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Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

Background: To explore the effects of postoperative adjuvant transarterial chemoembolization (PA-TACE) on the prognosis of HCC patients with Portal Vein Tumor Thrombus (PVTT) undergoing resection, and to develop a PA-TACE-related nomogram for predicting survival individually. Patients and Methods: Two hundred and ninety-three consecutive HCC patients with PVTT under R0 hepatectomy were recruited. Forty-seven cases had recurrence within one month after surgery. The remaining 246 cases consisted of 90 PA-TACE and 156 non-PA-TACE cases. COX regression analysis was performed for overall survival (OS) or recurrence-free survival (RFS) of these 246 cases, allowing the derivation of independent factors that were integrated into the nomogram. C-index, calibration curves, and risk stratification were performed to evaluate the performance and discriminative power of the nomograms. Results: In 246 patients without recurrence within one month after surgery, the OS and RFS for the PA-TACE group were significantly better than those for the non-PA-TACE group (P

OBJECTIVES The objective of this study was to establish a reliable and effective nomogram for predicting prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) with postoperative adjuvant transarterial chemoembolization (TACE). PATIENTS AND METHODS A derivation cohort of 370 HCC patients treated with postoperative TACE in the Eastern Hepatobiliary Surgery Hospital from January 2009 to December 2012 were retrospectively analyzed. Univariate and multivariate analysis were performed by Cox regression and independent prognostic factors for overall survival were determined to construct the nomogram. Concordance index (C-index), calibration curve and decision curve analysis were performed to evaluate the capability of the nomogram and the established nomogram was compared with TNM stage and Barcelona Clinic Liver Cancer (BCLC) stage to identify the superior model. The results were validated in a validation cohort of 123 HCC patients in the same center. RESULTS Multivariate analysis indicated that γ-glutamyl transferase, α-fetoprotein, tumor number, tumor size, satellite lesions, microvascular invasion, and HBV-DNA were independent prognostic factors for overall survival in the derivation cohort, and all these factors were selected into the nomogram. The C-index was 0.755 for survival prediction of the nomogram, which was significantly higher than the TNM stage (0.636, P

The poor prognosis of hepatocellular carcinoma (HCC) patients is mainly due to cancer metastasis. Methionine adenosyltransferase 2β (MAT2B) encodes a regulatory subunit (β) for methionine adenosyltransferase. Previous studies reveal that MAT2B provides a growth advantage for HCC, but its role in metastasis is unknown. This study showed that both in the xenograft zebra fish model and in the lung metastasis model in nude mice, the stable inhibition of MAT2B could suppress the metastasis of HCC cancer cells. Silencing of MAT2B in HCC cell lines could remarkably inhibit migration and invasion. By analysis of human phospho-kinase array membranes, we found several differentially expressed proteins, including phosphor-AKT, phospho-EGFR, phospho-Src family, phospho-FAK, phospho-STAT3 and phospho-ERK. We further confirmed the change of these EGFR pathway-related proteins was in accordance with MAT2B expression pattern through immunoblotting test. Finally, we found that MAT2B was overexpressed in HCC caner tissues and correlated with poor prognosis for HCC patients in clinical manifestation. Our study demonstrated that silencing of MAT2B could suppress liver cancer cell migration and invasion through the inhibition of EGFR signaling, which suggested that MAT2B might serve as a new prognostic marker and therapeutic target for HCC.

Background There are many reports of the anti-tumour effects of exogenous adenosine in gastrointestinal tumours. Gemcitabine, a first line agent for patients with poor performance status, and adenosine have structural similarities. For these reasons, it is worth exploring the therapeutic efficacy of adenosine and its underlying mechanism in pancreatic cancer. Methods Tumour volumes and survival periods were measured in a patient-derived xenograft (PDX) model of pancreatic cancer. The Akt-p21 signalling axis was blocked by p21 silencing or by the Akt inhibitor GSK690693. The combined effect of GSK690693 and adenosine was calculated by the Chou-Talalay equation and verified by measuring fluorescent areas in orthotopic models. Findings Among the PDX mice, the tumour volume in the adenosine treatment group was only 61% of that in the saline treatment group. Adenosine treatment in combination with the Akt inhibitor, GSK690693, or the silencing of p21 to interfere with the Akt-p21 axis can switch the senescence-to-apoptosis signal and alleviate drug resistance. A GSK690693-adenosine combination caused 37.4% further reduction of tumour fluorescent areas in orthotopic models compared with that observed in adenosine monotherapy. Interpretation: Our data confirmed the therapeutic effect of adenosine on pancreatic cancer, and revealed the potential of Akt inhibitors as sensitization agents in this treatment. Fund The work is supported by grants from the National Natural Science Foundation of China to Dongqin Yang ( 81572336 , 81770579 ) and Jie Liu ( 81630016 , 81830080 ), and jointly by the Development Fund for Shanghai Talents ( 201660 ).

With the development of RNA-seq technology, tens of thousands of circular RNAs (circRNAs), a novel class of RNAs, have been identified. However, little is known about circRNA formation and biogenesis in hepatocellular carcinoma (HCC). We performed ribosomal-depleted RNA-seq profiling of HCC and para-carcinoma tissues and analyzed the expression of a hotspot circRNA derived from the 3'UTR of the stearoyl-CoA desaturase (SCD) gene, termed SCD-circRNA 2. It was significantly upregulated in HCC and correlated with poor patient prognosis. Moreover, we observed that the production of SCD-circRNA 2 was dynamically regulated by RNA-binding protein 3 (RBM3). RBM3 overexpression was indicative of a short recurrence-free survival and poor overall survival for HCC patients. Furthermore, by modulating the RBM3 or SCD-circRNA 2 levels, we found that RBM3 promoted the HCC cell proliferation in a SCD-circRNA 2 dependent manner. Herein, we report that RBM3 is crucial for the SCD-circRNA 2 formation in HCC cells, which not only provides mechanistic insights into cancer-related circRNA dysregulation but also establishes RBM3 as an oncogene with both therapeutic potential and prognostic value. Funding Statement: This work was supported by the National Key Research and Development Program of China (2016YFC1302303), the National Natural Science Foundation of China (Grant No. 81672345 and 81402269). Declaration of Interests: There is no conflict of interest, financial or otherwise, related to the submitted work. Ethics Approval Statement: This research study was approved by the ethics committee of the Second Military Medical University, and all patients signed the informed consent provided by the committee. Patients whose consents were unavailable were excluded from this study.

