A UPR-Induced Soluble ER-Phagy Receptor Acts with VAPs to Confer ER Stress Resistance.

Autophagic degradation of the endoplasmic reticulum (ER-phagy) is triggered by ER stress in diverse organisms. However, molecular mechanisms governing ER stress-induced ER-phagy remain insufficiently understood. Here we report that ER stress-induced ER-phagy in the fission yeast Schizosaccharomyces pombe requires Epr1, a soluble Atg8-interacting ER-phagy receptor. Epr1 localizes to the ER through interacting with integral ER membrane proteins VAPs. Bridging an Atg8-VAP association is the main ER-phagy role of Epr1, as it can be bypassed by an artificial Atg8-VAP tether. VAPs contribute to ER-phagy not only by tethering Atg8 to the ER membrane, but also by maintaining the ER-plasma membrane contact. Epr1 is upregulated during ER stress by the unfolded protein response (UPR) regulator Ire1. Loss of Epr1 reduces survival against ER stress. Conversely, increasing Epr1 expression suppresses the ER-phagy defect and ER stress sensitivity of cells lacking Ire1. Our findings expand and deepen the molecular understanding of ER-phagy.

Bacterial cysteate dissimilatory pathway involves a racemase and d-cysteate sulfo-lyase.

The sulfite-reducing bacterium Bilophila wadsworthia, a common human intestinal pathobiont, is unique in its ability to metabolize a wide variety of sulfonates to generate sulfite as a terminal electron acceptor (TEA). The resulting formation of H2S is implicated in inflammation and colon cancer. l-cysteate, an oxidation product of l-cysteine, is among the sulfonates metabolized by B. wadsworthia, although the enzymes involved remain unknown. Here we report a pathway for l-cysteate dissimilation in B. wadsworthia RZATAU, involving isomerization of l-cysteate to d-cysteate by a cysteate racemase (BwCuyB), followed by cleavage into pyruvate, ammonia and sulfite by a d-cysteate sulfo-lyase (BwCuyA). The strong selectivity of BwCuyA for d-cysteate over l-cysteate was rationalized by protein structural modeling. A homolog of BwCuyA in the marine bacterium Silicibacter pomeroyi (SpCuyA) was previously reported to be a l-cysteate sulfo-lyase, but our experiments confirm that SpCuyA too displays a strong selectivity for d-cysteate. Growth of B. wadsworthia with cysteate as the electron acceptor is accompanied by production of H2S and induction of BwCuyA. Close homologs of BwCuyA and BwCuyB are present in diverse bacteria, including many sulfate- and sulfite-reducing bacteria, suggesting their involvement in cysteate degradation in different biological environments.

scAPAatlas: an atlas of alternative polyadenylation across cell types in human and mouse.

Alternative polyadenylation (APA) has been widely recognized as a crucial step during the post-transcriptional regulation of eukaryotic genes. Recent studies have demonstrated that APA exerts key regulatory roles in many biological processes and often occurs in a tissue- and cell-type-specific manner. However, to our knowledge, there is no database incorporating information about APA at the cell-type level. Single-cell RNA-seq is a rapidly evolving and powerful tool that enable APA analysis at the cell-type level. Here, we present a comprehensive resource, scAPAatlas (http://www.bioailab.com:3838/scAPAatlas), for exploring APA across different cell types, and interpreting potential biological functions. Based on the curated scRNA-seq data from 24 human and 25 mouse normal tissues, we systematically identified cell-type-specific APA events for different cell types and examined the correlations between APA and gene expression level. We also estimated the crosstalk between cell-type-specific APA events and microRNAs or RNA-binding proteins. A user-friendly web interface has been constructed to support browsing, searching and visualizing multi-layer information of cell-type-specific APA events. Overall, scAPAatlas, incorporating a rich resource for exploration of APA at the cell-type level, will greatly help researchers chart cell type with APA and elucidate the biological functions of APA.

eaQTLdb: An atlas of enhancer activity quantitative trait loci across cancer types.

