Giant Deformation Induced Staggered-Layer Structure Promoting the Thermoelectric and Mechanical Performance in n-Type Bi2(Te, Se)3.

Bismuth telluride has long been recognized as the most promising near-room temperature thermoelectric material for commercial application; however, the thermoelectric performance for n-type Bi2(Te, Se)3-based alloys is far lagging behind that of its p-type counterpart. In this work, a giant hot deformation (GD) process is implemented in an optimized Bi2Te2.694Se0.3I0.006+3 wt%K2Bi8Se13 precursor and generates a unique staggered-layer structure. The staggered-layered structure, which is only observed in severely deformed crystals, exhibits a preferential scattering on heat-carrying phonons rather than charge-carrying electrons, thus resulting in an ultralow lattice thermal conductivity while retaining high-weight carrier mobility. Moreover, the staggered-layer structure is located adjacent to the van der Waals gap in Bi2(Te, Se)3 lattice and is able to strengthen the interaction between anion layers across the gap, leading to obviously improved compressive strength and Vickers hardness. Consequently, a high peak figure of merit ZT of ≈ 1.3 at 423 K, and an average ZT of ≈ 1.2 at 300-473 K can be achieved in GD sample. This study demonstrates that the GD process can successfully decouple the electrical and thermal transports with simultaneously enhanced mechanic performance.

The involvement of Neuregulin-1 in the process of facial nerve injury repair through the utilization of dental pulp stem cells.

BACKGROUND: Facial nerve injury often results in poor prognosis due to the challenging process of nerve regeneration. Neuregulin-1, a human calmodulin, is under investigation in this study for its impact on the reparative capabilities of Dental Pulp Stem Cells (DPSCs) in facial nerve injury. METHODS: Lentivirus was used to transfect and construct Neuregulin-1 overexpressed DPSCs. Various techniques assessed the effects of Neuregulin-1: osteogenic induction, lipid induction, Reverse Transcription Polymerase Chain Reaction, Western Blot, Cell Counting Kit-8 assay, wound healing, immunofluorescence, Phalloidin staining, nerve stem action potential, Hematoxylin-eosin staining, transmission electron microscopy, and immunohistochemistry. RESULTS: Neuregulin-1 effectively enhanced the proliferation, migration, and cytoskeletal rearrangement of DPSCs, while simultaneously suppressing the expression of Ras homolog gene family member A (RhoA) and Microfilament actin (F-actin). These changes facilitated the neural differentiation of DPSCs. Additionally, in vivo experiments showed that Neuregulin-1 expedited the restoration of action potential in the facial nerve trunk, increased the thickness of the myelin sheath, and stimulated axon regeneration. CONCLUSION: Neuregulin-1 has the capability to facilitate the repair of facial nerve injuries by promoting the regenerative capacity of DPSCs. Thus, Neuregulin-1 is a significant potential gene in the reparative processes of nerve damage.

Identification of critical mitochondrial hub gene for facial nerve regeneration.

Mitochondria play a critical role in nerve regeneration, yet the impact of gene expression changes related to mitochondria in facial nerve regeneration remains unknown. To address this knowledge gap, we analyzed the expression profile of the facial motor nucleus (FMN) using data obtained from the Gene Expression Omnibus (GEO) database (GSE162977). By comparing different time points in the data, we identified differentially expressed genes (DEGs). Additionally, we collected mitochondria-related genes from the Gene Ontology (GO) database and intersected them with the DEGs, resulting in the identification of mitochondria-related DEGs (MIT-DEGs). To gain further insights, we performed functional enrichment and pathway analysis of the MIT-DEGs. To explore the interactions among these MIT-DEGs, we constructed a protein-protein interaction (PPI) network using the STRING database and identified hub genes using the Degree algorithm of Cytoscape software. To validate the relevance of these genes to nerve regeneration, we established a rat facial nerve injury (FNI) model and conducted a series of experiments. Through these experiments, we confirmed three MIT-DEGs (Myc, Lyn, and Cdk1) associated with facial nerve regeneration. Our findings provide valuable insights into the transcriptional changes of mitochondria-related genes in the FMN following FNI, which can contribute to the development of new treatment strategies for FNI.