Apoptosis and autophagy are distinct cellular processes that can be highly interconnected. The cross talk between the two processes is indispensable in determining the overall cell fate. Although the apoptosis-promoting effect of caspases has been demonstrated, the roles of autophagy-related proteins and even autophagy itself in regulating apoptosis remain poorly understood. In our present study, we found that downregulation of ubiquitin E3 ligase ASB3 led to enhanced mitochondrial apoptosis as well as autophagy, which synergistically promoted cell death in hepatocellular carcinoma (HCC). We observed the activation of caspase-8 and decrease of autophagy protein Beclin1 in apoptotic cells that were depleted of ASB3. Beclin1 was mainly cleaved by activated caspase-8 and active Beclin1 initiated mitochondrial apoptosis via locating its C-terminal fragment to mitochondria. In addition, knocking down of Beclin1 markedly blocked the apoptosis, indicating its essential role in the process. Notably, our study indicated that enhanced autophagy level might be involved in the activation of caspase-8 and promote the apoptosis. Taken together, our results demonstrated that ASB3 can regulate mitochondrial pathway of apoptosis by controlling caspase-8 mediated cleavage of Beclin1 in HCC. Therefore, ASB3 may potentially serve as a novel target for HCC therapy, especially when combined with autophagy agonist.

Purpose: To develop and validate a gene-related nomogram for predicting the risk of lymph node (LN) metastasis preoperatively in patients with colorectal cancer (CRC). Methods: RNA-seq data of 581 CRC and 51 normal cases with clinical features were downloaded from TCGA database. In the evaluation cohort with 381 CRC cases, the LASSO regression was used to reduce dimensionality of gene signatures extracted to build gene score. A gene-related nomogram was performed based on the multivariable logistic regression analysis. The performance of the nomogram was assessed by the discrimination, calibration, and clinical usefulness not only in the evaluation, but also in the validation cohort with 200 CRC cases. Results: A total of 12,590 differentially expressed genes were selected, in which 59 candidates associated with LN metastasis in differentially expressed genes set were screened by LASSO to form the gene score. Based on the analysis of multivariate logistic regression, the gene-related nomogram showed good calibration and discrimination not only in the evaluation cohort (concordance-index 0.93; 95%CI 0.91-0.96), but also in the validation cohort (concordance-index 0.70; 95%CI 0.63-0.78). The decision curve analysis of the gene-related nomogram also provides constructive guidance for the design of operation plan, preoperatively. Conclusions: The presented genes nomogram may predict the LN metastasis in CRC patients, preoperatively. And 59 hub genes were defined related to LN metastasis of CRC, which can serve as treatment targets for the further study. Preoperative biopsy and gene analysis are needed to develop the operation plan in clinical practice.

Mitochondrial disorders are clinically heterogeneous diseases associated with impaired oxidative phosphorylation (OXPHOS) activity. POLG, which encodes the DNA polymerase-γ (Polγ) catalytic subunit, is the most commonly mutated nuclear gene associated with mitochondrial disorders. We carried out whole-exome sequencing (WES) to identify the gene associated with progressive external ophthalmoplegia (PEO). We then performed histopathological analyses, assessed mitochondrial biology, and executed functional studies to evaluate the potential pathogenicity of the identified genetic mutations. Novel biallelic POLG mutations, including a large deletion mutation (exons 7–21) and a missense variant c.1796C>T (p.Thr599Ile) were detected in the proband. Histopathological analysis of a biopsied muscle sample from this patient revealed the presence of approximately 20% COX-negative fibers. Bioinformatics analyses confirmed that the detected mutations were pathogenic. Furthermore, levels of mitochondrial complex I, II, and IV subunit protein expressions were found to be decreased in the proband, and marked impairment of mitochondrial respiration was evident in cells harboring these mutations. This study expands the spectrum of known POLG variants associated with PEO and advances current understanding regarding the structural and functional impacts of these mutations.

Proteasome inhibitors represent effective anti-tumor drugs. ONX0912 is a novel oral proteasome inhibitor that selectively targets the chymotrypsin-like activity of 20S proteasome subunits β5 and LMP7 （Low molecular mass polypeptide-7）. It has been shown to be effective in hematologic malignancies. However, its anti-tumor effect in solid tumors remains unclear. Here, we discovered that ONX0912 suppressed the expansion of liver cancer cells. ONX0912 treatment led to an increased level of mitochondrial membrane potential collapse and mitochondrial ROS in tumor cells in a concentration- and exposure time-dependent manner, indicating ONX0912 triggers apoptosis through the intrinsic mitochondrial pathway. ONX0912 also induced mitophagy by activating Parkin/Pink pathway. Silencing mitophagy receptor protein, p62, aggravated the ONX0912-mediated apoptosis, which implied a new mechanism for the conversion between autophagy and apoptosis. Furthermore, we found that the ONX0912 target protein, LMP7 was overexpressed in liver cancer tissues compared to their adjacent tissues and increased level of LMP7 predicted worse clinical characteristics and poorer prognosis. In conclusion, we demonstrated that ONX0912 suppressed liver cancer cell expansion by inducing apoptosis and mitophagy. Our data also revealed ONX0912 as a potential clinical therapeutic drug for liver cancer therapy, and inhibition of mitophagy may sensitize the anti-tumor effect of ONX0912.

Background and ObjectivesSporadic late-onset nemaline myopathy (SLONM) is a treatable or otherwise fatal myopathy. Diagnosis of SLONM is still challenging, and no therapeutic consensus has been achieved. Here, we reported the clinicopathologic features and long-term follow-up data of SLONM in a Chinese cohort.MethodsWe performed a retrospective evaluation of clinical, pathologic, and treatment outcomes of 17 patients with SLONM diagnosed between March 1986 and April 2021 at our neuromuscular center. Immunohistochemistry (IHC) with antibodies against 5 Z-disc–associated proteins was performed in the muscle biopsies of SLONM to identify a potential pathologic marker in aid of diagnosis. In comparison, we also performed muscle IHC in patients with selective type II fiber atrophy (n = 22), neurogenic atrophy (n = 22), mitochondrial myopathy (n = 5), immune-mediated necrotizing myopathy (n = 5), and normal controls (n = 5).ResultsMost of the patients exhibited asymmetric limb muscles weakness (71%, 12/17) and neck extensor weakness (53%, 9/17). Immunofixation electrophoresis was performed in 11 patients, and 4 of them were identified with monoclonal gammopathy of undetermined significance (MGUS). EMG from 16 patients demonstrated a myopathic pattern with spontaneous activities in 69% (11/16) of them. Muscle MRI showed preferential involvement of paraspinal, gluteus minimus and medius, semimembranosus, and soleus muscles. Suspected nemaline bodies on modified Gomori trichrome were confirmed by IHC using anti–α-actinin antibody (100%, 17/17), anti-myotilin antibody (94%, 16/17), anti-desmin antibody (94%, 16/17), anti–α-B crystallin antibody (65%, 11/17), and anti-telethonin antibody (18%, 3/17) with various positive rates. Notably, anti–α-actinin IHC showed the highest percentage of strongly positive staining (77%, 13/17), being the only one without negative results. Moderate improvement following autologous stem cell transplantation (ASCT) was noted in 3/4 patients with MGUS; favorable outcomes were also achieved in 6/7 patients without MGUS, including 3 patients with complete recovery who were given a combined treatment of prednisone and another immunosuppressant.DiscussionSLONM is a treatable myopathy with ASCT or traditional immunotherapy, especially when combined with steroids and immunosuppressants. Anti–α-actinin immunostaining is the most reliable pathologic marker to identify rod-bearing fibers, and it should be performed routinely in adult patients with undiagnosed nonnecrotic myopathies.