Enhancers are key regulatory elements that exert crucial roles in diverse biological processes, including tumorigenesis and cancer development. Active enhancers could produce transcripts termed enhancer RNAs (eRNAs), which could be used as an index of enhancer activity. Here, we present a versatile data portal, enhancer activity quantitative trait loci database (eaQTLdb; http://www.bioailab.com:3838/eaQTLdb), for exploring the effects of genetic variants on enhancer activity and prioritizing candidate variants across different cancer types. By leveraging the accumulated multiomics data, we systematically identified genetic variants which influence enhancer activity in different cancer types, termed as eaQTLs. We have linked the eaQTLs to hallmarks of cancer and patients' overall survival to illustrate their potential biological roles in cancer development and progression. Notably, eaQTLs associated with the infiltration abundance of 24 different immune cell types were identified and incorporated into eaQTLdb. In addition, we applied colocalization analyses to examine 59 complex diseases and traits to identify eaQTLs colocalized with diseases/traits GWAS signals. Overall, eaQTLdb, incorporating a rich resource for exploration of eaQTLs in different cancer types, will not only benefit users in prioritizing candidate genetic variants and enhancers, but also help researchers decipher the roles of eaQTLs in the dysregulated pathways of cancer and tumor immune microenvironment, opening new diagnostic and therapeutic avenues in precise medicine.

DH5α Outer Membrane-Coated Biomimetic Nanocapsules Deliver Drugs to Brain Metastases but not Normal Brain Cells via Targeting GRP94.

Receptor-mediated vesicular transport has been extensively developed to penetrate the blood-brain barrier (BBB) and has emerged as a class of powerful brain-targeting delivery technologies. However, commonly used BBB receptors such as transferrin receptor and low-density lipoprotein receptor-related protein 1, are also expressed in normal brain parenchymal cells and can cause drug distribution in normal brain tissues and subsequent neuroinflammation and cognitive impairment. Here, the endoplasmic reticulum residing protein GRP94 is found upregulated and relocated to the cell membrane of both BBB endothelial cells and brain metastatic breast cancer cells (BMBCCs) by preclinical and clinical investigations. Inspired by that Escherichia coli penetrates the BBB via the binding of its outer membrane proteins with GRP94, avirulent DH5α outer membrane protein-coated nanocapsules (Omp@NCs) are developed to cross the BBB, avert normal brain cells, and target BMBCCs via recognizing GRP94. Embelin (EMB)-loaded Omp@EMB specifically reduce neuroserpin in BMBCCs, which inhibits vascular cooption growth and induces apoptosis of BMBCCs by restoring plasmin. Omp@EMB plus anti-angiogenic therapy prolongs the survival of mice with brain metastases. This platform holds the translational potential to maximize therapeutic effects on GRP94-positive brain diseases.

Gate-Tunable Berry Curvature Dipole Polarizability in Dirac Semimetal Cd_{3}As_{2}.

We reveal the gate-tunable Berry curvature dipole polarizability in Dirac semimetal Cd_{3}As_{2} nanoplates through measurements of the third-order nonlinear Hall effect. Under an applied electric field, the Berry curvature exhibits an asymmetric distribution, forming a field-induced Berry curvature dipole, resulting in a measurable third-order Hall voltage with a cubic relationship to the longitudinal electric field. Notably, the magnitude and polarity of this third-order nonlinear Hall effect can be effectively modulated by gate voltages. Furthermore, our scaling relation analysis demonstrates that the sign of the Berry curvature dipole polarizability changes when tuning the Fermi level across the Dirac point, in agreement with theoretical calculations. The results highlight the gate control of nonlinear quantum transport in Dirac semimetals, paving the way for promising advancements in topological electronics.

Switchable Regioselective 7-endo or 6-exo Iodocyclization of O-Homoallyl Benzimidates.

We present a facile switchable regioselective 7-endo or 6-exo iodocyclization of O-homoallyl benzimidates here, which affords various iodo-substituted 1,3-oxazines and tetrahydro-1,3-oxazepines in a controllable manner. The products can further undergo substitution reactions to afford a series of rich functionalized target heterocyclic molecules. The developed protocol has the advantages of mild conditions, simple operation, and excellent functional group compatibility.

Promoting physical activity among cancer survivors: an umbrella review of systematic reviews.

