70 dying from major NCDs. CONCLUSION: In China the burden of disease of NCDs and disabilities remains serious, although China has put significant efforts into its governance and surveillance and research. To improve, further action is needed on reducing tobacco consumption, increasing investment in the national health budget, and increasing the focus on system construction.

Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex.

Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains-especially in cytoskeletal proteins-and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.

[Evaluation study of the implementation of WHO Framework Convention on Tobacco Control in seven provinces/municipalities in China].

OBJECTIVE: To assess the implementation of World Health Organization Framework Convention on Tobacco Control (WHO FCTC) by organizations in seven provinces/municipalities in China. METHODS: A total of 901 organizations, including hospitals, schools, government departments, health administrative departments and public transportation facilities, were selected by multistage sampling method in five provinces and two municipalities in China, 2010 and 2012. Key informant interview and observation survey were conducted to collect data on implementation of WHO FCTC. Analysis was performed among three clusters of indexes, which were establishment of smoke-free environment, education and training on tobacco control, and tobacco cessation measures. RESULTS: The five types of organizations performed differently in creating smoke-free environment. The ratios of conducting complete smoke-free policy in hospitals, health administrative departments and schools were separately 83.3% (111/192), 81.6% (146/179) and 66.5% (121/182) in 2012, which were comparatively higher than those in governments (32.4%, 33/102) and public transport facilities (25.0%, 27/108) (χ(2) = 174.93, P < 0.01) . As for promotion and training programs of tobacco control information, the ratio of health administrative departments raised from 78.1% (150/192) to 100.0% (192/192), and the difference showed statistical significance (χ(2) = 42.00, P < 0.01). But those departments who provide training to social media only accounted for 11.8% (22/187), which was substantially lower than the percentage of those providing training to themselves (67.7%, 128/189) (χ(2) = 413.99, P < 0.01). Three indexes of tobacco cessation related work--offering help in tobacco use quitting, providing health workers with training on tobacco cessation skills and establishing tobacco cessation clinics, only reached as low as 41.1% (312/760) , 55.6% (104/187) and 45.9% (89/194), respectively. Among the seven provinces/municipalities, Shanghai did better than the others on most of the indexes. 27 out of 28 schools in Shanghai implemented complete smoke-free policy, which was the best among the seven, while only 3 out of 26 in Jiangxi, as the poorest (χ(2) = 47.63, P < 0.01). Meanwhile, all of the 24 schools in Shanghai had health education classes on tobacco control, followed by Zhejiang (23 out of 29), while Jiangxi was also the poorest, only 12 out of 26 (χ(2) = 17.95, P < 0.01). CONCLUSION: The implementation of WHO FCTC by the five types of organizations in the seven provinces/municipalities has improved to various degrees. Nevertheless, further actions should be taken to promote smoke-free environment especially in certain circumstances such as public transport facilities, to strengthen training programs of tobacco control for social media, and to enhance hospitals' abilities in providing tobacco cessation services.

Somatic mutations in cerebral cortical malformations.

BACKGROUND: Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. METHODS: Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. RESULTS: Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. CONCLUSIONS: Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).

Nuclear migration: rock and roll facilitated by dynein and kinesin.

The nucleus encounters other organelles as well as high cytoplasmic pressures during its migration within the cell. A new study describes how the action of kinesin and dynein motors is coordinated at the nuclear envelope to rock and roll the nucleus in Caenorhabditis elegans.

SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice.

Nuclear movement is critical during neurogenesis and neuronal migration, which are fundamental for mammalian brain development. Although dynein, Lis1, and other cytoplasmic proteins are known for their roles in connecting microtubules to the nucleus during interkinetic nuclear migration (INM) and nucleokinesis, the factors connecting dynein/Lis1 to the nuclear envelope (NE) remain to be determined. We report here that the SUN-domain proteins SUN1 and SUN2 and the KASH-domain proteins Syne-1/Nesprin-1 and Syne-2/Nesprin-2 play critical roles in neurogenesis and neuronal migration in mice. We show that SUN1 and SUN2 redundantly form complexes with Syne-2 to mediate the centrosome-nucleus coupling during both INM and radial neuronal migration in the cerebral cortex. Syne-2 is connected to the centrosome through interactions with both dynein/dynactin and kinesin complexes. Syne-2 mutants also display severe defects in learning and memory. These results fill an important gap in our understanding of the mechanism of nuclear movement during brain development.