Proteomics Platform Reveals Broad-Spectrum Nanobodies for SARS-CoV-2 Variant Neutralization.

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergence of different variants of concerns with immune evasion that have been prevalent over the past three years. Nanobodies, the functional variable regions of camelid heavy-chain-only antibodies, have garnered interest in developing neutralizing antibodies due to their smaller size, structural stability, ease of production, high affinity, and low immunogenicity, among other characteristics. In this work, we describe an integrated proteomics platform for the high-throughput screening of nanobodies against different SARS-CoV-2 spike variants. To demonstrate this platform, we immunized a camel with subunit 1 (S1) of the wild-type spike protein and constructed a nanobody phage library. The binding and neutralizing activities of the nanobodies against 72 spike variants were then measured, resulting in the identification of two nanobodies (C-282 and C-39) with broad neutralizing activity against six non-Omicron variants (D614G, Alpha, Beta, Gamma, Delta, Kappa) and five Omicron variants (BA.1-5). Their neutralizing capability was validated using in vitro pseudovirus-based neutralization assays. All these results demonstrate the utility of our proteomics platform to identify new nanobodies with broad neutralizing capability and to develop a treatment for patients with SARS-CoV-2 variant infection in the future.

Ferroelectric Domain Wall Delayer and Low-Dropout Regulator.

A switching-type power converter providing an accurate and stable switching output voltage against line/load variations and power supply ripple is mostly complicated in system-on-chip power management integrated circuits (PMICs) within a limited occupation area. Here we fabricated domain wall (DW) nanodevices using an X-cut LiNbO3 thin film on silicon. The domain switching event occurs after a delay time predicted by Merz's law under the applied voltage. But the output current is irrespective of the applied voltage and can be adjusted by conducting wall width as well as input resistance in the circuit. The regulating currents appear repetitively across the volatile interfacial domains between the nanodevice and electrode under intermittently applied voltages. A wall-current-limited domain switching model is developed to explain the phenomenon. The multifunctional DW nanodevices with smaller occupation areas can serve as compact low-dropout regulators in PMICs, time-domain delayers in energy-efficient neural network systems, and on-chip electrostatic discharge protection besides nonvolatile memories and selectors.

Clinical characteristics of choledochal cysts with intrahepatic bile duct dilatations: an observational study.

Purpose: Whether a dilated intrahepatic bile duct (IHBD) has any effect on the prognosis of choledochal cyst (CC) remains controversial. We aimed to summarize the clinical characteristics and prognosis of CC with IHBD dilatation. Methods: One hundred ninety-two children diagnosed with CC were identified, including 127 without IHBD dilatation (group A) and 65 with IHBD dilatation (group B). A retrospective analysis was performed to explore the clinical characteristics and prognosis of CC with IHBD dilatation based on clinical indices, symptoms, and complications. Results: Compared with group A, incidences of jaundice and fever were higher in group B (P = 0.010 and P = 0.033). Preoperative total bilirubin, direct bilirubin, and indirect bilirubin were increased in group B compared to group A (P = 0.005, P < 0.001, and P = 0.014), as were preoperative ALT, AST, γ-GT, and total bile acid (P = 0.006, P = 0.025, P < 0.001, and P = 0.024). The risk of liver fibrosis or cirrhosis was significantly increased for group B compared with group A (P = 0.012) and also occurred earlier in group B (P = 0.006). In the dilated IHBDs, 95.4% (62 of 65) recovered to normal, and more than half of dilated IHBDs (37 of 65) recovered to normal in 1 week. Conclusion: Most IHBDs can recover to normal postoperatively in a short time, and proactive treatment is recommended for CC patients with IHBD dilatation for significant abnormal liver functions.

How digital transformation facilitate synergy for pollution and carbon reduction: Evidence from China.

Frontier studies have neglected the impact of digital transformation (DT) on the synergy for pollution and carbon reduction (SPCR) from the perspective of micro enterprises. This paper explores the SPCR effect of DT, as well as its mechanism at micro-firm level. The study found that: (1) DT significantly facilitates corporate SPCR. For every 10% increase in the level of DT, the ranking of SPCR will rise by about 2.3 places. This effect is more obvious in high-tech firms and non-heavy polluters, firms in the eastern region in China, and non-SOE. (2) DT creates innovation-driven and structure-optimizing effects, which enhance the corporate green innovation ability, optimize the business structure and capital allocation structure of enterprises, and then drive the SPCR. (3) External public environmental concerns (PEC) and internal corporate ESG governance act as "accelerators" promoting the SPCR effect of DT. Based on these, policy implications are made to accelerate the pace of corporate DT, give full play to the first-mover advantage, and break the "pollution (carbon) lock-in" with a view to providing theoretical references for the listed enterprises' digitalized governance of SPCR, as well as the governmental departments' formulation of relevant guiding policies, and striving to achieve the high-quality development goal.

