Recombinant OC43 SARS-CoV-2 spike replacement virus: An improved BSL-2 proxy virus for SARS-CoV-2 neutralization assays.

We generated a replication-competent OC43 human seasonal coronavirus (CoV) expressing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike in place of the native spike (rOC43-CoV2 S). This virus is highly attenuated relative to OC43 and SARS-CoV-2 in cultured cells and animals and is classified as a biosafety level 2 (BSL-2) agent by the NIH biosafety committee. Neutralization of rOC43-CoV2 S and SARS-CoV-2 by S-specific monoclonal antibodies and human sera is highly correlated, unlike recombinant vesicular stomatitis virus-CoV2 S. Single-dose immunization with rOC43-CoV2 S generates high levels of neutralizing antibodies against SARS-CoV-2 and fully protects human ACE2 transgenic mice from SARS-CoV-2 lethal challenge, despite nondetectable replication in respiratory and nonrespiratory organs. rOC43-CoV2 S induces S-specific serum and airway mucosal immunoglobulin A and IgG responses in rhesus macaques. rOC43-CoV2 S has enormous value as a BSL-2 agent to measure S-specific antibodies in the context of a bona fide CoV and is a candidate live attenuated SARS-CoV-2 mucosal vaccine that preferentially replicates in the upper airway.

Dephosphorylation of T517 on Hemocyanin Is Required for Antibacterial Activity in Penaeus vannamei.

Posttranslational modifications expand the functions of immune-related proteins, especially during infections. The respiratory glycoprotein, hemocyanin, has been implicated in many other functions, but the role of phosphorylation modification in its functional diversity is not fully understood. In this study, we show that Penaeus vannamei hemocyanin (PvHMC) undergoes phosphorylation modification during bacterial infection. Dephosphorylation of PvHMC mediated by P. vannamei protein phosphatase 2A catalytic increases its in vitro antibacterial activity, whereas phosphorylation by P. vannamei casein kinase 2 catalytic subunit α decreases its oxygen-carrying capacity and attenuates its in vitro antibacterial activity. Mechanistically, we show that Thr517 is a critical phosphorylation modification site on PvHMC to modulate its functions, which when mutated attenuates the action of P. vannamei casein kinase 2 catalytic subunit α and P. vannamei protein phosphatase 2A catalytic, and hence abolishes the antibacterial activity of PvHMC. Our results reveal that phosphorylation of PvHMC modulates its antimicrobial functions in penaeid shrimp.

RNA helicase DDX6 and scaffold protein GW182 in P-bodies promote biogenesis of stress granules.

Two prominent cytoplasmic RNA granules, ubiquitous RNA-processing bodies (PB) and inducible stress granules (SG), regulate mRNA translation and are intimately related. In this study, we found that arsenite (ARS)-induced SG formed in a stepwise process is topologically and mechanically linked to PB. Two essential PB components, GW182 and DDX6, are repurposed under stress to play direct but distinguishable roles in SG biogenesis. By providing scaffolding activities, GW182 promotes the aggregation of SG components to form SG bodies. DEAD-box helicase DDX6 is also essential for the proper assembly and separation of PB from SG. DDX6 deficiency results in the formation of irregularly shaped 'hybrid' PB/SG granules with accumulated components of both PB and SG. Wild-type DDX6, but not its helicase mutant E247A, can rescue the separation of PB from SG in DDX6KO cells, indicating a requirement of DDX6 helicase activity for this process. DDX6 activity in biogenesis of both PB and SG in the cells under stress is further modulated by its interaction with two protein partners, CNOT1 and 4E-T, of which knockdown affects the formation of both PB and also SG. Together, these data highlight a new functional paradigm between PB and SG biogenesis during the stress.

Incidence, Risk Factors, and Temporal Trends of Small Intestinal Cancer: A Global Analysis of Cancer Registries.