Milletdb: a multi-omics database to accelerate the research of functional genomics and molecular breeding of millets.

Millets are a class of nutrient-rich coarse cereals with high resistance to abiotic stress; thus, they guarantee food security for people living in areas with extreme climatic conditions and provide stress-related genetic resources for other crops. However, no platform is available to provide a comprehensive and systematic multi-omics analysis for millets, which seriously hinders the mining of stress-related genes and the molecular breeding of millets. Here, a free, web-accessible, user-friendly millets multi-omics database platform (Milletdb, http://milletdb.novogene.com) has been developed. The Milletdb contains six millets and their one related species genomes, graph-based pan-genomics of pearl millet, and stress-related multi-omics data, which enable Milletdb to be the most complete millets multi-omics database available. We stored GWAS (genome-wide association study) results of 20 yield-related trait data obtained under three environmental conditions [field (no stress), early drought and late drought] for 2 years in the database, allowing users to identify stress-related genes that support yield improvement. Milletdb can simplify the functional genomics analysis of millets by providing users with 20 different tools (e.g., 'Gene mapping', 'Co-expression', 'KEGG/GO Enrichment' analysis, etc.). On the Milletdb platform, a gene PMA1G03779.1 was identified through 'GWAS', which has the potential to modulate yield and respond to different environmental stresses. Using the tools provided by Milletdb, we found that the stress-related PLATZs TFs (transcription factors) family expands in 87.5% of millet accessions and contributes to vegetative growth and abiotic stress responses. Milletdb can effectively serve researchers in the mining of key genes, genome editing and molecular breeding of millets.

The First Crested Duck Genome Reveals Clues to Genetic Compensation and Crest Cushion Formation.

The Chinese crested (CC) duck is a unique indigenous waterfowl breed, which has a crest cushion that affects its survival rate. Therefore, the CC duck is an ideal model to investigate the genetic compensation response to maintain genetic stability. In the present study, we first generated a chromosome-level genome of CC ducks. Comparative genomics revealed that genes related to tissue repair, immune function, and tumors were under strong positive selection, indicating that these adaptive changes might enhance cancer resistance and immune response to maintain the genetic stability of CC ducks. We also assembled a Chinese spot-billed (Csp-b) duck genome, and detected the structural variations (SVs) in the genome assemblies of three ducks (i.e., CC duck, Csp-b duck, and Peking duck). Functional analysis revealed that several SVs were related to the immune system of CC ducks, further strongly suggesting that genetic compensation in the anti-tumor and immune systems supports the survival of CC ducks. Moreover, we confirmed that the CC duck originated from the mallard ducks. Finally, we revealed the physiological and genetic basis of crest traits and identified a causative mutation in TAS2R40 that leads to crest formation. Overall, the findings of this study provide new insights into the role of genetic compensation in adaptive evolution.

VEGFA-modified DPSCs combined with LC-YE-PLGA NGCs promote facial nerve injury repair in rats.

