Mapping protein-protein interactions by mass spectrometry.

Protein-protein interactions (PPIs) are essential for numerous biological activities, including signal transduction, transcription control, and metabolism. They play a pivotal role in the organization and function of the proteome, and their perturbation is associated with various diseases, such as cancer, neurodegeneration, and infectious diseases. Recent advances in mass spectrometry (MS)-based protein interactomics have significantly expanded our understanding of the PPIs in cells, with techniques that continue to improve in terms of sensitivity, and specificity providing new opportunities for the study of PPIs in diverse biological systems. These techniques differ depending on the type of interaction being studied, with each approach having its set of advantages, disadvantages, and applicability. This review highlights recent advances in enrichment methodologies for interactomes before MS analysis and compares their unique features and specifications. It emphasizes prospects for further improvement and their potential applications in advancing our knowledge of PPIs in various biological contexts.

Assessing the value of incorporating a polygenic risk score with non-genetic factors for predicting breast cancer diagnosis in the UK Biobank.

BACKGROUND: Previous studies have demonstrated that incorporating a polygenic risk score (PRS) to existing risk prediction models for breast cancer improves model fit, but to determine its clinical utility the impact on risk categorisation needs to be established. We add a PRS to two well-established models and quantify the difference in classification using the net reclassification improvement (NRI). METHODS: We analysed data from 126,490 post-menopausal women of "White British" ancestry, aged 40-69 years at baseline from the UK Biobank prospective cohort. The breast cancer outcome was derived from linked registry data and hospital records. We combined a PRS for breast cancer with 10-year risk scores from the Tyrer-Cuzick and Gail models, and compared these to the risk scores from the models using phenotypic variables alone. We report metrics of discrimination and classification, and consider the importance of the risk threshold selected. RESULTS: The Harrell's C statistic of the 10-year risk from the Tyrer-Cuzick and Gail models was 0.57 and 0.54, respectively, increasing to 0.67 when the PRS was included. Inclusion of the PRS gave a positive NRI for cases in both models (0.080 (95% confidence interval: 0.053, 0.104) and 0.051 (95% CI: 0.030, 0.073), respectively), with negligible impact on controls. CONCLUSIONS: The addition of a PRS for breast cancer to the well-established Tyrer-Cuzick and Gail models provides a substantial improvement in the prediction accuracy and risk stratification. IMPACT: These findings could have important implications for the ongoing discussion about the value of PRS in risk prediction models and screening.

Disruption of KLHL6 Fuels Oncogenic Antigen Receptor Signaling in B-cell Lymphoma.

Pathomechanisms that activate oncogenic B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma (DLBCL), are largely unknown. Kelch-like family member 6 (KLHL6) encoding a substrate-adapter for Cullin-3-RING E3 ubiquitin-ligase (CRL) with poorly established targets is recurrently mutated in DLBCL. By applying high-throughput protein interactome screens and functional characterization, we discovered that KLHL6 regulates BCR by targeting its signaling subunits CD79A and CD79B. Loss of physiological KLHL6 expression pattern was frequent among the MCD/C5-like activated B-cell DLBCLs and was associated with higher CD79B levels and dismal outcome. Mutations in the BTB domain of KLHL6 disrupted its localization and heterodimerization, and increased surface BCR levels and signaling, whereas Kelch domain mutants had the opposite effect. Malfunctions of KLHL6 mutants extended beyond proximal BCR signaling with distinct phenotypes from KLHL6 silencing. Collectively, our findings uncover how recurrent mutations in KLHL6 alter BCR signaling and induce actionable phenotypic characteristics in DLBCL.

Visual identification for species and sex derived from bloodstain based on phosphate-mediated isothermal amplification colorimetric system.