BACKGROUND & AIMS: Small intestinal cancer is a rare cancer, with limited studies exploring its epidemiology. To our knowledge, this study is the first effort to comprehensively analyze the incidence, risk factors, and trends for small intestinal cancer by sex, age, and country. METHODS: Global Cancer Observatory, Cancer Incidence in Five Continents Plus, and Global Burden of Disease were accessed to estimate the age-standardized rates of small intestinal cancer incidence (International Classification of Diseases, 10th Revision, Clinical Modification: C17) and prevalence of lifestyle risk factors, metabolic risk factors, and inflammatory bowel disease (IBD). Risk factor associations were assessed by linear and logistic regressions. Average annual percent change was calculated using joinpoint regression. RESULTS: A total of 64,477 small intestinal cancer cases (age-standardized rate, 0.60 per 100,000) were estimated globally in 2020, with a higher disease burden found in North America (1.4). Higher small intestinal cancer incidence was associated with higher human development index; gross domestic product; and prevalence of smoking, alcohol drinking, physical inactivity, obesity, diabetes, lipid disorder, and IBD (ß = 0.008-0.198; odds ratios, 1.07-10.01). There was an overall increasing trend of small intestinal cancer incidence (average annual percent change, 2.20-21.67), and the increasing trend was comparable among the 2 sexes but more evident in the older population aged 50-74 years than in the younger population aged 15-49 years. CONCLUSION: There was a substantial geographic disparity in the burden of small intestinal cancer, with higher incidence observed in countries with higher human development index; gross domestic product; and prevalence of unhealthy lifestyle habits, metabolic disorders, and IBD. There was an overall increasing trend in small intestinal cancer incidence, calling for the development of preventive strategies.

A Programmable Microfluidic Paper-Based Analytical Device for Simultaneous Colorimetric and Photothermal Visual Sensing of Multiple Enzyme Activities.

New strategies for the simultaneous and portable detection of multiple enzyme activities are highly desirable for clinical diagnosis and home care. However, the methods developed thus far generally suffer from high costs, cumbersome procedures, and heavy reliance on large-scale instruments. To satisfy the actual requirements of rapid, accurate, and on-site detection of multiple enzyme activities, we report herein a smartphone-assisted programmable microfluidic paper-based analytical device (µPAD) that utilizes colorimetric and photothermal signals for simultaneous, accurate, and visual quantitative detection of alkaline phosphatase (ALP) and butyrylcholinesterase (BChE). Specifically, the operation of this µPAD sensing platform is based on two sequential steps. Cobalt-doped mesoporous cerium oxide (Co-m-CeO2) with remarkable peroxidase-like activities under neutral conditions first catalytically decomposes H2O2 for effectively converting colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxidized TMB (oxTMB). The subsequent addition of ALP or BChE to their respective substrates produces a reducing substance that can somewhat inhibit the oxTMB transformation for compromised colorimetric and photothermal signals of oxTMB. Notably, these two-step bioenzyme-nanozyme cascade reactions strongly support the straightforward and excellent processability of this platform, which exhibit lower detection limits for ALP and BChE with a detection limit for BChE an order of magnitude lower than those of the other reported paper-based detection methods. The practicability and efficiency of this platform are further demonstrated through the analysis of clinical serum samples. This innovative platform exhibits great potential as a facile yet robust approach for simultaneous, accurate, and on-site visual detection of multiple enzyme activities in authentic samples.

Association between drinking water quality and mental health and the modifying role of diet: a prospective cohort study.

BACKGROUND: Environmental factors play an important role in developing mental disorders. This study aimed to investigate the associations of metal and nonmetal elements in drinking water with the risk of depression and anxiety and to assess whether diets modulate these associations. METHODS: We conducted a prospective cohort study including 24,285 participants free from depression and anxiety from the Yinzhou Cohort study in the 2016-2021 period. The exposures were measured by multiplying metal and nonmetal element concentrations in local pipeline terminal tap water samples and total daily drinking water intakes. Cox regression models adjusted for multi-level covariates were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (95%CIs). RESULTS: During an average follow-up period of 4.72 and 4.68 years, 773 and 1334 cases of depression and anxiety were identified, respectively. A 1 standard deviation (SD) increase in manganese exposure reduced the incidence of depression by 8% (HR 0.92, 95%CI 0.88 to 0.97). In contrast, with a 1 SD increase in copper and cadmium exposure, the incidence of depression increased by 6% (HR 1.06, 95%CI 1.01 to 1.11) and 8% (HR 1.08, 95%CI 1.00 to 1.17), respectively. The incidence of anxiety increased by 39% (HR 1.39, 95%CI 1.20 to 1.62), 33% (HR 1.33, 95%CI 1.03 to 1.71), and 14% (HR 1.14, 95%CI 1.03 to 1.25) respectively for a 1 SD increase in manganese, iron, and selenium exposure. Diets have a moderating effect on the associations of metal and nonmetal elements with the risk of anxiety. Stronger associations were observed in older, low-income groups and low-education groups. CONCLUSIONS: We found significant associations between exposure to metal and nonmetal elements and depression and anxiety. Diets regulated the associations to some extent.