Objective: The aim of this research was to investigate the effect of vascular endothelial growth factor A (VEGFA)-overexpressing rat dental pulp stem cells (rDPSCs) combined with laminin-coated and yarn-encapsulated poly(l-lactide-co-glycolide) (PLGA) nerve guidance conduit (LC-YE-PLGA NGC) in repairing 10 mm facial nerve injury in rats. Study Design: rDPSCs isolated from rat mandibular central incisor were cultured and identified in vitro and further transfected with the lentiviral vectors (Lv-VEGFA). To investigate the role and mechanisms of VEGFA in neurogenic differentiation in vitro, semaxanib (SU5416), Cell Counting Kit-8 (CCK-8), real-time quantitative polymerase chain reaction (qPCR) and Western blotting were performed. Ten-millimeter facial nerve defect models in rats were established and bridged by LC-YE-PLGA NGCs. The repair effects were detected by transmission electron microscopy (TEM), compound muscle action potential (CMAP), immunohistochemistry and immunofluorescence. Results: Extracted cells exhibited spindle-shaped morphology, presented typical markers (CD44+CD90+CD34-CD45-), and presented multidirectional differentiation potential. The DPSCs with VEGFA overexpression were constructed successfully. VEGFA enhanced the proliferation and neural differentiation ability of rDPSCs, and the expression of neuron-specific enolase (NSE) and ßIII-tubulin was increased. However, these trends were reversed with the addition of SU5416. This suggests that VEGFA mediates the above effects mainly through vascular endothelial growth factor receptor 2 (VEGFR2) binding. The LC-YE-NGC basically meet the requirements of facial nerve repair. For the in vivo experiment, the CMAP latency period was shorter in DPSCS-VEGFA-NGC group in comparison with other experimental groups, while the amplitude was increased. Such functional recovery correlated well with an increase in histological improvement. Further study suggested that VEGFA-modified DPSCs could increase the myelin number, thickness and axon diameter of facial nerve. NSE, ßIII-tubulin and S100 fluorescence intensity and immunohistochemical staining intensity were significantly enhanced. Conclusion: VEGFA-modified rDPSCs combined with LC-YE-PLGA NGCs have certain advantages in the growth and functional recovery of facial nerves in rats.

Determination of the optimal concentration and duration of C5aR antagonist application in an inflammatory model of human dental pulp cells.

Deep tooth decay approaching the pulp may develop into pulpitis; to prevent this, pulp cells need to balance the rapid immune response to avoid rapid swelling of the pulp. Current treatment of deep decay that approaches the pulp involves the application of drugs that induce low-level inflammation in the dental pulp to promote its repair, but this treatment is sometimes insufficient. However, the unsuccessful treatment often resulted in pulpitis. The C5a-C5aR is the initial stage of the immune cascade response. Blocking the binding of C5a-C5aR can slow the immune response in the narrow pulp cavity, so that dental pulp cells have enough time to proliferate, migrate, and differentiate. In this study, we compared lipoteichoic acid (LTA) and lipopolysaccharides (LPS) at different concentrations and time points and used the C5aR antagonist W54011 to block the C5a-C5aR axis. The blocking effect was detected by analyzing the expression of C5a, C5aR, interleukin (IL)-6, and Toll-like receptors 2 and 4 (TLR-2, 4). Next, we determined the optimal concentration and duration of LTA and LPS treatment in combination with W54011. Based on our results, we selected 1.0 µg·mL-1 LPS treatment for 48 h to generate an inflammatory model of human dental pulp cells. We then regrouped the cells and conducted expression analyses to monitor the expression of C5a, C5aR, IL-6, and TLR-4 at the protein and mRNA levels. LPS stimulation for 48 h and treatment with W54011 for 48 h effectively inhibited inflammation and did not affect C5a expression. This study provides a basis for follow-up studies of W54011 in dental pulp cells.

Effects of early cognitive rehabilitation training on cognitive function and quality of life in critically ill patients with cognitive impairment: A randomised controlled trial.