A Comparison of Patient Characteristics and Outcomes Between Patients Receiving Flexor Digitorum Superficialis Slip Excision or Isolated A1 Pulley Release for Trigger Finger.

PURPOSE: Resection of the radial or ulnar slip of the flexor digitorum superficialis (FDS) tendon is a known treatment option for persistent trigger finger. Risk factors for undergoing FDS slip excision are unclear. We hypothesized that patients who underwent A1 pulley release with FDS slip excision secondary to persistent triggering would have a higher comorbidity burden compared to those receiving A1 pulley release alone. METHODS: We identified all adult patients who underwent A1 pulley release with FDS slip excision because of persistent triggering either intraoperatively or postoperatively from 2018 to 2023. We selected a 3:1 age- and sex-matched control group who underwent isolated A1 pulley release. Charts were retrospectively reviewed for demographics, selected comorbidities, trigger finger history, and postoperative course. We performed multivariable logistic regression to assess the probability of FDS slip excision after adjusting for several variables that were significant in bivariate comparisons. RESULTS: We identified 48 patients who underwent A1 pulley release with FDS slip excision and 144 controls. Our multivariable model showed that patients with additional trigger fingers and a preoperative proximal interphalangeal (PIP) joint contracture were significantly more likely to undergo FDS slip excision. CONCLUSIONS: Patients who underwent A1 pulley release with FDS slip excision were significantly more likely to have multiple trigger fingers or a preoperative PIP joint contracture. Clinicians should counsel patients with these risk factors regarding the potential for FDS slip excision in addition to A1 pulley release to alleviate triggering of the affected digit. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.

Long-term immunogenicity and safety of heterologous boosting with a SARS-CoV-2 mRNA vaccine (SYS6006) in Chinese participants who had received two or three doses of inactivated vaccine.

The emerging new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) needs booster vaccination. We evaluated the long-term safety and immunogenicity of heterologous boosting with a SARS-CoV-2 messenger RNA vaccine SYS6006. A total of 1000 participants aged 18 years or more who had received two (Group A) or three (Group B) doses of SARS-CoV-2 inactivated vaccine were enrolled and vaccinated with one dose of SYS6006 which was designed based on the prototype spike protein and introduced mutation sites. Adverse events (AEs) through 30 days and serious AEs during the study were collected. Live-virus and pseudovirus neutralizing antibody (Nab), binding antibody (immunoglobulin G [IgG]) and cellular immunity were tested through 180 days. Solicited all, injection-site and systemic AEs were reported by 618 (61.8%), 498 (49.8%), and 386 (38.6%) participants, respectively. Most AEs were grade 1. The two groups had similar safety profile. No vaccination-related SAEs were reported. Robust wild-type (WT) live-virus Nab response was elicited with peak geometric mean titers (GMTs) of 3769.5 (Group A) and 5994.7 (Group B) on day 14, corresponding to 1602.5- and 290.8-fold increase versus baseline, respectively. The BA.5 live-virus Nab GMTs were 87.7 (Group A) and 93.2 (Group B) on day 14. All participants seroconverted for WT live-virus Nab. Robust pseudovirus Nab and IgG responses to wild type and BA.5 were also elicited. ELISpot assay showed robust cellular immune response, which was not obviously affected by virus variation. In conclusion, SYS6006 heterologous boosting demonstrated long-term good safety and immunogenicity in participants who had received two or three doses of SARS-CoV-2 inactivated vaccine.

Integrated omics analysis reveals a correlation between gut microbiota and egg production in captive African penguins (Spheniscus demersus).