Global burden, risk factors, and temporal trends of ureteral cancer: a comprehensive analysis of cancer registries.

BACKGROUND: Ureteral cancer is a rare cancer. This study aimed to provide an up-to-date and comprehensive analysis on the global trends of ureteral cancer incidence and its association with lifestyle and metabolic risk factors. METHODS: The incidence of ureteral cancer was estimated from the Cancer Incidence in Five Continents Plus and Global Cancer Observatory databases. We analyzed the (1) global incidence of ureteral cancer by region, country, sex, and age group by age-standardized rates (ASR); (2) associated risk factors on a population level by univariable linear regression with logarithm transformation; and (3) incidence trend of ureteral cancer by sex and age group in different countries by Average Annual Percentage Change (AAPC). RESULTS: The global age-standardized rate of ureteral cancer incidence in 2022 was 22.3 per 10,000,000 people. Regions with higher human development index (HDI), such as Europe, Northern America, and East Asia, were found to have a higher incidence of ureteral cancer. Higher HDI and gross domestic product (GDP) and a higher prevalence of smoking, alcohol drinking, physical inactivity, unhealthy dietary, obesity, hypertension, diabetes, and lipid disorder were associated with higher incidence of ureteral cancer. An overall increasing trend of ureteral cancer incidence was observed for the past decade, especially among the female population. CONCLUSIONS: Although ureteral cancer was relatively rare, the number of cases reported was rising over the world. The rising trends among females were more evident compared with the other subgroups, especially in European countries. Further studies could be conducted to examine the reasons behind these epidemiological changes and confirm the relationship with the risk factors identified.

Enhanced Hydrogen Evolution Catalysis of Pentlandite due to the Increases in Coordination Number and Sulfur Vacancy during Cubic-Hexagonal Phase Transition.

The search for new phases is an important direction in materials science. The phase transition of sulfides results in significant changes in catalytic performance, such as MoS2 and WS2. Cubic pentlandite [cPn, (Fe, Ni)9S8] can be a functional material in batteries, solar cells, and catalytic fields. However, no report about the material properties of other phases of pentlandite exists. In this study, the unit-cell parameters of a new phase of pentlandite, sulfur-vacancy enriched hexagonal pentlandite (hPn), and the phase boundary between cPn and hPn are determined for the first time. Compared to cPn, the hPn shows a high coordination number, more sulfur vacancies, and high conductivity, which result in significantly higher hydrogen evolution performance of hPn than that of cPn and make the non-nano rock catalyst hPn superior to other most known nanosulfide catalysts. The increase of sulfur vacancies during phase transition provides a new approach to designing functional materials.

Genome-wide regulation of KSHV RNA splicing by viral RNA-binding protein ORF57.

RNA splicing plays an essential role in the expression of eukaryotic genes. We previously showed that KSHV ORF57 is a viral splicing factor promoting viral lytic gene expression. In this report, we compared the splicing profile of viral RNAs in BCBL-1 cells carrying a wild-type (WT) versus the cells containing an ORF57 knock-out (57KO) KSHV genome during viral lytic infection. Our analyses of viral RNA splice junctions from RNA-seq identified 269 RNA splicing events in the WT and 255 in the 57KO genome, including the splicing events spanning large parts of the viral genome and the production of vIRF4 circRNAs. No circRNA was detectable from the PAN region. We found that the 57KO alters the RNA splicing efficiency of targeted viral RNAs. Two most susceptible RNAs to ORF57 splicing regulation are the K15 RNA with eight exons and seven introns and the bicistronic RNA encoding both viral thymidylate synthase (ORF70) and membrane-associated E3-ubiquitin ligase (K3). ORF57 inhibits splicing of both K15 introns 1 and 2. ORF70/K3 RNA bears two introns, of which the first intron is within the ORF70 coding region as an alternative intron and the second intron in the intergenic region between the ORF70 and K3 as a constitutive intron. In the WT cells expressing ORF57, most ORF70/K3 transcripts retain the first intron to maintain an intact ORF70 coding region. In contrast, in the 57KO cells, the first intron is substantially spliced out. Using a minigene comprising of ORF70/K3 locus, we further confirmed ORF57 regulation of ORF70/K3 RNA splicing, independently of other viral factors. By monitoring protein expression, we showed that ORF57-mediated retention of the first intron leads to the expression of full-length ORF70 protein. The absence of ORF57 promotes the first intron splicing and expression of K3 protein. Altogether, we conclude that ORF57 regulates alternative splicing of ORF70/K3 bicistronic RNA to control K3-mediated immune evasion and ORF70 participation of viral DNA replication in viral lytic infection.