As an aspartic protease, β-site APP cleaving enzyme 1 (BACE1) can efficiently cleave amyloid precursor protein (APP) to produce amyloid beta (Aβ), a chief constituent of senile plaques in Alzheimer's disease. Thus, BACE1 inhibitor is identified as a therapeutic candidate for AD. However, recent failures of clinical trials using BACE1 inhibitors emphasized that comprehensively understanding of BACE1 function is particularly important. Kv2.1, a potassium channel, modulates potassium current in cortical neurons and potassium efflux is a requisite event in the process of cell apoptosis. Previously we showed that BACE2 cleaves Kv2.1 and reduces neuronal apoptosis. Our study here showed that BACE1 cleaves Kv2.1, and results in decreased I

Background To study the influence of preoperative transcatheter arterial chemoembolization (TACE) on the incidence of microvascular invasion (MVI) and long‐term survival outcomes in hepatocellular carcinoma (HCC) patients. Methods Between January 1, 2010 and December 1, 2014, consecutive HCC patients who underwent curative liver resection were enrolled in this study. Univariable and multivariable regression analyses were used to identify independent predictive factors of MVI. Propensity score matching (PSM) was used to compare the incidences of MVI and prognosis between patients who did and did not receive preoperative TACE. Factors associated with Disease‐Free Survival (DFS) and Overall survival (OS) were identified using Cox regression analyses. Results Of 1624 patients, 590 received preoperative TACE. The incidence of MVI was significantly lower in patients with preoperative TACE than those without preoperative TACE (39.15% vs. 45.36%, p = 0.015). After PSM, the incidences of MVI were similar in the two groups (38.85% vs. 41.10%, p = 0.473). Multivariable regression analysis revealed preoperative TACE to have no impact on the incidence of MVI. Before PSM, survival of patients with preoperative TACE was significantly worse than those without preoperative TACE (p = 0.032 for DFS and p = 0.027 for OS). After PSM, the difference became insignificant (p = 0.465 for DFS and p = 0.307 for OS). After adjustment for other prognostic variables in the propensity‐matched cohort, preoperative TACE was still found not to be associated with DFS and OS after HCC resection. Both before and after PSM, the prognosis of patients was not significantly different between the two groups for BCLC stages 0, A, and B. Conclusions Preoperative TACE did not influence the incidence of MVI and prognosis of patients with HCC who underwent ‘curative’ liver resection., Preoperative TACE did not influence the incidence of MVI and prognosis of patients with HCC who underwent ‘curative’ liver resection.

For fields with hard and brittle shale sections that have microfractures (either preexisting in the formation or induced by drilling operations), we experienced troublesome drilling with a relatively low rate of penetration (ROP). A systematic experimental work has been implemented to discover whether nanoparticles added to drilling fluids penetrate shale formations and improve wellbore stability. Starting with quantitative analysis of the shale rocks, we found the mineralogy and clay composition of these rocks by using X-ray diffraction (XRD). The XRD analysis shows that the shale rocks consist of mixed-layer clays and are very heterogeneous. The shale samples were then characterized by X-ray computed tomography (XCT) and scanning electron microscopy (SEM) to gain an understanding of preexisting microfractures. The XCT results show that multiple cracks are irregularly distributed inside the shale with widths between 10 to 25 μm. Smaller cracks with widths ranging from 100 to 250 nm were also observed via imaging on the shale sample surface using SEM. To answer whether adding the nanoparticles improves wellbore stability, we first designed the nanoparticle infiltration test by flowing nanoparticle dispersions through the shale assembly at an inflow pressure of around 800 kPa. After the shale samples were subjected to infiltration tests with durations between 9 to 27 days, the injected depths of nanoparticle along cracks was determined to range from 190 to 420 μm, as seen by optical microscope images. Higher resolution SEM images show that the maximum infiltration depths of the nanoparticles range from 2 to 5 μm in different crack-free locations. Nanoindentation tests were then conducted under the continuous stiffness measurement (CSM) mode to probe the mechanical properties of the pre-treated and post-treated shale samples. At two indentation depths, the averaged Young's modulus E for the shale sample before and after nanoparticle infiltration significantly increased from 29.5 to 34.0 GPa (at a depth of 500 nm) and from 29.0 to 33.3 GPa (at a depth 3000 nm), respectively. The nanoparticle infiltration and nanoindentation test results demonstrate that nanoparticles can filter into and further strengthen the shale formation. We also formulated nanoparticles in our drilling fluid and performed the pressure transmission test (PTT) to see their sealing effect on the field cores. A highly favorable plugging result was obtained from the PTT using base mud with nanoparticles. Therefore, it is concluded that our systematic experimental work has delivered results, which support the practice of using nanoparticles to improve wellbore stability for shale formations.