Species and sex confirmation of the biological specimen play a crucial role in crime investigation. However, the specimen found in the scene is always trace quantity, which is hard to be analyzed by current methods. Moreover, the time-consuming DNA extraction, sophisticated apparatus, and complex data processing make it difficult to satisfy the demand of speediness and convenience for point-of-care tests. In this study, we first exhibit a phosphate-based visual system for field-based species and sex identification derived from trace bloodstain. By introducing phosphate ion-based colorimetry into loop-mediated isothermal amplification (LAMP) for result interpretation, not only the bloodstain can be directly submitted to mitochondrial variant amplification owing to the enhanced amplification efficiency by pyrophosphate ion hydrolyzation, but also the colorimetric signal can be recognized by the naked eye for result output within 30 min through molybdophosphate generation. Aerosol contamination, the major conflict of LAMP, has been solved once and for all by integrating uracil-DNA glycosylase into this system that still holds on a constant temperature. As a demonstration, cytochrome b and Y-chromosomal amelogenin are employed to identify species and sex respectively, which has achieved a highly sensitive and specific distinguishability under a strong interferential background. Accurate results can be obtained from both the simulative degraded and dated specimen, which indicates that this novel system may serve as a promising tool in forensic practice.

Incorporating polygenic risk into the Leicester Risk Assessment score for 10-year risk prediction of type 2 diabetes.

AIMS: We evaluated whether incorporating information on ethnic background and polygenic risk enhanced the Leicester Risk Assessment (LRA) score for predicting 10-year risk of type 2 diabetes. METHODS: The sample included 202,529 UK Biobank participants aged 40-69 years. We computed the LRA score, and developed two new risk scores using training data (80% sample): LRArev, which incorporated additional information on ethnic background, and LRAprs, which incorporated polygenic risk for type 2 diabetes. We assessed discriminative and reclassification performance in a test set (20% sample). Type 2 diabetes was ascertained using primary care, hospital inpatient and death registry records. RESULTS: Over 10 years, 7,476 participants developed type 2 diabetes. The Harrell's C indexes were 0.796 (95% Confidence Interval [CI] 0.785, 0.806), 0.802 (95% CI 0.792, 0.813), and 0.829 (95% CI 0.820, 0.839) for the LRA, LRArev and LRAprs scores, respectively. The LRAprs score significantly improved the overall reclassification compared to the LRA (net reclassification index [NRI] = 0.033, 95% CI 0.015, 0.049) and LRArev (NRI = 0.040, 95% CI 0.024, 0.055) scores. CONCLUSIONS: Polygenic risk moderately improved the performance of the existing LRA score for 10-year risk prediction of type 2 diabetes.

GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.

Mitochondrial fission is a tightly regulated process involving multiple proteins and cell signaling. Despite extensive studies on mitochondrial fission factors, our understanding of the regulatory mechanisms remains limited. This study shows the critical role of a mitochondrial GTPase, GTPBP8, in orchestrating mitochondrial fission in mammalian cells. Depletion of GTPBP8 resulted in drastic elongation and interconnectedness of mitochondria. Conversely, overexpression of GTPBP8 shifted mitochondrial morphology from tubular to fragmented. Notably, the induced mitochondrial fragmentation from GTPBP8 overexpression was inhibited in cells either depleted of the mitochondrial fission protein Drp1 (also known as DNM1L) or carrying mutated forms of Drp1. Importantly, downregulation of GTPBP8 caused an increase in oxidative stress, modulating cell signaling involved in the increased phosphorylation of Drp1 at Ser637. This phosphorylation hindered the recruitment of Drp1 to mitochondria, leading to mitochondrial fission defects. By contrast, GTPBP8 overexpression triggered enhanced recruitment and assembly of Drp1 at mitochondria. In summary, our study illuminates the cellular function of GTPBP8 as a pivotal modulator of the mitochondrial division apparatus, inherently reliant on its influence on Drp1.

Diamond-Like Carbon Depositing on the Surface of Polylactide Membrane for Prevention of Adhesion Formation During Tendon Repair.