PURPOSE: Exercise is the core element of rehabilitation for cancer patients. However, most of the patients' exercise levels failed to meet the indicators recommended by the guidelines or even decreased. Therefore, this umbrella review aims to provide an overview of review articles addressing the evidence of interventions to promote physical activity behavior change and increase physical activity among cancer patients. METHODS: We searched nine databases from inception to 12 May 2022 to obtain systematic reviews and meta-analyses of interventions to promote physical activity among cancer patients. The AMSTAR-2 was used for the quality assessment. RESULTS: Twenty-six individual systematic reviews including 13 studies performed meta-analyses. A total of 16 studies' designs were all in randomized controlled trial. Most reviews included studies that were mainly delivered in home settings. The most frequent and mean duration of the interventions was 12 weeks. Interventions mainly included electronic, wearable health technology-based, behavior change techniques (BCTs), and theory-based strategies. CONCLUSIONS: Electronic, wearable health technology-based, BCTs, and theory-based interventions were effective and feasible in promoting physical activity in cancer survivors. Clinical practitioners should take corresponding intervention measures according to the characteristics of patients in different groups. IMPLICATIONS FOR CANCER SURVIVORS: Future research may benefit cancer survivors by more comprehensively applying electronic, wearable health technology-based, BCTs, and theory-based interventions.

Geometry Sampling-Based Adaption to DCGAN for 3D Face Generation.

Despite progress in the past decades, 3D shape acquisition techniques are still a threshold for various 3D face-based applications and have therefore attracted extensive research. Moreover, advanced 2D data generation models based on deep networks may not be directly applicable to 3D objects because of the different dimensionality of 2D and 3D data. In this work, we propose two novel sampling methods to represent 3D faces as matrix-like structured data that can better fit deep networks, namely (1) a geometric sampling method for the structured representation of 3D faces based on the intersection of iso-geodesic curves and radial curves, and (2) a depth-like map sampling method using the average depth of grid cells on the front surface. The above sampling methods can bridge the gap between unstructured 3D face models and powerful deep networks for an unsupervised generative 3D face model. In particular, the above approaches can obtain the structured representation of 3D faces, which enables us to adapt the 3D faces to the Deep Convolution Generative Adversarial Network (DCGAN) for 3D face generation to obtain better 3D faces with different expressions. We demonstrated the effectiveness of our generative model by producing a large variety of 3D faces with different expressions using the two novel down-sampling methods mentioned above.

Enzymatic Synthesis of the Unnatural Nucleotide 2'-Deoxyisoguanosine 5'-Monophosphate.

Naturally occurring DNA contains four canonical bases, forming two Watson-Crick base pairs (adenine-thymine, guanine-cytosine). Efforts over the past decades have led to the development of several unnatural base pairs, enabling the synthesis of unnatural DNA with an expanded genetic alphabet. The engineering of organisms capable of de novo biosynthesis of unnatural DNA would have significant technological and philosophical implications, but remains a challenge. Here we report the enzymatic conversion of 2'-deoxyxanthosine 5'-monophosphate (dXMP) into deoxyisoguanosine monophosphate (dBMP), a precursor of the unnatural isoguanine-isocytosine base pair. The reaction is catalyzed by the bacteriophage enzyme PurZ and bacterial PurB, and is a key addition to the toolbox for de novo biosynthesis of unnatural DNA.

The lip gene contributes to the virulence of Aeromonas veronii strain TH0426.

Aeromonas veronii (A. veronii) is a pathogen that can infect aquatic organisms and mammals and has caused irrecoverable economic losses to the aquaculture industry. The results of an epidemiological investigation showed that the number of cases of A. veronii have increased gradually in recent years, and its drug resistance and virulence has shown an upward trend. In this study, we constructed an A. veronii mutant strain Δlip, by homologous recombination and studied its function. The results showed that there was no significant difference in the biofilm formation ability between the Δlip and the wild-type strain, but the toxicity of the Δlip to EPC cells and its ability to adhere to EPC cells were significantly reduced. The LD50 value of the Δlip to zebrafish was 7.40-fold higher than that of the wild-type strain. In addition, after 24 h and 72 h, the bacterial loads of the Δlip in the organs of crucian carp were significantly lower than those in the wild-type strain. In conclusion, the mutant strain Δlip led to a decrease in the adhesion and virulence of the wild-type strain, which lays a foundation to further understand lip gene function and the pathogenic mechanism of A. veronii.