Jian Huang,1,* Yun Yang,1,* Yong Xia,2,* Fu-Chen Liu,1,* Lei Liu,1 Peng Zhu,1 Sheng-Xian Yuan,1 Fang-Ming Gu,1 Si-Yuan Fu,1 Wei-Ping Zhou,1 Hui Liu,1 Bei-Ge Jiang,1 Ze-Ya Pan1 1The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 201805, People’s Republic of China; 2Department of Medical Oncology, Shanghai Mengchao Cancer Hospital, Shanghai, 201805, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ze-Ya Pan; Bei-Ge Jiang No. 700, MoYu North Road, Jiading, Shanghai, People’s Republic of ChinaTel +86-13391236437; +86-13764561303Email hjluffy@126.com; jiang_beige@aliyun.comPurpose: To predict patient survival in early-stage hepatocellular carcinoma (HCC) following hepatic resection. We evaluated the prognostic potential of the aspartate aminotransferase to platelet ratio index (APRI) in order to use it to model a nomogram.Patients and Methods: We randomized 901 early-stage HCC patients treated with hepatic resection at our center into training and validation cohorts that were followed from January 2009 to December 2012. X-tile software was used to establish the APRI cut-off threshold in the training cohort. The validation cohort was subsequently assessed to determine threshold value accuracy. Data generated from the multivariate analysis in the training cohort were used to design a prognostic nomogram. Decision curve analyses (DCA), concordance index values (C-index) and calibration curves were used to determine the performance of the nomogram.Results: X-tile software revealed that the optimal APRI cut-off threshold in the training cohort that distinguished between patients with different prognoses was 0.9. We, therefore, validated its prognostic value. Multivariate analyses showed that poor overall survival was associated with APRI above 0.9, blood loss of more than 400 mL, liver cirrhosis, multiple tumors, tumor size greater than 5 cm, microvascular invasion and satellite lesions. When the independent risk factors were integrated into the prognostic nomogram, it performed well with accurate predictions. Indeed, the performance was better than comparative prognosticators (P< 0.05 for all) with 0.752 as the C-index (95% CI: 0.706– 0.798). These results were verified by the validation cohort.Conclusion: APRI was a noninvasive and accurate predictive indicator for patients with early-stage HCC. Following hepatic resection to treat early-stage HCC, individualized patient survival predictions can be aided by the nomogram based on APRI.Keywords: hepatocellular carcinoma, hepatic resection, survival, nomogram, aspartate aminotransferase to platelet ratio index, APRI

Mitochondrial disorders are a group of heterogeneous diseases characterized by biochemical disturbances in oxidative phosphorylation (OXPHOS). Mutations in mitochondrial transfer RNA (mt-tRNA) genes are the most frequently in mitochondrial disease. However, few studies have detailed the molecular mechanisms behind these mutations.We performed clinical evaluation, genetic analysis, muscle histochemistry, and molecular and biochemical investigations in muscle tissue and proband-derived cybrid cell lines.We found a mitochondrial tRNAOur findings offer valuable new insights into the tRNA

The mitochondrial tRNA

Distal myopathies are a group of clinically and genetically heterogeneous hereditary muscle disorders characterized by progressive muscular weakness starting in the distal parts of the limbs. The most common subtype of distal myopathy is GNE myopathy, a rare muscle disease with autosomal recessive inheritance. Limb-girdle muscular dystrophy 2G (LGMD2G) is a rare autosomal recessive subtype of LGMDs caused by TCAP variant. Patients with LGMD2G can present with distal myopathy and rimmed vacuoles on muscle pathology. Thus far, the most reported TCAP mutations related to LGMD2G were recessive frameshift or nonsense variants. Here, we described four Chinese patients from unrelated families with LGMD2G due to TCAP mutations. The clinical symptoms of our patients were similar to those previously reported in LGMD2G patients. Three different pathogenic TCAP variants were identified in these patients, including two frameshift variants and one intronic variant. Autophagolysosomes have been observed in one patient by electron microscopy. Our research expands the genetic spectrum of TCAP mutations in China, indicating c.165-166insG is likely the common pathogenic variant. We also provide evidences that autophagy may be involved in the pathophysiology of LGMD2G.

Potassium channel Kv2.1 regulates potassium current in cortical neurons and potassium efflux is necessary for cell apoptosis. As a major component of delayed rectifier current potassium channels, Kv2.1 forms clusters in the membrane of hippocampal neurons. BACE2 is an aspartyl protease to cleave APP to prevent the generation of Aβ, a central component of neuritic plaques in Alzheimer's brain. We now identified Kv2.1 as a novel substrate of BACE2. We found that BACE2 cleaved Kv2.1 at Thr376, Ala717, and Ser769 sites and disrupted Kv2.1 clustering on cell membrane, resulting in decreased Ik of Kv2.1 and a hyperpolarizing shift in primary neurons. Furthermore, we discovered that the BACE2-cleaved Kv2.1 forms, Kv2.1-1-375, Kv2.1-1-716, and Kv2.1-1-768, depressed the delayed rectifier Ik surge and reduced neuronal apoptosis. Our study suggests that BACE2 plays a neuroprotective role by cleavage of Kv2.1 to prevent the outward potassium currents, a potential new target for Alzheimer's treatment.

To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type–specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease., Data was generated as part of the PsychENCODE Consortium, supported by MH103339, MH106934, and MH110926. Additional support was provided by NIH grants MH109904, MH106874, AG048918, DK111178, and NS092988 (National Chimpanzee Brain Resource), the Kavli Foundation, the James S. McDonnell Foundation, NSF grant BCS-1316829, MINECO BFU2014-55090-P (FEDER), Howard Hughes International Early Career, and Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya.

// Fuchen Liu 1, 2, * , Guangyong Wang 3, * , Xiaoqiang Wang 4, * , Zhihui Che 2 , Wei Dong 1 , Xinggang Guo 1 , Zhenguang Wang 1 , Ping Chen 2 , Daisen Hou 2 , Qi Zhang 2 , Wenli Zhang 2 , Yida Pan 2 , Dongqin Yang 2 , Hui Liu 1 1 The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China 2 Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China 3 Department of Gastroenterology, 411 Hospital of PLA, Shanghai 200081, China 4 Department of Neurosurgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China * These authors contributed equally to this work Correspondence to: Dongqin Yang, email: kobesakura@163.com Hui Liu, email: liuhuigg@hotmail.com Keywords: Aurora A/B kinases, SNS-314, HCC, YAP, P21 Received: November 18, 2016 Accepted: February 20, 2017 Published: March 02, 2017 ABSTRACT The Aurora kinases A and B control tumorigenesis by inhibiting apoptosis and promoting proliferation and metastasis, however, it remains unknown whether Aurora A and B overexpressed concomitantly and its clinical significance in hepatocellular carcinoma (HCC). Here, we obsearved Aurora A and B tended to overexpress parallelly on protein level ( r = 0.8679, P 4N) formation and apoptosis in HCC. High YAP expression (YAP H ) was associated with Aurora A H B H , and appeared to be an independent predictor for survival, but P21 not. Moreover, silencing YAP also induced P21 accumulation, and knockdown P21, which enhanced YAP accumulation and weakened the SNS-314-induced YAP reduction, impaired SNS-314-induced apoptosis. Therefore, P21 enhanced the apoptotic effect of SNS-314 in HCC. Taken together, our findings indicated Aurora kinases/YAP/P21 was an oncogenic signaling axis in HCC, and revealed targeting Aurora A H B H induced apoptosis by YAP suppression. Our results also provided a solid evidence for SNS-314 as a potential targeted therapy, and a proof-of-concept evidence for a possible combined therapy of SNS-314 plus Hippo pathway inhibitors on HCC.