Post-traumatic peritendinous adhesion presents a significant challenge in clinical medicine. This study proposes the use of diamond-like carbon (DLC) deposited on polylactic acid (PLA) membranes as a biophysical mechanism for anti-adhesion barrier to encase ruptured tendons in tendon-injured rats. The results indicate that PLA/DLC composite membrane exhibits more efficient anti-adhesion effect than PLA membrane, with histological score decreasing from 3.12 ± 0.27 to 2.20 ± 0.22 and anti-adhesion effectiveness increasing from 21.61% to 44.72%. Mechanistically, the abundant C=O bond functional groups on the surface of DLC can reduce reactive oxygen species level effectively; thus, the phosphorylation of NF-κB and M1 polarization of macrophages are inhibited. Consequently, excessive inflammatory response augmented by M1 macrophage-originated cytokines including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) is largely reduced. For biocompatibility evaluation, PLA/DLC membrane is slowly absorbed within tissue and displays prolonged barrier effects compared to traditional PLA membranes. Further studies show the DLC depositing decelerates the release of degradation product lactic acid and its induction of macrophage M2 polarization by interfering esterase and PLA ester bonds, which further delays the fibrosis process. It was found that the PLA/DLC membrane possess an efficient biophysical mechanism for treatment of peritendinous adhesion.

A complementary learning systems model of how sleep moderates retrieval practice effects.

While many theories assume that sleep is critical in stabilizing and strengthening memories, our recent behavioral study (Liu & Ranganath, 2021, Psychonomic Bulletin & Review, 28[6], 2035-2044) suggests that sleep does not simply stabilize memories. Instead, it plays a more complex role, integrating information across two temporally distinct learning episodes. In the current study, we simulated the results of Liu and Ranganath (2021) using our biologically plausible computational model, TEACH, developed based on the complementary learning systems (CLS) framework. Our model suggests that when memories are activated during sleep, the reduced influence of temporal context establishes connections across temporally separated events through mutual training between the hippocampus and neocortex. In addition to providing a compelling mechanistic explanation for the selective effect of sleep, this model offers new examples of the diverse ways in which the cortex and hippocampus can interact during learning.

One-year efficacy of myopia control by the defocus distributed multipoint lens: a multicentric randomised controlled trial.

AIMS: To report the 1-year results of the efficacy of a defocus distributed multipoint (DDM) lens in controlling myopia progression in a multicentre, randomised controlled trial. METHODS: Overall, 168 children aged 6-13 years were recruited and randomly assigned to wear a DDM lens (n=84) or single-vision (SV) lens (n=84) in three centres. Cycloplegic autorefraction (spherical equivalent refraction (SER)) and axial length (AL) were measured. Linear mixed model analysis was performed to compare between-group SER and AL changes. Logistic regression analysis was used to analyse the between-group difference in rapid myopia progression (SER increase≥0.75 D per year or AL growth≥0.40 mm per year). RESULTS: After 1 year, mean changes in SER were significantly lower in the DDM group (-0.47±0.37 D) than in the SV group (-0.71±0.42 D) (p<0.001). Similarly, mean changes in AL were significantly lower in the DDM group (0.21±0.17 mm) than in the SV group (0.34±0.16 mm) (p<0.001). After adjusting for age, sex, daily wearing time and parental myopia, rapid myopia progression risk was higher in the SV group than in the DDM group (OR=3.51, 95% CI: 1.77 to 6.99), especially for children who wore a lens for >12 hours per day, boys and younger children (6-9 years) with ORs (95% CIs) of 10.82 (3.22 to 36.37), 5.34 (1.93 to 14.78) and 8.73 (2.6 to 29.33), respectively. CONCLUSIONS: After 1 year, DDM lenses effectively retarded myopia progression in children. Longer daily wearing time of DDM lens improved the efficacy of myopia control. Future long-term studies are needed for validation. TRIAL REGISTRATION NUMBER: NCT05340699.

Antiadhesion Biomaterials in Tendon Repair: Application Status and Future Prospect.