Comparison of Short-Term Outcomes After Robotic Versus Laparoscopic Radical Gastrectomy for Advanced Gastric Cancer in Elderly Individuals: A Propensity Score-Matching Study.

BACKGROUND: Robotic gastrectomy (RG) has been widely used to treat gastric cancer. However, whether the short-term outcomes of robotic gastrectomy are superior to those of laparoscopic gastrectomy (LG) for elderly patients with advanced gastric cancer has not been reported. METHODS: The study enrolled of 594 elderly patients with advanced gastric cancer who underwent robotic or laparoscopic radical gastrectomy. The RG cohort was matched 1:3 with the LG cohort using propensity score-matching (PSM). RESULTS: After PSM, 121 patients were included in the robot group and 363 patients in the laparoscopic group. Excluding the docking and undocking times, the operation time of the two groups was similar (P = 0.617). The RG group had less intraoperative blood loss than the LG group (P < 0.001). The time to ambulation and first liquid food intake was significantly shorter in the RG group than in the LG group (P < 0.05). The incidence of postoperative complications did not differ significantly between the two groups (P = 0.14). Significantly more lymph nodes were dissected in the RG group than in the LG group (P = 0.001). Postoperative adjuvant chemotherapy was started earlier in the RG group than in the LG group (P = 0.02). CONCLUSIONS: For elderly patients with advanced gastric cancer, RG is safe and feasible. Compared with LG, RG is associated with less intraoperative blood loss; a faster postoperative recovery time, allowing a greater number of lymph nodes to be dissected; and earlier adjuvant chemotherapy.

Identification of a novel and plant height-independent QTL for coleoptile length in barley and validation of its effect using near isogenic lines.

KEY MESSAGE: This study reported the identification and validation of novel QTL conferring coleoptile length in barley and predicted candidate genes underlying the largest effect QTL based on orthologous analysis and comparison of the whole genome assemblies for both parental genotypes of the mapping population. Coleoptile length (CL) is one of the most important agronomic traits in cereal crops due to its direct influence on the optimal depth for seed sowing which facilitates better seedling establishment. Varieties with longer coleoptiles are preferred in drought-prone areas where less moisture maintains at the top layer of the soil. Compared to wheat, genetic study on coleoptile length is limited in barley. Here, we reported a study on detecting the genomic regions associated with CL in barley by assessing a population consisting of 201 recombinant inbred lines. Four putative QTL conferring CL were consistently identified on chromosomes 1H, 5H, 6H, and 7H in each of the trials conducted. Of these QTL, the two located on chromosomes 5H and 6H (designated as Qcl.caf-5H and Qcl.caf-6H) are likely novel and Qcl.caf-5H showed the most significant effect explaining up to 30.9% of phenotypic variance with a LOD value of 15.1. To further validate the effect of this putative QTL, five pairs of near isogenic lines (NILs) were then developed and assessed. Analysis of the NILs showed an average difference of 21.0% in CL between the two isolines. Notably, none of the other assessed morphological characteristics showed consistent differences between the two isolines for each pair of the NILs. Candidate genes underlying the Qcl.caf-5H locus were also predicted by employing orthologous analysis and comparing the genome assemblies for both parental genotypes of the mapping population in the present study. Taken together, these findings expand our understanding on genetic basis of CL and will be indicative for further gene cloning and functional analysis underly this locus in barley.

Dissecting the genetic basis of Fusarium crown rot resistance in wheat by genome wide association study.