Pioneering studies have shown that individual correlation measures from resting‐state functional magnetic resonance imaging studies can identify another scan from that same individual. This method is known as “connectotyping” or functional connectome “fingerprinting.” We analyzed a unique dataset of 12–30 years old (N = 140) individuals who had two distinct resting state scans on the same day and again 12–18 months later to assess the sensitivity and specificity of fingerprinting accuracy across different time scales (same day, ~1.5 years apart) and developmental periods (youths, adults). Sensitivity and specificity to identify one's own scan was high (average AUC = 0.94), although it was significantly higher in the same day (average AUC = 0.97) than 1.5‐years later (average AUC = 0.91). Accuracy in youths (average AUC = 0.93) was not significantly different from adults (average AUC = 0.96). Multiple statistical methods revealed select connections from the Frontoparietal, Default, and Dorsal Attention networks enhanced the ability to identify an individual. Identification of these features generalized across datasets and improved fingerprinting accuracy in a longitudinal replication data set (N = 208). These results provide a framework for understanding the sensitivity and specificity of fingerprinting accuracy in adolescents and adults at multiple time scales. Importantly, distinct features of one's “fingerprint” contribute to one's uniqueness, suggesting that cognitive and default networks play a primary role in the individualization of one's connectome., The ability to accurately identify an individual's resting state scan is similar in youths and adults. Identification accuracy of resting‐state functional magnetic resonance scans in both youths and adults is more accurate when scans are closer together in time. Predictive edges generalize across data sets and methods, providing a sparse feature set for identifying individual scans.

Pathogenic point mutations of mitochondrial DNA (mtDNA) are associated with a large number of heterogeneous diseases involving multiple systems with which patients may present with a wide range of clinical phenotypes. In this study, we describe a novel heteroplasmic missense mutation, m.11406T>A, of the ND4 gene encoding the subunit 4 of mitochondrial complex I in a 32-year-old woman with recurrent epileptic seizure, headache and bilateral hearing loss. Skeletal muscle histochemistry demonstrated that approximately 20% of fibers were cytochrome C oxidase (COX) deficient with increased activity of succinate dehydrogenase (SDH). Further investigations in muscle specimens showed significantly reduced level of ND4 protein. It is interesting that the subunits of complex I (ND1 and NDFUB8) and complex IV(CO1) were also remarkably decreased. These findings indicate that ND1, NDFUB8 and CO1 are more susceptible than other subunits to mutations in the mitochondrial ND4 gene.

Background: There is no information whether gender-associated prognostic factor disparity exists in patients with intrahepatic cholangiocarcinoma (ICC). Methods: A total of 732 ICC patients with pathological confirmation who underwent surgical resection between Nov 2011 and Apr 2015 was studied. Detection of prognostic factors was respectively performed for male and female patients using the Cox model. Gender-dependent nomograms were generated for survival prediction. Predictive performance was validated by receiver operating curves with area under curve (AUC) and calibration curves. Spearman’s rank correlation test was performed to identify gender-associated demographic and clinical factors. Results: There were 469 (64.1%) male and 263 (35.9%) female patients with ICC. Males achieved more favorable prognosis compared to females (overall survival; hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.02-1.48; P = 0.032; recurrence-free survival; HR, 1.12; 95% CI, 0.94-1.33; P = 0.197). Survival prediction was validated to be excellent for both genders (AUC, 0.71 and 0.68). Nomograms-stratified high risk showed a HR of 2.06 (P < 0.001) and 2.08 (P = 0.006) for male and female, respectively. Male showed nearest correlation with smoking, alpha fetoprotein, hepatitis B virus infection, and liver cirrhosis, whereas serum platelet count, tumor size, carbohydrate antigen (CA) 242, CA19-9, CA125, lymph node metastasis, and carcinoembryonic antigen were mostly correlated with female. Conclusions: There is a gender-associated disparity in prognostic factors for ICC after resection. Gender-dependent respective survival prediction seems to improve predictive accuracy. Large-scale prospective studies are needed to evaluate impact of gender on outcomes of other treatment modalities. Funding Statement: This work was supported by the National Natural Science Foundation of China (81772529, 81970453), the State Key Project of China (2017YFA0504503), International Science and Technology Cooperation Program of the Ministry of Science and Technology (2011DFA32980), National Key Basic Research Program of China 973 Program (2012CB526706). Declaration of Interests: The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Ethics Approval Statement: This study was approved by the local ethics committee and informed consents were obtained from all patients.

Tight oil reservoirs need stimulation in order to produce the trapped oil. The most common form of stimulation used by the oil and gas industry is hydraulic fracturing. Fracturing operations tend to create fractures including primary fractures and microfractures. The objective of this study is to develop a fracturing fluid which can be converted into microproppant, beads, and channelized-proppant as desired in-situ during a fracturing operation to enhance the hydraulic conductivity of the microfractures and the primary fractures, and simplify the hydraulic fracturing operation, where the channelized-proppant is defined as the pillars surrounded by channels. Resin, curing agents, surfactants, and aqueous phase were mixed together to form O/W emulsion to serve as fracturing fluid. After curing process, resin and curing agent would react and form proppant in-situ. The parameters affect the proppant formation such as the curing temperatures, pressure, mixing strength, surfactant concentration, and size control additives were all studied and thus through controlling the parameters, microproppant, beads, and channelized-proppant can form in-situ as desired. The particle size distribution, sphericity, roundness, conductivity, acid solubility, and crush strength were tested. Through controlling the experimental parameters and adding size control additives, fracturing fluid can be converted into microproppant, beads, and channelized-proppant as desired at a temperature from 30° C to 90° C. Almost 100% of the resin and the curing agents were converted into proppant with a specific density of 1.09g/ml. For the beads, both the sphericity and roundness are over 0.9, less than 2% fines were generated after being loaded to 15 kpsi, the acid solubility is 2.37%, and the conductivity of the beads of 20/40 mesh tested with proppant loading of 1 lb/ft2 at 4000 psi at room temperature was 227 mD-ft. For the microproppant, both the sphericity and roundness are close to 1 with d50 about 80 µm. Furthermore, channelized-proppant was formed in an artificial fracture with walls made of glass sheets. Thus, with the fracturing fluid developed, the conductivity of the well can be maximally optimized through the in-situ formation of channelized proppant and microproppant to keep the primary fractures and microfractures open respectively.