BACKGROUND: Patients often develop cognitive dysfunction during admission to the ICU and after being transferred out of the ICU, which leads to physical disorders, sleep disorders, and psychological stress.Cognitive rehabilitation training can significantly improve patients' planning, decision-making ability, and executive function. OBJECTIVE: The aim of this study was to explore the role of early cognitive rehabilitation training in improving cognitive impairment in critically ill patients. METHODS: This study was a prospective, randomised, controlled clinical trial conducted from January 2017 to June 2021. Critically ill patients with cognitive impairment admitted to the Department of Intensive Care Medicine of The Third Hospital of Mianyang were randomly divided into the control (n = 68) and intervention groups (n = 68). Cognitive rehabilitation training (including digital operating system training, music therapy, aerobic training, and mental health intervention) was applied to the patients in the intervention group for 6 months, while the control group did not receive any cognitive intervention. Before 3 and 6 months after enrolment, the Montreal Cognitive Assessment and the 36-Item Short Form Health Survey Scale were used to evaluate cognitive function and quality of life, respectively, in both groups. RESULTS: A total of 136 critical patients were included in the final analysis. There were no significant differences in sex, age, years of education, complications, intensive care unit hospitalisation time, mechanical ventilation time, or the total score of the Montreal Cognitive Assessment scale when transferred out of the intensive care unit in 24 hours between the two groups. Six months later, the results of the follow-up showed that the cognitive function score in the intervention group was significantly higher than that in the control group (26.69 ± 2.49 vs. 23.03 ± 3.79). The analysis of quality of life showed that the scores in all areas in the intervention group improved. There were significant differences in physical functioning (69.02 ± 8.14 vs. 63.38 ± 11.94), role physical (62.02 ± 12.18 vs. 58.09 ± 8.83), general health (46.00 ± 15.21 vs. 40.38 ± 13.77), vitality (61.00 ± 11.01 vs. 54.38 ± 13.80), social functioning (70.00 ± 10.29 vs. 64.41 ± 13.61), role emotional (78.00 ± 8.00 vs. 72.15 ± 12.18), and mental health (71.00 ± 12.33 vs. 55.37 ± 10.76) between the two groups (P < 0.05). CONCLUSION: Early cognitive rehabilitation training can improve cognitive impairment in critically ill patients and their quality of life.

Proteogenomics refines the molecular classification of chronic lymphocytic leukemia.

Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic-based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterize the proteome and transcriptome alongside genetic and ex-vivo drug response profiling in a clinically annotated CLL discovery cohort (n = 68). Unsupervised clustering of the proteome data reveals six subgroups. Five of these proteomic groups are associated with genetic features, while one group is only detectable at the proteome level. This new group is characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). Classifiers developed to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n = 165, n = 169) confirm that ASB-CLL comprises about 20% of CLL patients. The inferior overall survival in ASB-CLL is also independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling.

Proteome profiling of whole plasma and plasma-derived extracellular vesicles facilitates the detection of tissue biomarkers in the non-obese diabetic mouse.

The mechanism by which pancreatic beta cells are destroyed in type 1 diabetes (T1D) remains to be fully understood. Recent observations indicate that the disease may arise because of different pathobiological mechanisms (endotypes). The discovery of one or several protein biomarkers measurable in readily available liquid biopsies (e.g. blood plasma) during the pre-diabetic period may enable personalized disease interventions. Recent studies have shown that extracellular vesicles (EVs) are a source of tissue proteins in liquid biopsies. Using plasma samples collected from pre-diabetic non-obese diabetic (NOD) mice (an experimental model of T1D) we addressed if combined analysis of whole plasma samples and plasma-derived EV fractions increases the number of unique proteins identified by mass spectrometry (MS) compared to the analysis of whole plasma samples alone. LC-MS/MS analysis of plasma samples depleted of abundant proteins and subjected to peptide fractionation identified more than 2300 proteins, while the analysis of EV-enriched plasma samples identified more than 600 proteins. Of the proteins detected in EV-enriched samples, more than a third were not identified in whole plasma samples and many were classified as either tissue-enriched or of tissue-specific origin. In conclusion, parallel profiling of EV-enriched plasma fractions and whole plasma samples increases the overall proteome depth and facilitates the discovery of tissue-enriched proteins in plasma. If applied to plasma samples collected longitudinally from the NOD mouse or from models with other pathobiological mechanisms, the integrated proteome profiling scheme described herein may be useful for the discovery of new and potentially endotype specific biomarkers in T1D.

Engineering of near-PAMless adenine base editor with enhanced editing activity and reduced off-target.

About 47% of pathogenic point mutations could be corrected by ABE-induced A·T-to-G·C conversions. However, the applications of ABEs are still hindered by undesired editing efficiency, limited editing scopes, and off-targeting effects. Here, we develop a new adenine base editor, by embedding TadA-8e monomer into SpRY-nCas9, named as CE-8e-SpRY, which exhibits higher activity at NRN than NYN PAMs favored by SpRY nuclease. CE-8e-SpRY could target nearly all genomic sites in principle and induces the highest targeting efficiency among tested SpRY-based ABEs. In addition, CE-8e-SpRY also shows reduced RNA and DNA off-targeting activities. With optimized sgRNAs, CE-8e-SpRY induces efficient or desired target editing at some disease-relevant loci where conventional ABEs were unable to induce precise and satisfied editing. Taken together, our CE-8e-SpRY could broaden the applicability of ABEs in correcting or introducing pathogenic point mutations.