The egg production of captive African penguins differs considerably between individuals. An understanding of the physiological differences in African penguins with relatively greater and lesser egg production is meaningful for the captive breeding program of this endangered species. The objective of this study was to investigate differential microbial composition and metabolites in captive African penguins with different egg production. Fecal samples were collected from captive female African penguins during the breeding season. The results of 16 S rRNA gene sequencing showed that African penguins with different egg production had similar microbial diversities, whereas a significant difference was observed between their microbial community structure. African penguins with relatively greater egg production exhibited a higher relative abundance of Alphaproteobacteria, Rhizobiales, Bradyrhizobiaceae, Bradyrhizobium and Bosea. Meanwhile, penguins with relatively lesser egg production had an increased proportion of Klebsiella and Plesiomonas. We further identified a total of 1858 metabolites in female African penguins by liquid chromatography-mass spectrometry analysis. Among these metabolites, 13 kinds of metabolites were found to be significantly differential between African penguins with different egg production. In addition, the correlation analysis revealed that the egg production had significant correlations with most of the differential microbial bacteria and metabolites. Our findings might aid in understanding the potential mechanism underlying the phenomenon of abnormal egg production in captive African penguins, and provide novel insights into the relationship between gut microbiota and reproduction in penguins.

Comparative stigmatic transcriptomics reveals self and cross pollination responses to heteromorphic incompatibility in Plumbago auriculata Lam.

"Heteromorphic self-incompatibility" (HetSI) in plants is a mechanism of defense to avoid self-pollination and promote outcrossing. However, the molecular mechanism underlying HetSI remains largely unknown. In this study, RNA-seq was conducted to explore the molecular mechanisms underlying self-compatible (SC, "T × P" and "P × T") and self-incompatible (SI, "T × T" and "P × P") pollination in the two types of flowers of Plumbago auriculata Lam. which is a representative HetSI plant. By comparing "T × P" vs. "T × T", 3773 (1407 upregulated and 2366 downregulated) differentially expressed genes (DEGs) were identified, 1261 DEGs between "P × T" and "P × P" (502 upregulated and 759 downregulated). The processes in which these DEGs were significantly enriched were "MAPK (Mitogen-Activated Protein Kinases-plant) signaling pathway", "plant-pathogen interaction","plant hormone signal transduction", and "pentose and glucuronate interconversion" pathways. Surprisingly, we discovered that under various pollination conditions, multiple notable genes that may be involved in HetSI exhibited distinct regulation. We can infer that the HetSI strategy might be unique in P. auriculata. It was similar to "sporophytic self-incompatibility" (SSI) but the HetSI mechanisms in pin and thrum flowers are diverse. In this study, new hypotheses and inferences were proposed, which can provide a reference for crop production and breeding.

Health Benefits of Electrolyzed Hydrogen Water: Antioxidant and Anti-Inflammatory Effects in Living Organisms.

Molecular hydrogen, the smallest and lightest molecule, serves as an intense reducing agent. Its distinct characteristics, including minimal size and neutral charge, enhance bioavailability and facilitate significant biological effects. Previously considered physiologically inert, hydrogen has gained recognition as a powerful therapeutic agent, known for its antioxidative and anti-inflammatory properties. Electrolyzed hydrogen water (EHW), enriched with molecular hydrogen, demonstrates remarkable antioxidative capabilities, indicating potential benefits for various diseases. Inflammation-induced reactive oxygen species (ROS) amplify inflammation, leading to secondary oxidative stress and creating a crosstalk between ROS and inflammatory responses. This crosstalk contributes to the pathogenesis and progression of chronic diseases. EHW interrupts this crosstalk, reducing inflammatory cytokines and oxidative stress across various disease models, suggesting therapeutic potential. EHW is also known for its anti-inflammatory effects, extending to pain management, as evidenced in models like sciatic nerve ligation and inflammatory pain. In an inflammatory bowel disease (IBD) model, EHW effectively alleviates abdominal pain, mitigating 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced inflammation and oxidative stress, offering insights for clinical applications. Additionally, hydrogen selectively targets harmful radicals, and EHW intake helps balance stress-induced hormonal dysregulation, potentially easing disorders associated with chronic stress.

Characteristics and source apportionment of water-soluble organic nitrogen (WSON) in PM2.5 in Hong Kong: With focus on amines, urea, and nitroaromatic compounds.