The commonly used cross-correlation time delay estimation method in three-point ranging does not perform well under the condition of low SNR, this article proposes an improved method for three point ranging, which try to combined generalized cross-correlation with second correlation delay estimation method and modify the time delay estimation flow path of three point ranging. Compared with the conventional three-point ranging algorithm, the new method combines the advantages of those two methods and has more steps in time delay estimation flow path. First, the three signals are pre-filtered. Next, a second correlation process is designed between the three signals to obtain two cross-correlation functions. Finally, cross-correlation is performed between the two cross-correlation functions and a final time delay is produced. With the time delay, the distance can be measured by the three-point ranging principle. Repeated simulation experiments show that the improved method has higher ranging accuracy under low SNR conditions than the traditional method.

BackgroundResting-state functional neuroimaging captures large-scale network organization; whether this organization is intact or disrupted during adolescent development across the psychosis spectrum is unresolved. We investigated the integrity of network organization in psychosis spectrum youth and those with first episode psychosis (FEP) from late childhood through adulthood.MethodsWe analyzed data from Philadelphia Neurodevelopmental Cohort (PNC; typically developing = 450, psychosis spectrum = 273, 8–22 years), a longitudinal cohort of typically developing youth (LUNA; N = 208, 1–3 visits, 10–25 years), and a sample of FEP (N = 39) and matched controls (N = 34). We extracted individual time series and calculated correlations from brain regions and averaged them for 4 age groups: late childhood, early adolescence, late adolescence, adulthood. Using multiple analytic approaches, we assessed network stability across 4 age groups, compared stability between controls and psychosis spectrum youth, and compared group-level network organization of FEP to controls. We explored whether variability in cognition or clinical symptomatology was related to network organization.ResultsNetwork organization was stable across the 4 age groups in the PNC and LUNA typically developing youth and PNC psychosis spectrum youth. Psychosis spectrum and typically developing youth had similar functional network organization during all age ranges. Network organization was intact in PNC youth who met full criteria for psychosis and in FEP. Variability in cognitive functioning or clinical symptomatology was not related to network organization in psychosis spectrum youth or FEP.DiscussionThese findings provide rigorous evidence supporting intact functional network organization in psychosis risk and psychosis from late childhood through adulthood.

The following will illustrate how laws and public concerns can serve as a framework for oil and gas exploration, drilling, and production. It will outline several case histories and how different laws and motivations intersect and shape the industry. This is a comprehensive analysis of laws governing a particular region's actions and examined on a federal, state and, in some cases, local level. Other factors, including public image and community feedback are evaluated, too. Three case histories are explored. These are presented via a timeline of events leading up to an implementation, reevaluation, and/or development of legislation and/or legal decision. Other legislation is assessed on how an Act (e.g. Clean Air, Clean Water) is initiated apart from the oil and gas realm and then eventually adopted to address certain public concerns. In most cases, regulations were already set in place and oil and gas entities had to interpret accordingly and work within determined protocols. In some cases, incidents occurred that, in turn, created new legislation and/or set expectations that had implications for how the industry would execute future projects. Incidents include a case of negligence and how the specific company responded as well as other operators located in the immediate vicinity. The regulations and/or best management practices that were created because of the incident will also be discussed. Other cases illustrate the cultural norms surrounding a particular set of legislation. An operator may be familiar with one area yet when branching out to other locations, conclude that the new area is not financially feasible for them due to the different technology and documentation required. Bigger and/or local operators have made these ventures profitable. A comprehensive report on regulations and how operators execute them will also be provided. Impacts and effects on the oil and gas entities as well as the social and natural communities are assessed, illustrating the important connection between the residential/individual communities and the business entities via the government bodies to hear both sides and appropriately represent the cases at hand.

Background Precise prediction of survival after treatment is of great importance for patients with diseases with high mortality. RNA sequencing data and deep learning (DL) methods are expected to become promising approaches in the development of prediction models in the future. We aimed to evaluate the optimal covariates and methodology for patients with hepatocellular carcinoma (HCC) undergoing surgical resection. Methods The Cox proportional hazards regression model and the DL approach were used to develop prediction models incorporating clinical, genetic, and combined clinical and genetic variables for survival prediction in patients with HCC after resection. A total of 1,114 patients and 184 patients were enrolled in the present study from 2,163 and 601 patients from Eastern Hepatobiliary Surgery Hospital and Renji Hospital, respectively. The models were internally validated through random sampling and externally validated in clinical cohorts. Between-model comparisons were carried out in terms of the integrated discrimination improvement and net reclassification index. Results The Cox and DL clinical models were developed by adopting 7 independent prognostic factors (total bilirubin, prothrombin time, tumor size, tumor number, lymph node metastasis, and vascular invasion) and 22 clinical factors, respectively. Both the Cox clinical model and the DL clinical model showed excellent performances in the derivation [area under the curve (AUC): 0.75 vs. 0.77] and validation (AUC: 0.83 vs. 0.80) sets. The derived Cox genetic model with 6 significant prognostic genes was not as effective as the DL approach involving 686 genes. A combined clinical and genetic approach modified the performances of both the Cox and DL models. The integrated discrimination improvement and net reclassification index of the DL clinical model were generally better than those of the Cox clinical model. Conclusions Our Cox clinical model sufficiently provided precise survival prediction in patients with HCC after resection. It may serve as an accurate and cost-effective tool for predicting survival in such patients.