Identification of novel deep intronic PAH gene variants in patients diagnosed with phenylketonuria.

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) gene variants. Previously, 94.21% of variants were identified using Sanger sequencing and multiplex ligation-dependent probe amplification. To investigate the remaining variants, we performed whole-genome sequencing for four patients with PKU and unknown genotypes to identify deep intronic or structural variants. We identified three novel heterozygous variants (c.706+368T>C, c.1065+241C>A, and c.1199+502A>T) in a deep PAH gene intron. We detected a c.1199+502A>T variant in 60% (6/10) of PKU patients with genetically undetermined PKU. In silico predictions indicated that the three deep variants may impact splice site selection and result in the inclusion of a pseudo-exon. A c.1199+502A>T PAH minigene and reverse transcription PCR (RT-PCR) on blood RNA from a PKU patient with biallelic variants c.1199+502A>T and c.1199G>A confirmed that the c.1199+502A>T variant may strengthen the predicted branch point and leads to the inclusion of a 25-nt pseudo-exon in the PAH mRNA. Reverse transcription polymerase chain reaction (RT-PCR) on the minigene revealed that c.706+368T>C may create an SRSF2 (SC35) binding site via a 313-nt pseudo-exon, whereas c.1065+241C>A may produce an 81-nt pseudo-exon that strengthens the predicted SRSF1 (SF2/ASF) binding site. These results augment current knowledge of PAH genotypes and show that deep intronic analysis of PAH can genetically diagnose PKU.

Molecular evaluation of five different isolation methods for extracellular vesicles reveals different clinical applicability and subcellular origin.

Extracellular vesicles (EVs) are increasingly tested as therapeutic vehicles and biomarkers, but still EV subtypes are not fully characterised. To isolate EVs with few co-isolated entities, a combination of methods is needed. However, this is time-consuming and requires large sample volumes, often not feasible in most clinical studies or in studies where small sample volumes are available. Therefore, we compared EVs rendered by five commonly used methods based on different principles from conditioned cell medium and 250 µl or 3 ml plasma, that is, precipitation (ExoQuick ULTRA), membrane affinity (exoEasy Maxi Kit), size-exclusion chromatography (qEVoriginal), iodixanol gradient (OptiPrep), and phosphatidylserine affinity (MagCapture). EVs were characterised by electron microscopy, Nanoparticle Tracking Analysis, Bioanalyzer, flow cytometry, and LC-MS/MS. The different methods yielded samples of different morphology, particle size, and proteomic profile. For the conditioned medium, Izon 35 isolated the highest number of EV proteins followed by exoEasy, which also isolated fewer non-EV proteins. For the plasma samples, exoEasy isolated a high number of EV proteins and few non-EV proteins, while Izon 70 isolated the most EV proteins. We conclude that no method is perfect for all studies, rather, different methods are suited depending on sample type and interest in EV subtype, in addition to sample volume and budget.

Evaluation of Spin Columns for Human Plasma Depletion to Facilitate MS-Based Proteomics Analysis of Plasma.

High abundant protein depletion is a common strategy applied to increase analytical depth in global plasma proteomics experiment setups. The standard strategies for depletion of the highest abundant proteins currently rely on multiple-use HPLC columns or multiple-use spin columns. Here we evaluate the performance of single-use spin columns for plasma depletion and show that the single-use spin reduces handling time by allowing parallelization and is easily adapted to a nonspecialized lab environment without reducing the high plasma proteome coverage and reproducibility. In addition, we evaluate the effect of viral heat inactivation on the plasma proteome, an additional step in the plasma preparation workflow that allows the sample preparation of SARS-Cov2-infected samples to be performed in a BSL3 laboratory, and report the advantage of performing the heat inactivation postdepletion. We further show the possibility of expanding the use of the depletion column cross-species to macaque plasma samples. In conclusion, we report that single-use spin columns for high abundant protein depletion meet the requirements for reproducibly in in-depth plasma proteomics and can be applied on a common animal model while also reducing the sample handling time.