Water-soluble organic nitrogen (WSON) is ubiquitous in fine particulate matter (PM2.5) and poses health and environmental risks. However, there is limited knowledge regarding its comprehensive speciation and source-specific contributions. Here, we conducted chemical characterization and source apportionment of WSON in 65 PM2.5 samples collected in Hong Kong during a 1-yr period. Using various mass-spectrometry-based techniques, we quantified 22 nitrogen-containing organic compounds (NOCs), including 17 nitroaromatics (NACs), four amines, and urea. The most abundant amine and NACs were dimethylamine and 4-nitrocatechol, respectively. Two secondary (i.e., secondary formation and secondary nitrate) and five primary sources (i.e., sea salt, fugitive dust, marine vessels, vehicle exhaust, and biomass burning) of WSON and these three categories of NOCs were identified. Throughout the year, secondary sources dominated WSON formation (69.0%), while primary emissions had significant contributions to NACs (77.1%), amines (75.9%), and urea (83.7%). Fugitive dust was the leading source of amines and urea, while biomass burning was the main source of NACs. Our multi-linear regression analysis revealed the significant role of sulfate, NO3, nitrate, liquid water content, and particle pH on WSON formation, highlighting the importance of nighttime NO3 processing and heterogeneous and aqueous-phase formation of NOCs in the Hong Kong atmosphere.

Multidimensional IRT for forced choice tests: A literature review.

The Multidimensional Forced Choice (MFC) test is frequently utilized in non-cognitive evaluations because of its effectiveness in reducing response bias commonly associated with the conventional Likert scale. Nonetheless, it is critical to recognize that the MFC test generates ipsative data, a type of measurement that has been criticized due to its limited applicability for comparing individuals. Multidimensional item response theory (MIRT) models have recently sparked renewed interest among academics and professionals. This is largely due to the development of several models that make it easier to collect normative data from forced-choice tests. The paper introduces a modeling framework made up of three key components: response format, measurement model, and decision theory. Under this paradigm, four IRT models were chosen as examples. Following that, a comprehensive study is carried out to compare and characterize the parameter estimation techniques used in MFC-IRT models. This work then examines empirical research on the concept by analyzing three distinct domains: parameter invariance testing, computerized adaptive testing (CAT), and validity investigation. Finally, it is recommended that future research initiatives follow four distinct paths: modeling, parameter invariance testing, forced-choice CAT, and validity studies.

Identification and Validation of Genes Related to Macrophage Polarization and Cell Death Modes Under Mycobacterium tuberculosis Infection.

Purpose: To investigate the correlation between M1/M2 macrophages (M1/M2 Mφ) and cell death mode under Mycobacterium tuberculosis (Mtb) infection. Methods: Raw gene expression profiles were collected from the Gene Expression Omnibus (GEO) database. Genes related to different cell death modes were collected from the KEGG, FerrDb and GSEA databases. The differentially expressed genes (DEGs) of the gene expression profiles were identified using the limma package in R. The intersection genes of M1/M2 Mφ with different cell death modes were obtained by the VennDiagram package. Hub genes were obtained by constructing the protein-protein interactions (PPI) network and Receiver Operating Characteristic (ROC) curve analysis. The expression of cell death modes marker genes and Hub genes were verified by Western Blot and Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Results: Bioinformatics analysis was performed to screen Hub genes of Mtb-infected M1 Mφ and different cell death modes, naming NFKB1, TNF, CFLAR, TBK1, IL6, RELA, SOCS1, AIM2; Hub genes of Mtb-infected M2 Mφ and different cell death modes, naming TNF, BIRC3, MAP1LC3C, DEPTOR, UVRAG, SOCS1. Combined with experimental validation, M1 Mφ under Mtb infection showed higher expression of death (including apoptosis, autophagy, ferroptosis, and pyroptosis) genes compared to M2 Mφ and genes such as NFKB1, TNF, CFLAR, TBK1, IL6, RELA, AIM2, BIRC3, DEPTOR show differential expression. Conclusion: NFKB1, TNF, CFLAR, TBK1, IL6, RELA, AIM2 in Mtb-infected M1 Mφ, and TNF, BIRC3, DEPTOR in Mtb-infected M2 Mφ might be used as potential diagnostic targets for TB. At early stage of Mtb infection, apoptosis, autophagy, ferroptosis, and pyroptosis occurred more significantly in M1 Mφ than that in M2 Mφ, which may contribute to the transition of Mtb-infected Mφ from M1-dominant to M2-dominant and contribute to the immune escape mechanisms of Mtb.

Antibody Profiling of Pan-Cancer Viral Proteome Reveals Biomarkers for Nasopharyngeal Carcinoma Diagnosis and Prognosis.