The healing process after tendon injury is often accompanied by the formation of peritendinous adhesion, contributing to limb dysfunction and exerting detrimental effects on the individuals, as well as the development of society and economy. With the continuous development of material science, as well as the augmented understanding of tendon healing and the mechanism of peritendinous adhesion formation, materials used for the fabrication of barrier membranes against peritendinous adhesion emerge endlessly. In this article, based on the analysis of the mechanism of adhesion formation, we first review the commonly used natural and synthetic materials, along with their corresponding fabrication strategies, in order to furnish valuable insights for the future optimization and development of antiperitendinous adhesion barrier membranes. This article also discusses the interaction between antiadhesion materials and cells for ameliorating peritendinous adhesion.

Swimming trapper decreases the proportion of chromosomally unbalanced spermatozoa in human Robertsonian translocation carriers.

BACKGROUND: Carriers of reciprocal translocations often have more unbalanced spermatozoa and higher DNA fragmentation rates, elevating reproductive risk. The simple swim-up method (SSUM) can decrease the amount of spermatozoa with abnormal chromatin structure and fragmented DNA, however, it has limited efficacy in eliminating chromosomally unbalanced sperm. METHODS: The spermatozoa of eight Robertsonian translocation (Rob) carriers were split into three groups: original raw semen group (control group); SSUM and swimming trapper method group (STM) processed semen samples. After different semen preparation procedures, semen qualities, sperm chromosomal aneuploidy, and sperm fragmented DNA were evaluated. RESULTS: Although spermatozoa with higher motility was obtained by both SSUM and STM, the population of faster forward moving sperm was greater with STM as compared to SSUM. While the rates of DNA fragmentation were statistically much lower in both groups than ejaculated semen sample, our data showed better effect on the decrease of DNA fragmentation index (DFI) after selection by STM for patients who have high DFI (>20%) in neat semen. For all patients, significant decrease in the frequency of chromosomally unbalanced spermatozoa was observed after selection using STM. Although similar trends can be seen in the SSUM group, a significant difference was identified in one patient only. CONCLUSIONS: Use of swimming trapper (STM) is superior for enriching high-motile and genetically competent sperm in comparison with SSUM.

Uptake of ox-LDL by binding to LRP6 mediates oxidative stress-induced BMSCs senescence promoting obesity-related bone loss.

Obesity has long been thought to be a main cause of hyperlipidemia. As a systemic disease, the impact of obesity on organs, tissues and cells is almost entirely negative. However, the relationship between obesity and bone loss is highly controversial. On the one hand, obesity has long been thought to have a positive effect on bone due to increased mechanical loading on the skeleton, conducive to increasing bone mass to accommodate the extra weight. On the other hand, obesity-related metabolic oxidative modification of low-density lipoprotein (LDL) in vivo causes a gradual increase of oxidized LDL (ox-LDL) in the bone marrow microenvironment. We have reported that low-density lipoprotein receptor-related protein 6 (LRP6) acts as a receptor of ox-LDL and mediates the bone marrow stromal cells (BMSCs) uptake of ox-LDL. We detected elevated serum ox-LDL in obese mice. We found that ox-LDL uptake by LRP6 led to an increase of intracellular reactive oxygen species (ROS) in BMSCs, and N-acetyl-L-cysteine (NAC) alleviated the cellular senescence and impairment of osteogenesis induced by ox-LDL. Moreover, LRP6 is a co-receptor of Wnt signaling. We found that LRP6 preferentially binds to ox-LDL rather than dickkopf-related protein 1 (DKK1), both inhibiting Wnt signaling and promoting BMSCs senescence. Mesoderm development LRP chaperone (MESD) overexpression inhibits ox-LDL binding to LRP6, attenuating oxidative stress and BMSCs senescence, eventually rescuing bone phenotype.

High immigration rates critical for establishing emigration-driven diversity in microbial communities.