// Mingming Zhang 1 , Yida Pan 1 , Robert G. Dorfman 3 , Zhaogui Chen 4 , Fuchen Liu 5 , Qian Zhou 6 , Shan Huang 7 , Jun Zhang 1 , Dongqin Yang 1 , Jie Liu 1, 2 1 Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China 2 Collaborative Innovation Center of Genetics and Development, Institutes of Biomedical Sciences and Department of Immunology, Shanghai Medical School, Fudan University, Shanghai, China 3 Northwestern University Feinberg School of Medicine, Chicago, IL, USA 4 Department of Gastroenterology, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China 5 Department of Hepatobiliary Surgery, The Eastern Hepatobiliary Surgery Hospital of Second Military Medical University, Shanghai, China 6 School of Life Sciences, Fudan University, Shanghai, China 7 Department of Pathology, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, China Correspondence to: Dongqin Yang, e-mail: kobesakura@163.com Jie Liu, e-mail: jieliu@fudan.edu.cn Keywords: AR-42, apoptosis, hepatocellular carcinoma, HDAC5, prognosis Received: May 11, 2015 Accepted: February 23, 2016 Published: March 14, 2016 ABSTRACT Histone deacetylases (HDACs) play critical roles in apoptosis and contribute to the proliferation of cancer cells. AR-42 is a novel Class I and II HDAC inhibitor that shows cytotoxicity against various human cancer cell lines. The present study aims to identify the target of AR-42 in hepatocellular carcinoma (HCC) as well as evaluate its therapeutic efficacy. We found that HDAC5 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. CCK8 and colony-formation assays showed that HDAC5 overexpression promotes proliferation in HCC cell lines. Treatment with AR-42 decreased HCC cell growth and increased caspase-dependent apoptosis, and this was rescued by HDAC5 overexpression. We demonstrated that AR-42 can inhibit the deacetylation activity of HDAC5 and its downstream targets in vitro and in vivo . Taken together, these results demonstrate for the first time that AR-42 targets HDAC5 and induces apoptosis in human hepatocellular carcinoma cells. AR-42 therefore shows potential as a new drug candidate for HCC therapy.

INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).

A target's radial velocity estimation technique with single receiver in shallow water is proposed. Based on normal mode theory, the periodic oscillation characteristics of cross-correlated pressure field at two separated ranges are analyzed. The interference period of the cross-correlated field contains information of radial source velocity, which can be obtained by Fourier transform for broadband continuous spectrum signals. Aiming at multiple line spectrum signals, compressive sensing is applied to extract the interference period of the cross-correlated field and estimate the radial source velocity. The Basis Pursuit De-Noising(BPDN) algorithm is used in simulation and sea trial data processing. The results show that the proposed algorithm can achieve radial source velocity effectively, it does not require any knowledge of the waveguide environment and is suitable for uniform and variable speed moving target.

Mitochondrial defects have been associated with a series of muscular diseases. Dysferlinopathy, however, has been rarely reported with mitochondrial dysfunction. Here we report a cohort of dysferlinopathy patients with mitochondrial abnormalities found in muscle.Clinical data and muscle pathologies of nine cases with dysferlinopathy were retrospectively studied. mtDNA copy number, protein levels and activities of mitochondrial enzyme complexes were assayed.Nine patients were diagnosed as having dysferlinopathy by DYSF sequencing and quantification of dysferlin levels in muscle homogenates. Muscle biopsies exhibited dystrophic changes (n = 9), ragged-red fibers (n = 9) and cytochrome c oxidase-deficient fibers (n = 9). mtDNA copy number increased significantly in 56% (15/27) of fibers with mitochondrial histology. Protein levels of complex IV subunits II (n = 5), complex III subunit core 2 (n = 2) and complex I NDUFB1 (n = 1) decreased. Impaired activities of complexes I, III and IV were observed in 56%, 33% and 78% of subjects and the activities were reduced by 21%, 18% and 40%, respectively. Besides, loss activities of complexes I/IV and decreased ATP level were also found in fibroblasts from dysferlinopathy.Prominent mitochondrial abnormalities are common pathological findings in muscle from dysferlinopathy. Our data indicated that mitochondria may play a significant role in the progression of dysferlinopathy and also highlighted the potential of mitochondrial protective drugs in rescuing the symptoms of dysferlinopathy.

Adenosine, a metabolite of ATP, ubiquitously exists in a wide range of organs and tissues. We previously reported that adenosine was implicated in apoptosis in many cancer cells by extrinsic and/or intrinsic pathways. Here, we found that adenosine suppresses the cell growth by induction of apoptosis of human colonic cancer cells through a novel mechanism. Adenosine suppresses the cell growth of human SW620 and SW480 colon cells in an adenosine transporter and adenosine kinase dependent manner. Moreover, the cell growth suppression is induced by apoptosis through activation of caspase-3 and PARP, and accumulation of ROS in cells. Importantly, we found that adenosine increases the expression of TNFR1 and RIPK1 and the phosphorylation of p38. Knockdown of TNFR1 or RIPK1 impairs the activation of p38, blocks the cleavage of PARP, and provides partially, yet significantly protection from cell death, including reducing the ROS generation in the colon cancer cells. These results indicate that a TNFR1/RIPK1/P38 axis is present in adenosine-induced apoptosis of colonic cancer cells. This axis triggers apoptosis and plays crucial roles in relay of the death signaling. Our study also provides additional experimental evidence for adenosine as a potent therapeutic drug in cancer therapy.

Community detection is challenging when the network structure is estimated with uncertainty. Dynamic networks present additional challenges but also add information across time periods. We propose a global community detection method, persistent communities by eigenvector smoothing (PisCES), that combines information across a series of networks, longitudinally, to strengthen the inference for each period. Our method is derived from evolutionary spectral clustering and degree correction methods. Data-driven solutions to the problem of tuning parameter selection are provided. In simulations we find that PisCES performs better than competing methods designed for a low signal-to-noise ratio. Recently obtained gene expression data from rhesus monkey brains provide samples from finely partitioned brain regions over a broad time span including pre- and postnatal periods. Of interest is how gene communities develop over space and time; however, once the data are divided into homogeneous spatial and temporal periods, sample sizes are very small, making inference quite challenging. Applying PisCES to medial prefrontal cortex in monkey rhesus brains from near conception to adulthood reveals dense communities that persist, merge, and diverge over time and others that are loosely organized and short lived, illustrating how dynamic community detection can yield interesting insights into processes such as brain development.