CACNA1B facilitates breast cancer cell growth and migration by regulating cyclin D1 and EMT: the implication of CACNA1B in breast cancer.

PURPOSE: This study mainly aimed to explore the influences of Calcium Voltage-Gated Channel Subunit Alpha1 B (CACNA1B) on the development of breast cancer and the related mechanism. MATERIALS AND METHODS: The information of patients with breast cancer from TCGA database was used for analyses of CACNA1B expression and its prognostic value. Loss- and gain- of functions of CACNA1B were conducted in MCF7 and Bcap-37 cells, respectively. CCK-8, colony formation and transwell assays were applied for evaluating the cell viability and motility. Western blot was used for protein expression detection. RESULTS: We revealed that highly expressed CACNA1B in breast cancer tissues was related to poor prognosis according to the data gained from TCGA database. The outcomes of functional assays showed that depletion of CACNA1B restrained MCF7 cell growth, invasion and migration and high-expression of CACNA1B fortified the growth, invasion and migration in Bcap-37 cells. Finally, we manifested that silencing CACNA1B obviously raised the protein expression level of E-cadherin and reduced the protein levels of Cyclin D1, N-cadherin and Snail in MCF7 cells, whilst, over-expression of CACNA1B reduced the level of E-cadherin and increased the expression of Cyclin D1, N-cadherin and Snail in Bcap-37 cells. CONCLUSIONS: These results identified CACNA1B as a forwarder of the growth, invasion and migration in breast cancer cells.

Nonaffine Strains Control Ductility of Metallic Glasses.

The origin of limited plasticity in metallic glasses is elusive, with no apparent link to their atomic structure. We propose that the response of the glassy structure to applied stress, not the original structure itself, provides a gauge to predict the degree of plasticity. We carried out high-energy x-ray diffraction on various bulk metallic glasses (BMGs) under uniaxial compression within the elastic limit and evaluated the anisotropic pair distribution function. We show that the extent of local deviation from the affine (uniform) deformation in the elastic regime is strongly correlated with the plastic behavior of BMGs beyond yield, across chemical compositions and sample history. The results suggest that the propensity for collective local atomic rearrangements under stress promotes plasticity.

NIS-Promoted Selective Amino-Diazidation and Amino-Iodoazidation of O-Homoallyl Benzimidates: Synthesis of Vicinal Diazido 1,3-Oxazines and Vicinal Iodoazido 1,3-Oxazines.

Amines, especially those with multi-nitrogen moieties, are widespread in natural products and biologically active compounds. Thus, the development of direct and efficient methods to introduce multiple nitrogen-containing fragments into compounds in one step is highly desirable yet challenging. Herein, we report an NIS-promoted selective amino-diazidation and amino-iodoazidation of O-homoallyl benzimidates with NaN3. By using this protocol, a variety of vicinal diazido-substituted 1,3-oxazines and vicinal iodoazido-substituted 1,3-oxazines were directly synthesized in a controllable manner. Preliminary mechanistic investigations revealed that the reaction operates through a NIS-promoted four-step cascade process. The developed method has the merits of metal-free, excellent functional group compatibility, simple operation, and mild conditions.

Effect of oxygen partial pressure on the performance of homojunction amorphous In-Ga-Zn-O thin-film transistors.

In this study, the homojunction thin-film transistors (TFTs) with amorphous indium gallium zinc oxide (a-IGZO) as active channel layers and source/drain electrodes were fabricated by RF magnetron sputtering. The effect of oxygen partial pressure on the phase, microstructure, optical and electrical properties of IGZO thin films was investigated. The results showed that amorphous IGZO thin films always exhibit a high transmittance above 90% and wide band gaps of around 3.9 eV. The resistivity increases as the IGZO thin films are deposited at a higher oxygen partial pressure due to the depletion of oxygen vacancies. In addition, the electrical behaviors in homojunction IGZO TFTs were analyzed. When the active channel layers were deposited with an oxygen partial pressure of 1.96%, the homojunction IGZO TFTs exhibited optimal transfer and output characteristics with a field-effect mobility of 13.68 cm2V-1s-1. Its sub-threshold swing, threshold voltage and on/off ratio are 0.6 V/decade, 0.61 V and 107, respectively.