KEY MESSAGE: A locus conferring Fusarium crown rot resistance was identified on chromosome arm 3DL through genome wide association study and further validated in two recombinant inbred lines populations. Fusarium crown rot (FCR) is a severe soil borne disease in many wheat growing regions of the world. In this study, we attempted to detect loci conferring FCR resistance through a new seedling inoculation assay. A total of 223 wheat accessions from different geography origins were used to assemble an association panel for GWAS analysis. Four genotypes including Heng 4332, Luwanmai, Pingan 998 and Yannong 24 showed stable resistance to FCR. A total of 54 SNPs associated with FCR resistance were identified. Among the 10 putative QTLs represented by these SNPs, seven QTLs on chromosome 2B, 3A, 3D, 4A, 7A and 7B were novel and were consistently detected in at least two of the three trials conducted. Qfcr.cau.3D-3, which was targeted by 38 SNPs clustered within a genomic region of approximately 5.57 Mb (609.12-614.69 Mb) on chromosome arm 3DL, was consistently detected in all the three trials. The effects of Qfcr.cau.3D-3 were further validated in two recombinant inbred line populations. The presence of this locus reduced FCR severity up to 21.55%. Interestingly, the collinear positions of sequences containing the four SNPs associated with two FCR loci (Qfcr.cau.3A and Qfcr.cau.3B) were within the regions of Qfcr.cau.3D-3, suggesting that genes underlying these three loci may be homologous. Our results provide useful information for improving FCR resistance in wheat.

A novel QTL conferring Fusarium crown rot resistance on chromosome 2A in a wheat EMS mutant.

KEY MESSAGE: A novel QTL on chromosome 2A for Fusarium crown rot resistance was identified and validated in wheat. Fusarium crown rot (FCR) is a fungal disease that causes significant yield losses in many cereal growing regions in the world. In this study, genetic analysis was conducted for a wheat EMS mutant C549 which showed stable resistance to FCR at seedling stage. A total of 10 QTL were detected on chromosomes 1A, 2A, 3B, 4A, 6B, and 7B using a population of 138 F7 recombinant inbred lines (RILs) derived from a cross between C549 and a Chinese germplasm 3642. A novel locus Qfcr.cau-2A, which accounted for up to 24.42% of the phenotypic variation with a LOD value of 12.78, was consistently detected across all six trials conducted. Furthermore, possible effects of heading date (HD) and plant height on FCR severity were also investigated in the mapping population. While plant height had no effects on FCR resistance, a weak and negative association between FCR resistance and HD was observed. A QTL for HD (Qhd.cau-2A.2) was coincident with Qfcr.cau-2A. Conditional QTL mapping indicated that although Qfcr.cau-2A and Qhd.cau-2A.2 had significant interactions, Qfcr.cau-2A remained significant after the effects of HD was removed. It is unlikely that genes underlying these two loci are same. Nevertheless, the stable expression of Qfcr.cau-2A in the validation population of 148 F7 RILs developed between C549 and its wild parent Chuannong 16 demonstrated the potential value of this locus in FCR resistance breeding programs.

Transcriptomic insights into shared responses to Fusarium crown rot infection and drought stresses in bread wheat (Triticum aestivum L.).

KEY MESSAGE: Shared changes in transcriptomes caused by Fusarium crown rot infection and drought stress were investigated based on a single pair of near-isogenic lines developed for a major locus conferring tolerance to both stresses. Fusarium crown rot (FCR) is a devastating disease in many areas of cereal production worldwide. It is well-known that drought stress enhances FCR severity but possible molecular relationship between these two stresses remains unclear. To investigate their relationships, we generated several pairs of near isogenic lines (NILs) targeting a locus conferring FCR resistance on chromosome 2D in bread wheat. One pair of these NILs showing significant differences between the two isolines for both FCR resistance and drought tolerance was used to investigate transcriptomic changes in responsive to these two stresses. Our results showed that the two isolines likely deployed different strategies in dealing with the stresses, and significant differences in expressed gene networks exist between the two time points of drought stresses evaluated in this study. Nevertheless, results from analysing Gene Ontology terms and transcription factors revealed that similar regulatory frameworks were activated in coping with these two stresses. Based on the position of the targeted locus, changes in expression following FCR infection and drought stresses, and the presence of non-synonymous variants between the two isolines, several candidate genes conferring resistance or tolerance to these two types of stresses were identified. The NILs generated, the large number of DEGs with single-nucleotide polymorphisms detected between the two isolines, and the candidate genes identified would be invaluable in fine mapping and cloning the gene(s) underlying the targeted locus.