The importance of the ZBED6-IGF2 axis for metabolic regulation in mouse myoblast cells.

The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5'-GGCTCG-3' in intron 1 of Igf2. Deletion of this motif (Igf2ΔGGCT ) or complete ablation of Zbed6 leads to ~20-fold upregulation of the IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Zbed6-/- and Igf2ΔGGCT myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Zbed6-/- myoblasts. Both Zbed6-/- and Igf2ΔGGCT myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O2 consumption rate, due to IGF2 upregulation. Transcriptome analysis revealed ~30% overlap between differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with an enrichment of upregulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities, and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Zbed6-/- and Igf2ΔGGCT myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study adds new insights how the ZBED6-Igf2 axis affects muscle metabolism.

Identification and Validation of Novel Long Non-coding RNA Biomarkers for Early Diagnosis of Oral Squamous Cell Carcinoma.

Long non-coding RNAs (lncRNAs) are recently emerging as a novel promising biomarker for cancer diagnosis and prognosis. Despite these previous investigations, the expression pattern and diagnostic role of lncRNAs in oral squamous cell carcinoma (OSCC) remain unclear. In this study, we identified six novel lncRNA biomarkers (LINC01697, LINC02487, LOC105376575, AC005083.1, SLC8A1-AS1, and U62317.1) from a list of 29 differentially expressed lncRNAs using the least absolute shrinkage and selection operator (LASSO) method in the discovery dataset of 167 OSCC samples and 45 normal oral tissues. Using the logistic regression method, we constructed a six lncRNAs-based diagnostic risk model (6lncRNAScore) which was able to differentiate between OSCC samples and control samples with high performance with AUC of 0.995 and high diagnostic specificity of 88.9% and sensitivity of 98.2% in the discovery dataset. The diagnostic performance of the 6lncRNAScore was further validated in another two independent OSCC dataset with AUC of 0.968 and 1.0. Functional enrichment analysis for lncRNA biomarkers-related mRNAs suggested that lncRNAs biomarkers tended to be involved in the lipid metabolic process. Together, our study highlighted the importance of lncRNAs in OSCC and demonstrated the utility of lncRNA expression as a promising biomarker for early diagnosis of OSCC.

First isolation and characterization of Brucella suis from yak.

Brucella spp., facultative intracellular pathogens that can persistently colonize animal host cells and cause zoonosis, affect public health and safety. A Brucella strain was isolated from yak in Qinghai Province. To detect whether this isolate could cause an outbreak of brucellosis and to reveal its genetic characteristics, several typing and whole-genome sequencing methods were applied to identify its species and genetic characteristics. Phylogenetic analysis based on MLVA and whole-genome sequencing revealed the genetic characteristics of the isolated strain. The results showed that the isolated strain is a B. suis biovar 1 smooth strain, and this isolate was named B. suis QH05. The results of comparative genomics and MLVA showed that B. suis QH05 is not a vaccine strain. Comparison with other B. suis strains isolated from humans and animals indicated that B. suis QH05 may be linked to specific animal and human sources. In conclusion, B. suis QH05 does not belong to the Brucella epidemic species in China, and as the first isolation of B. suis from yak, this strain expands the host range of B. suis.

Compound heterozygous variants of the FBXO7 gene resulting in infantile-onset Parkinsonian-pyramidal syndrome in siblings of a Chinese family.