Construction and immune efficacy of recombinant Lactobacillus casei expressing OmpAI of Aeromonas veronii C5-I as molecular adjuvant.

Despite advancements in diagnosis and control, Aeromonas infections are considered the leading cause of economic aquaculture loss. In this study, to enhance DNA vaccine efficacy against Aeromonas infections, a fused DNA fragment (1504 bp) of the OmpAI gene from Aeromonas veronii (A. veronii) combined with the C5-I gene from the common carp was generated with splicing by overlapping PCR (SOE-PCR) and expressed in Lactobacillus casei strain CC16. Protein C5-I served as a molecular adjuvant for the antigen OmpAI. Two types of fusion antigens were developed (anchored and secretory). Generally, anchored-type antigens are more effective in inducing immune responses in fish than secretory antigens. Western blot analysis showed that the bands of both antigens were present at 58 kDa. After oral immunization, both DNA vaccines enhanced the serum levels of AKP, ACP, SOD and LZM in immunized carp; the genes IL-10, IL-1ß, TNF-α, and IFN-γ in the heart, liver, spleen, head kidney, and intestinal tract were upregulated; and a stronger phagocytic response was triggered in immunized fish. In addition, common carp administered the fused antigens were more protected from Aeromonas challenge (60-73.3% protection). Recombinant Lactobacillus bacteria expressing the fused protein showed a greater propensity for colonization in the intestinal tract in immunized fish than in controls. Here, we provide a promising approach to improve DNA vaccine immunogenicity for protecting common carp from A. veronii infections.

A Pathway for Isethionate Dissimilation in Bacillus krulwichiae.

Hydroxyethyl sulfonate (isethionate) is widely distributed in the environment as an industrial pollutant and as a product of microbial metabolism. It is used as a substrate for growth by metabolically diverse environmental bacteria. Aerobic pathways for isethionate dissimilation in Gram-negative bacteria involve the cytochrome c-dependent oxidation of isethionate to sulfoacetaldehyde by a membrane-bound flavoenzyme (IseJ), followed by C-S cleavage by the thiamine pyrophosphate (TPP)-dependent enzyme sulfoacetaldehyde acetyltransferase (Xsc). Here, we report a bioinformatics analysis of Xsc-containing gene clusters in Gram-positive bacteria, which revealed the presence of an alternative isethionate dissimilation pathway involving the NAD+-dependent oxidation of isethionate by a cytosolic metal-dependent alcohol dehydrogenase (IseD). We describe the biochemical characterization of recombinant IseD from the haloalkaliphilic environmental bacterium Bacillus krulwichiae AM31DT and demonstrate the growth of this bacterium using isethionate as its sole carbon source, with the excretion of sulfite as a waste product. The IseD-dependent pathway provides the only mechanism for isethionate dissimilation in Gram-positive species to date and suggests a role of the metabolically versatile Bacilli in the mineralization of this ubiquitous organosulfur compound.IMPORTANCE Isethionate of biotic and industrial sources is prevalent. Dissimilation of isethionate under aerobic conditions is thus far only known in Gram-negative bacteria. Here, we report the discovery of a new pathway in Gram-positive Bacillus krulwichiae Isethionate is oxidized by a cytosolic metal-dependent alcohol dehydrogenase (which we named IseD), with NAD+ as the electron acceptor, generating sulfoacetaldehyde for subsequent cleavage by Xsc. This work highlights the diversity of organisms and pathways involved in the degradation of this ubiquitous organosulfonate. The new pathway that we discovered may play an important role in organosulfur mineralization and in the sulfur cycle in certain environments.

Transcriptome Analysis Identifies a Zinc Finger Protein Regulating Starch Degradation in Kiwifruit.