A co-located QTL for seven spike architecture-related traits shows promising breeding use potential in common wheat (Triticum aestivum L.).

KEY MESSAGE: A co-located novel QTL for TFS, FPs, FMs, FFS, FFPs, KWS, and KWPs with potential of improving wheat yield was identified and validated. Spike-related traits, including fertile florets per spike (FFS), kernel weight per spike (KWS), total florets per spike (TFS), florets per spikelet (FPs), florets in the middle spikelet (FMs), fertile florets per spikelet (FFPs), and kernel weight per spikelet (KWPs), are key traits in improving wheat yield. In the present study, quantitative trait loci (QTL) for these traits evaluated under various environments were detected in a recombinant inbred line population (msf/Chuannong 16) mainly genotyped using the 16 K SNP array. Ultimately, we identified 60 QTL, but only QFFS.sau-MC-1A for FFS was a major and stably expressed QTL. It was located on chromosome arm 1AS, where loci for TFS, FPs, FMs, FFS, FFPs, KWS, and KWPs were also simultaneously co-mapped. The effect of QFFS.sau-MC-1A was further validated in three independent segregating populations using a Kompetitive Allele-Specific PCR marker. For the co-located QTL, QFFS.sau-MC-1A, the presence of a positive allele from msf was associate with increases for all traits: + 12.29% TFS, + 10.15% FPs, + 13.97% FMs, + 17.12% FFS, + 14.75% FFPs, + 22.17% KWS, and + 19.42% KWPs. Furthermore, pleiotropy analysis showed that the positive allele at QFFS.sau-MC-1A simultaneously increased the spike length, spikelet number per spike, and thousand-kernel weight. QFFS.sau-MC-1A represents a novel QTL for marker-assisted selection with the potential for improving wheat yield. Four genes, TraesCS1A03G0012700, TraesCS1A03G0015700, TraesCS1A03G0016000, and TraesCS1A03G0016300, which may affect spike development, were predicted in the physical interval harboring QFFS.sau-MC-1A. Our results will help in further fine mapping QFFS.sau-MC-1A and be useful for improving wheat yield.

Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors.

The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74-/- mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PLPNs-dSTRFSIs) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PLPNs-BLAPNs) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL-dSTR or PL-BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL-dSTR and PL-BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.

LHPP, a risk factor for major depressive disorder, regulates stress-induced depression-like behaviors through its histidine phosphatase activity.

Histidine phosphorylation (pHis), occurring on the histidine of substrate proteins, is a hidden phosphoproteome that is poorly characterized in mammals. LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) is one of the histidine phosphatases and its encoding gene was recently identified as a susceptibility gene for major depressive disorder (MDD). However, little is known about how LHPP or pHis contributes to depression. Here, by using integrative approaches of genetics, behavior and electrophysiology, we observed that LHPP in the medial prefrontal cortex (mPFC) was essential in preventing stress-induced depression-like behaviors. While genetic deletion of LHPP per se failed to affect the mice's depression-like behaviors, it markedly augmented the behaviors upon chronic social defeat stress (CSDS). This augmentation could be recapitulated by the local deletion of LHPP in mPFC. By contrast, overexpressing LHPP in mPFC increased the mice's resilience against CSDS, suggesting a critical role of mPFC LHPP in stress-induced depression. We further found that LHPP deficiency increased the levels of histidine kinases (NME1/2) and global pHis in the cortex, and decreased glutamatergic transmission in mPFC upon CSDS. NME1/2 served as substrates of LHPP, with the Aspartic acid 17 (D17), Threonine 54 (T54), or D214 residue within LHPP being critical for its phosphatase activity. Finally, reintroducing LHPP, but not LHPP phosphatase-dead mutants, into the mPFC of LHPP-deficient mice reversed their behavioral and synaptic deficits upon CSDS. Together, these results demonstrate a critical role of LHPP in regulating stress-related depression and provide novel insight into the pathogenesis of MDD.

Incidence, risk factors, and temporal trends of penile cancer: a global population-based study.