Diagnosing, predicting disease outcome, and identifying effective treatment targets for virus-related cancers are lacking. Protein biomarkers have the potential to bridge the gap between prevention and treatment for these types of cancers. While it has been shown that certain antibodies against EBV proteins could be used to detect nasopharyngeal carcinoma (NPC), antibodies targeting are solely a tiny part of the about 80 proteins expressed by the EBV genome. Furthermore, it remains unclear what role other viruses play in NPC since many diseases are the result of multiple viral infections. For the first time, this study measured both IgA and IgG antibody responses against 646 viral proteins from 23 viruses in patients with NPC and control subjects using nucleic acid programmable protein arrays. Candidate seromarkers were then validated by ELISA using 1665 serum samples from three clinical cohorts. We demonstrated that the levels of five candidate seromarkers (EBV-BLLF3-IgA, EBV-BLRF2-IgA, EBV-BLRF2-IgG, EBV-BDLF1-IgA, EBV-BDLF1-IgG) in NPC patients were significantly elevated than controls. Additional examination revealed that NPC could be successfully diagnosed by combining the clinical biomarker EBNA1-IgA with the five anti-EBV antibodies. The sensitivity of the six-antibody signature at 95% specificity to diagnose NPC was comparable to the current clinically-approved biomarker combination, VCA-IgA, and EBNA1-IgA. However, the recombinant antigens of the five antibodies are easier to produce and standardize compared to the native viral VCA proteins. This suggests the potential replacement of the traditional VCA-IgA assay with the 5-antibodies combination to screen and diagnose NPC. Additionally, we investigated the prognostic significance of these seromarkers titers in NPC. We showed that NPC patients with elevated BLLF3-IgA and BDLF1-IgA titers in their serum exhibited significantly poorer disease-free survival, suggesting the potential of these two seromarkers as prognostic indicators of NPC. These findings will help develop serological tests to detect and treat NPC in the future.

Life-Space of Older Adults after Discharge from Skilled Nursing Facilities.

OBJECTIVES: Describe (1) patient or caregiver perceptions of physical function in 30 days after skilled nursing facility (SNF) discharge indicated by Life-Space Assessment (LSA) scores, and (2) patient and caregiver factors associated with LSA scores. DESIGN: Secondary analysis of baseline and outcomes data from the cluster randomized trial of the Connect-Home transitional care intervention. SETTING AND PARTICIPANTS: Six SNFs in North Carolina. Patient and caregiver dyads with LSA scores (N = 245). METHODS: SNF patients or their caregivers serving as proxy reported the life-space of the SNF patient using the LSA tool, a measure of environmental and social factors that influence physical mobility. Simple scores for highest life-space attained depending on equipment and/or caregiver support range from 0 to 5, with higher scores indicating greater mobility. Multiple linear regression models for simple LSA scores and Composite Life-Space (0-120), adjusted for treatment, time via a COVID pandemic indicator, and treatment × COVID effect as fixed effects, were used to estimate the association of patient and caregiver variables and life-space. RESULTS: Patients had a mean age of 76.3 years, 62.6% were female, and 74.7% were white. Caregivers were commonly female (73.9%) and adult children of the patient (46.5%). The mean Composite Life-Space score was 22.6 (16.09). The mean Assisted Life-Space score (range: 0-5) was 1.6 (1.47), and 76.3% of patients could not move beyond their bedroom, house, and yard without assistance of another person. Higher Composite Life-Space scores were associated with lower levels of cognitive impairment and shorter SNF length of stay. CONCLUSIONS AND IMPLICATIONS: SNF patients and their caregivers reported very low LSA scores in 30 days after SNF care. Findings indicate the need for care redesign to promote recovery of physical function of older adults after SNF discharge, such as optimizing SNF rehabilitative therapy and adding postdischarge rehabilitative supports at home.

The Applications of CircRNA in the Diagnosis and Treatment of Alzheimer's Disease.

Early diagnosis and intervention are key to the treatment of Alzheimer's disease (AD). There is an urgent need for new biomarkers and molecular targets for the detection and treatment of early Alzheimer's pathology. Circular RNA (circRNA) is a newly discovered non-coding RNA with a special type of covalently closed single strand, with potential preventive and therapeutic applications in a variety of diseases. New studies in the field of circRNA in AD have made many exciting new discoveries in recent years, some of which have not received sufficient attention but have important research implications. This review will focus on existing studies of circRNA in AD and discuss future translational perspectives of proposed circRNA strategies for clinical application in AD.

Predicting Risk of Bullying Victimization among Primary and Secondary School Students: Based on a Machine Learning Model.