Ripening, including softening, is a critical factor in determining the postharvest shelf-life of fruit and is controlled by enzymes involved in cell wall metabolism, starch degradation, and hormone metabolism. Here, we used a transcriptomics-based approach to identify transcriptional regulatory components associated with texture, ethylene, and starch degradation in ripening kiwifruit (Actinidia deliciosa). Twelve differentially expressed structural genes, including seven involved in cell wall metabolism, four in ethylene biosynthesis, and one in starch degradation, and 14 transcription factors (TFs) induced by exogenous ethylene treatment and inhibited by the ethylene signaling inhibitor 1-methylcyclopropene were identified as changing in transcript levels during ripening. Moreover, analysis of the regulatory effects of differentially expressed genes identified a zinc finger TF, DNA BINDING WITH ONE FINGER (AdDof3), which showed significant transactivation on the AdBAM3L (ß-amylase) promoter. AdDof3 interacted physically with the AdBAM3L promoter, and stable overexpression of AdBAM3L resulted in lower starch content in transgenic kiwifruit leaves, suggesting that AdBAM3L is a key gene for starch degradation. Moreover, transient overexpression analysis showed that AdDof3 up-regulated AdBAM3L expression in kiwifruit. Thus, transcriptomics analysis not only allowed the prediction of some ripening-regulating genes but also facilitated the characterization of a TF, AdDof3, and a key structural gene, AdBAM3L, in starch degradation.

The facile and visualizable identification of broad-spectrum inhibitors of MDM2/p53 using co-expressed protein complexes.

MDM2 is a well-known oncoprotein overexpressed in a variety of cancers, and the identification of inhibitors that disrupt the MDM2/p53 interaction is of great interest in anticancer drug development. Here we designed a platform for the facile and visualizable identification of inhibitors of MDM2 using co-expressed protein complexes of MDM2/p53. A hexahistidine-tag on MDM2 allows the binding of the protein complex to the Ni-NTA affinity resin, while the fluorescent protein fused to p53 enables the direct visualization of the interaction of p53 with MDM2. Hence, the inhibition of the MDM2/p53 interaction can be observed with the naked eye. The assay can be set up by directly loading cell lysate to the Ni-NTA affinity resin, and no chemical modification of proteins is needed. In addition to the qualitative analyses, the binding affinity of inhibitors to the MDM2 protein can be quantified by fluorescence titration. The applications of this system have been verified using small molecules and peptide inhibitors. As a proof of concept, we screened a small library using this platform. Interestingly, two types of novel inhibitors of MDM2, including cyclohexyl-triphenylamine derivatives and platinum complexes, were identified and their binding affinities were obtained. Quantitative measurements show that these new types of inhibitors demonstrate a high binding affinity (up to Kd = 51.9 nM) to MDM2.

Clinical Value of Serum HE4, CA125, CA72-4, and ROMA Index for Diagnosis of Ovarian Cancer and Prediction of Postoperative Recurrence.

BACKGROUND: Ovarian cancer is one of the most common cancers among women. With cancer, early detection is paramount to saving lives. However, early detection of ovarian cancer has been fraught with difficulty. The diagnostic performance of HE4, CA125, ROMA index, and CA72-4 was evaluated for ovarian cancer. METHODS: This was a diagnostic study enrolling 97 patients with pelvic masses who had been scheduled for surgery and 33 healthy women. Serum levels of tumor markers, including human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125), and carbohydrate antigen 72-4 (CA72-4) were detected in each patient and analyzed using the risk of ovarian malignancy algorithm (ROMA) index for sensitivity, specificity, positive predictive values, negative predictive values, and accuracy. ROC curve analysis was conducted to compare the diagnostic performances of serum HE4, CA125, CA72-4, and ROMA index in ovarian cancer. The dynamic changes of these biomarkers were analyzed in patients with ovarian cancer after operation. RESULTS: HE4 had the best specificity, CA72-4 had the lowest sensitivity, and ROMA index had the best diagnostic efficiency among these biomarkers for diagnosis of ovarian cancer. CA125 had better specificity in the post-menopausal group than in non-menopausal group. The kinetic changes of HE4, CA125, and ROMA index in patients with ovarian cancer were consistent with the remission and recurrence of the disease. CONCLUSIONS: HE4 and ROMA index which reference intervals are established according to the menopausal status have important clinical significance in the diagnosis of ovarian cancer. Regular detection of serum HE4, CA125, and ROMA index can help predict postoperative recurrence of ovarian cancer.