OBJECTIVES: To examine the global disease burden and country-specific trends of penile cancer incidence by age group and investigate its associations with several factors. MATERIALS AND METHODS: The Global Cancer Observatory database was interrogated for penile cancer incidence. The 10-year cancer incidence rates were collected from the Cancer Incidence in Five Continents Plus. The country-specific data were extracted from the World Health Organization Global Health Observatory and Global Burden of Disease databases for conducting risk factors analysis. The penile cancer incidence was presented using age-standardised rates. Its associations with various factors were examined by linear regression, while the incidence trend was estimated using joinpoint regression and presented as average annual percentage change with 95% confidence intervals in different age groups. RESULTS: There were an estimated 36 068 new cases of penile cancer in 2020. There was a considerable geographical disparity in the disease burden of penile cancer, with South America reporting the highest incidence. Overall, alcohol drinking, human immunodeficiency virus (HIV) infection, and unsafe sex were positively associated with a higher penile cancer incidence, while circumcision was found to be a protective factor. There has been a mixed trend in penile cancer incidence overall, but an increasing trend was found among younger males. CONCLUSIONS: There was a global variation in the penile cancer burden associated with prevalence of alcohol drinking, HIV infection, unsafe sex, and circumcision. The increasing penile cancer incidence in the younger population is worrying and calls for early detection and preventive interventions.

A mesothelin microsensor based on an embedded thionine electronic medium within an imprinted polymer on an acupuncture needle electrode.

An electrochemical microsensor for mesothelin (MSLN) based on an acupuncture needle (AN) was constructed in this work. To prepare the microsensor, MSLN was self-assembled on 4-mercaptophenylboronic acid (4-MPBA) by an interaction force between the external cis-diol and phenylboronic acid. This was followed by the gradual electropolymerization of thionine (TH) and eriochrome black T (EBT) around the anchored protein. The thickness of the surface imprinted layers influenced the sensing performance and needed to be smaller than the height of the anchored protein. The polymerized EBT was not electrically active, but the polymerized TH provided a significant electrochemical signal. Therefore, electron transfer smoothly proceeded through the eluted nanocavities. The imprinted nanocavities were highly selective toward MSLN, and the rebinding of insulating proteins reduced the electrochemical signal of the embedded pTH. The functionalized interface was characterized by SEM and electrochemical methods, and the preparation conditions were studied. After optimization, the sensor showed a linear response in the range of 0.1 to 1000 ng mL-1 with a detection limit of 10 pg mL-1, indicating good performance compared with other reported methods. This microsensor also showed high sensitivity and stability, which can be attributed to the fine complementation of the imprinted organic nanocavities. The sensitivity of this sensor was related to the nanocavities used for electron transport around the AuNPs. In the future, microsensors that can directly provide electrochemical signals are expected to play important roles especially on AN matrices.

Metal Hydrogen-Bonded Organic Frameworks as Open Lewis Acid Catalysts for Two Types of CO2 Transformations.

Efficient and multiple CO2 utilization into high-value-added chemicals holds significant importance in carbon neutrality and industry production. However, most catalysis systems generally exhibit only one type of CO2 transformation with the efficiency to be improved. The restricted abundance of active catalytic sites or an inefficient utilization rate of these sites results in the constraint. Consequently, we designed and constructed two metal hydrogen-bonded organic frameworks (M-HOFs) {[M3(L3-)2(H2O)10]·2H2O}n (M = Co (1), Ni (2); L = 1-(4-carboxyphenyl)-1H-pyrazole-3,5-dicarboxylic acid) in this research. 1 and 2 are well-characterized, and both show excellent stability. The networks connected by multiple hydrogen bonds enhance the structural flexibility and create accessible Lewis acidic sites, promoting interactions between the substrates and catalytic centers. This enhancement facilitates efficient catalysis for two types of CO2 transformations, encompassing both cycloaddition reactions with epoxides and aziridines to afford cyclic carbonates and oxazolidinones. The catalytic activities (TON/TOF) are superior compared with those of most other catalysts. These heterogeneous catalysts still exhibited high performance after being reused several times. Mechanistic studies indicated intense interactions between the metal sites and substrates, demonstrating the reason for efficient catalysis. This marks the first instance on M-HOFs efficiently catalyzing two types of CO2 conversions, finding important significance for catalyst design and CO2 utilization.