BACKGROUND: Mutations in the FBXO7 gene can cause a rare chromosomal recessive neurodegenerative disease, Parkinsonian-pyramidal syndrome (PPS). Patients with this syndrome mainly show early-onset Parkinson's syndrome. Here, we present a Chinese family with infantile-onset PPS caused by FBXO7 mutations. METHODS: The clinical phenotypes and medical records of the proband and his family members were collected. The proband, his sibling, and his parents underwent whole-exome sequencing (WES) by next-generation sequencing. RESULTS: The proband and his sibling had a typical PPS phenotype with onset during infancy. WES identified compound heterozygous variants in the FBXO7 gene, including a nonsense mutation, p. Trp134*, and a splicing mutation, IVS5-1G > A, which were shared by both siblings and inherited from each of the parents. These variants have not been reported in literatures or databases. According to the American College of Medical Genetics and Genomics guidelines, the p. Trp134* and IVS5-1G > A mutations were classified as pathogenic variants. CONCLUSIONS: We report a case of siblings in a Chinese family with infantile-onset PPS caused by FBXO7 gene mutations determined by WES. These findings will contribute to the in-depth study of the pathogenesis of PPS among patients with FBXO7 gene mutations.

Immediate Adaptation Analysis Implicates BCL6 as an EGFR-TKI Combination Therapy Target in NSCLC.

Drug resistance is a major obstacle to curative cancer therapies, and increased understanding of the molecular events contributing to resistance would enable better prediction of therapy response, as well as contribute to new targets for combination therapy. Here we have analyzed the early molecular response to epidermal growth factor receptor (EGFR) inhibition using RNA sequencing data covering 13,486 genes and mass spectrometry data covering 10,138 proteins. This analysis revealed a massive response to EGFR inhibition already within the first 24 h, including significant regulation of hundreds of genes known to control downstream signaling, such as transcription factors, kinases, phosphatases and ubiquitin E3-ligases. Importantly, this response included upregulation of key genes in multiple oncogenic signaling pathways that promote proliferation and survival, such as ERBB3, FGFR2, JAK3, and BCL6, indicating an early adaptive response to EGFR inhibition. Using a library of more than 500 approved and experimental compounds in a combination therapy screen, we could show that several kinase inhibitors with targets including JAK3 and FGFR2 increased the response to EGFR inhibitors. Further, we investigated the functional impact of BCL6 upregulation in response to EGFR inhibition using siRNA-based silencing of BCL6. Proteomics profiling revealed that BCL6 inhibited transcription of multiple target genes including p53, resulting in reduced apoptosis which implicates BCL6 upregulation as a new EGFR inhibitor treatment escape mechanism. Finally, we demonstrate that combined treatment targeting both EGFR and BCL6 act synergistically in killing lung cancer cells. In conclusion, or data indicates that multiple different adaptive mechanisms may act in concert to blunt the cellular impact of EGFR inhibition, and we suggest BCL6 as a potential target for EGFR inhibitor-based combination therapy.

First Draft Genome of the Sable, Martes zibellina.

Members of genus Martes provide early warning signals about forest ecosystem health and are designated as a Management Indicator Species. As one of the most widespread members in Martes, the sable (Martes zibellina) is a circumboreal small predator found throughout all taiga zoogeographical zones of Eurasia and shows distinct population differentiation and morphological variations. To support further studies on striking local adaptation and population evolution, we present the first sable genome, assembled de novo from an individual originating in the Great Khingan Mountains (China). The assembled genome is 2.42 Gb, consisting of 15,814 scaffolds with a scaffold N50 of 5.20 Mb. Searches for complete Mammalia BUSCO (Benchmarking Universal Single-Copy Ortholog) gene groups found that 95.15% of the curated single-copy orthologs were assembled as complete, suggesting a high level of completeness of the genome. We totally predicted 19,413 protein-coding genes, and 0.82 Gb of repeat sequences was annotated. We also detected 1,257 olfactory receptor genes and found more functional olfactory receptor genes in sable than in other Mustelidae species, which provide a possible genetic explanation for the acute sense of smell of the sable for searching the preys under deep snow. Phylogenetic analyses revealed that the ferret (Mustela putorius furo) and sea otter (Enhydra lutris) form a clade that is sister to the sable, which was dated ∼16.4 Ma. Overall, our study provided the first reference genome for research in a broad range of areas including local adaptations, population evolution, conservation, and management for sable.