School bullying among primary and secondary school students has received increasing attention, and identifying relevant factors is a crucial way to reduce the risk of bullying victimization. Machine learning methods can help researchers predict and identify individual risk behaviors. Through a machine learning approach (i.e., the gradient boosting decision tree model, GBDT), the present longitudinal study aims to systematically examine individual, family, and school environment factors that can predict the risk of bullying victimization among primary and secondary school students a year later. A total of 2767 participants (2065 secondary school students, 702 primary school students, 55.20% female students, mean age at T1 was 12.22) completed measures of 24 predictors at the first wave, including individual factors (e.g., self-control, gender, grade), family factors (family cohesion, parental control, parenting style), peer factor (peer relationship), and school factors (teacher-student relationship, learning capacity). A year later (i.e., T2), they completed the Olweus Bullying Questionnaire. The GBDT model predicted whether primary and secondary school students would be exposed to school bullying after one year by training a series of base learners and outputting the importance ranking of predictors. The GBDT model performed well. The GBDT model yielded the top 6 predictors: teacher-student relationship, peer relationship, family cohesion, negative affect, anxiety, and denying parenting style. The protective factors (i.e., teacher-student relationship, peer relationship, and family cohesion) and risk factors (i.e., negative affect, anxiety, and denying parenting style) associated with the risk of bullying victimization a year later among primary and secondary school students are identified by using a machine learning approach. The GBDT model can be used as a tool to predict the future risk of bullying victimization for children and adolescents and to help improve the effectiveness of school bullying interventions.

New perspectives on the potential of tetrandrine in the treatment of non-small cell lung cancer: bioinformatics, Mendelian randomization study and experimental investigation.

BACKGROUND: Although there are numerous treatment methods for NSCLC, long-term survival remains a challenge for patients. The objective of this study is to investigate the role and causal relationship between the target of tetrandrine and non-small cell lung cancer (NSCLC) through transcriptome and single-cell sequencing data, summary-data-based Mendelian Randomization (SMR) and basic experiments. The aim is to provide a new perspective for the treatment of NSCLC. METHODS: We obtained the drug target gene of tetrandrine through the drug database, and then used the GSE19188 data set to obtain the NSCLC pathogenic gene, established a drug-disease gene interaction network, screened out the hub drug-disease gene, and performed bioinformatics and tumor cell immune infiltration analysis. Single-cell sequencing data (GSE148071) to determine gene location, SMR to clarify causality and drug experiment verification. RESULTS: 10 drug-disease genes were obtained from 213 drug targets and 529 disease genes. DO/GO/KEGG analysis showed that the above genes were all related to the progression and invasion of NSCLC. Four drug-disease genes were identified from a drug-disease PPI network. These four genes were highly expressed in tumors and positively correlated with plasma cells, T cells, and macrophages. Subsequent single-cell sequencing data confirmed that these four genes were distributed in epithelial cells, and SMR analysis revealed the causal relationship between CCNA2 and CCNB1 and the development of NSCLC. The final molecular docking and drug experiments showed that CCNA2 and CCNB1 are key targets for tetrandrine in the treatment of NSCLC.

Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif.

The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find that a conserved, intrinsically disordered, six-residue Short Linear Motif at the extreme Drp1 C-terminus, named CT-SLiM, constitutes a critical allosteric site that controls Drp1 structure and function in vitro and in vivo. Extension of the CT-SLiM by non-native residues, or its interaction with the protein partner GIPC-1, constrains Drp1 subunit conformational dynamics, alters self-assembly properties, and limits cooperative GTP hydrolysis, surprisingly leading to the fission of model membranes in vitro. In vivo, the involvement of the native CT-SLiM is critical for productive mitochondrial and peroxisomal fission, as both deletion and non-native extension of the CT-SLiM severely impair their progression. Thus, contrary to prevailing models, Drp1-catalyzed membrane fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics.

Review of Australia's funding commitments for suicide prevention from 2021-22 to 2026-27.

Objective Examine the distribution of funding for suicide prevention in Australia from 2021-22 to 2026-27. Methods Government websites were reviewed to locate budget documents related to suicide prevention funding. Information was extracted on the program/service to be funded, and the funder entity, duration, and year allocation. Extracted data was reviewed to identify commonly targeted sub-populations. Results The majority of suicide prevention-related funding was allocated to aftercare for persons who have attempted suicide, consistent with the effectiveness of these services, followed by programs targeting the general population. Little funding was allocated to other specific sub-populations, such as young people and Aboriginal and Torres Strait Islander peoples. The amount of funding allocated to suicide prevention varied across jurisdictions, which is only partially explained by suicide rates. Conclusions There is a need for greater investment in care for specific sub-populations who are at higher risk of suicide. This study provides a baseline for comparing future investments in suicide prevention in Australia.