Aberrant expression of Ras homolog enriched in brain (RHEB) has been observed in a variety of cancer tissues and is closely associated with clinicopathological features. However, the expression profile of RHEB in patients with hepatocellular carcinoma (HCC) and its clinical signature with underlying mechanisms have not been explored thus far. To analyze the association between RHEB expression and clinicopathological features, the RHEB expression levels were determined in the present study using gene microarrays, immunohistochemistry and western blotting in 60 liver cancer tissues and 35 normal liver tissues. Downregulation of RHEB expression in liver cancer cell lines was achieved by RNA interfering technology to explore its biological function in HCC. RHEB expression was high in liver cancer tissues, with an increase of 2.00±0.19-fold compared with normal tissues and of 2.00±0.27-fold compared with adjacent non-cancer tissues. RHEB expression increased along with the clinical staging of HCC, and the overall survival and mortality of patients were closely correlated to RHEB levels, micro-vascular invasion, hepatitis B virus-DNA titer, tumor differentiation and pathological satellites (P

Dynamical contrast enhanced (DCE) imaging allows non invasive access to tissue micro-vascularization. It appears as a promising tool to build imaging biomark-ers for diagnostic, prognosis or anti-angiogenesis treatment monitoring of cancer. However, quantitative analysis of DCE image sequences suffers from low signal to noise ratio (SNR). SNR may be improved by averaging functional information in a large region of interest when it is functionally homogeneous. We propose a novel method for automatic segmentation of DCE image sequences into functionally homogeneous regions, called DCE-HiSET. Using an observation model which depends on one parameter a and is justified a posteri-ori, DCE-HiSET is a hierarchical clustering algorithm. It uses the p-value of a multiple equivalence test as dissimilarity measure and consists of two steps. The first exploits the spatial neighborhood structure to reduce complexity and takes advantage of the regularity of anatomical features, while the second recovers (spatially) disconnected homogeneous structures at a larger (global) scale. Given a minimal expected homogeneity discrepancy for the multiple equivalence test, both steps stop automatically by controlling the Type I error. This provides an adaptive choice for the number of clusters. Assuming that the DCE image sequence is functionally piecewise constant with signals on each piece sufficiently separated, we prove that DCE-HiSET will retrieve the exact partition with high probability as soon as the number of images in the sequence is large enough. The minimal expected homogeneity discrepancy appears as the tuning parameter controlling the size of the segmentation. DCE-HiSET has been implemented in C++ for 2D and 3D image sequences with competitive speed. Keywords : DCE imaging, automatic clustering, hierarchical segmentation, equivalence test, Comment: 58 pages

Summary Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene’s contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.

In the part of geophysics researches, the method Double Beam Forming (DBF) was found for separating the surface waves from the seismic waves. According to one of the kernels of DBF : extraction of group velocity and phase velocity, this paper benefit from this idea and concentrate on the time delay estimation (TDE) which is one of the key techniques in the array signal processing. The sound velocity is one of the major factor of the TDE, and the DBF image which is built with delay and slowness makes it possible to find the relationship: how the velocity touch the delay. Based on a linear array which is separated into two sub-arrays, the method DBF is applied to simulate data with other two approaches combined: generated cross-correlation (GCC) and generated cross-correlation with phase transform (GCC-PHAT). Thus the research focuses on the sensibility of this factor to TDE, by controlling variables: distance of source, sample frequency, the frequency band. By comparing results of all the cases, we obtain the action of this factor for TDE and analyze the effects in different simulations.

Underwater target discrimination plays an important role in military defense and attack, this paper proceeds with the acoustic field wavenumber spectrum difference excitateded by the surface target and underwater target, a method of passive target classification based on mode energy difference characteristic of the wavenumber spectrum is proposed. Firstly, according to wavenumber integration acoustic theory, an approach to sound field wavenumber spectrum acquisition method by horizontal arrays is introduced. Secondly, combined with ray acoustic model and normal mode acoustic model, the difference character of acoustic spectrum between surface target and underwater target is quantitative analyzed, the wavenumber spectrum energy difference character which can distinguish surface target and underwater target is excavated, its acoustic physical nature character is the energy ratio between low-rank and high-rank normal mode in wavenumber spectrum. At last, a method of passive target classification based on mode energy difference characteristic in the wavenumber spectrum is proposed; several numerical simulations of typical conditions are tested. The simulation result shows that, by extracting the mode energy difference characteristic to discriminate the surface target and underwater target is valid, and this method is robust with various environments. The method proposed by this paper may provide a novel way to the problem of underwater targets classification and recognition.

As the complexity of the ocean environment, shape of towed array changes with time and space, so the accurate measurement shape of towed array is the key to improve the performance of signal processing. To solve this problem this paper proposes an estimation method based on genetic algorithm, firstly, established the objective function according to a known distance and azimuth of the target by beam forming, then use genetic algorithm to optimize objective function and obtain the maximum power of output beam forming parameters, finally compare detection effect of the estimated array shape with linear array. Through numerical simulation, we can see the estimation of array shape relative to linear array can significantly improve the detection effect.

Objective Riboflavin-responsive multiple acyl-coenzyme A dehydrogenation deficiency (RR-MADD) is an inherited fatty acid metabolism disorder mainly caused by genetic defects in electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). The variant ETF:QO protein folding deficiency, which can be corrected by therapeutic dosage of riboflavin supplement, has been identified in HEK-293 cells and is believed to be the molecular mechanism of this disease. To verify this hypothesis in vivo, we generated Etfdh (h)A84T knockin (KI) mice. Methods Tissues from these mice as well as muscle biopsies and fibroblasts from 7 RR-MADD patients were used to examine the flavin adenine dinucleotide (FAD) concentration and ETF:QO protein amount. Results All of the homozygous KI mice (Etfdh (h)A84T/(h)A84T , KI/KI) were initially normal. After being given a high-fat and vitamin B2 -deficient (HF-B2 D) diet for 5 weeks, they developed weight loss, movement ability defects, lipid storage in muscle and liver, and elevated serum acyl-carnitine levels, which are clinically and biochemically similar to RR-MADD patients. Both ETF:QO protein and FAD concentrations were significantly decreased in tissues of HF-B2 D-KI/KI mice and in cultured fibroblasts from RR-MADD patients. After riboflavin treatment, ETF:QO protein increased in proportion to elevated FAD concentrations, but not related to mRNA levels. These results were further confirmed in cultured fibroblasts from RR-MADD patients. Interpretation For the first time, we successfully developed a RR-MADD mice model and confirmed that FAD homeostasis disturbances played a crucial role on the pathomechanism of RR-MADD in this mouse model and culture cells from patients. Supplementation of riboflavin may stabilize variant ETF:QO protein by rebuilding FAD homeostasis. Ann Neurol 2018;84:667-681.

The disappearance of fine motor control Manual skills are much better developed in primates than in rodents. This difference is in part due to species-specific differences in the control of motoneurons by the brain. Gu et al. used a range of approaches to evaluate potential corticospinal tract projections in neonatal mice. These projections exist immediately after birth but disappear within the first 2 postnatal weeks owing to the actions of plexin A, a member of the semaphorin receptor family. Targeted deletion of semaphorin receptors in mutant mice prevented elimination of corticospinal tract projection and loss of functional monosynaptic input to spinal motoneurons. Science , this issue p. 400