Unraveling the mechanisms governing the diversity of ecological communities is a central goal in ecology. Although microbial dispersal constitutes an important ecological process, the effect of dispersal on microbial diversity is poorly understood. Here, we sought to fill this gap by combining a generalized Lotka-Volterra model with experimental investigations. Our model showed that emigration increases the diversity of the community when the immigration rate crosses a defined threshold, which we identified as Ineutral. We also found that at high immigration rates, emigration weakens the relative abundance of fast-growing species and thus enhances the mass effect and increases the diversity. We experimentally confirmed this finding using co-cultures of 20 bacterial strains isolated from the soil. Our model further showed that Ineutral decreases with the increase of species pool size, growth rate, and interspecies interaction. Our work deepens the understanding of the effects of dispersal on the diversity of natural communities.

Oculocutaneous albinism type 4: Novel compound heterozygous mutations in the SLC45A2 gene in a Chinese case.

BACKGROUND: Oculocutaneous albinism type 4 (OCA4) is a rare autosomal recessive disorder characterized by a reduction of pigmentation in skin, hair, and eyes, and OCA4 is mainly seen in the SLC45A2 gene variants. OBJECTIVE: To report a Chinese patient suspected of oculocutaneous albinism and identify the causing mutation. METHODS: Genomic DNA was extracted from the peripheral blood samples of the patient, his parents, and elder brother. Whole exome sequencing was performed in the family, and Sanger sequencing was then used to verify the mutations. RESULTS: Compound heterozygous variants, c.1304C>A (p.S435Y) and c.301C>G (p.R101G) in SLC45A2 gene, were detected in the proband, which were inherited from his father and mother respectively. Based on the ACMG guidelines, we can interpret the c.1304C>A (p.S435Y) variant as a suspected pathogenic variant and the c.301C>G (p.R101G) variant as a clinically significant unspecified variant. The diagnosis of OCA4 is confirmed. CONCLUSION: We firstly reported this case of OCA4 with the compound heterozygous variants in the SLC45A2 gene. Our findings further enrich the reservoir of SLC45A2 mutations in OCA4.

22% Record Efficiency in Nanorod Light-Emitting Diodes Achieved by Gradient Shells.

The external quantum efficiency (EQE) in light-emitting diodes (LEDs) based on isotropic quantum dots has approached the theoretical limit of close to 20%. Anisotropic nanorods can break this limit by taking advantage of their directional emission. However, the progress towards higher EQE by using CdSe/CdS nanorods (NRs) faces several challenges, primarily involving the low quantum yield and unbalanced charge injection in devices. Herein, the seeded growth method is modified and anisotropic nanorods are obtained with photoluminescence quantum yield up to 98% by coating a gradient alloyed CdZnSe shell around conventional spherical CdSe seeds. This intermediate alloyed CdZnSe shell combined with a subsequent rod-shaped CdZnS/ZnS shell can effectively suppress the electron delocalization in the typical CdSe/CdS nanorods due to their small conduction bandgap offset. Additionally, this alloyed shell can reduce the hole-injection barrier and create a larger barrier for electron injection, both effects promoting a balanced injection of electrons and holes in LEDs. Hence, LEDs are reached with high brightness (160341 cd m-2) and high efficiency (EQE = 22%, current efficiency = 23.19 cd A-1), which are the highest values to date for nanorod LEDs.

Internal Vanadium Doping and External Modification Design of P2-Type Layered Mn-Based Oxides as Competitive Cathodes toward Sodium-Ion Batteries.

P2-type layered manganese-based oxides have attracted considerable interest as economical, cathode materials with high energy density for sodium-ion batteries (SIBs). Despite their potential, these materials still face challenges related to sluggish kinetics and structural instability. In this study, a composite cathode material, Na0.67Ni0.23Mn0.67V0.1O2@Na3V2O2(PO4)2F was developed by surface-coating P2-type Na0.67Ni0.23Mn0.67V0.1O2 with a thin layer of Na3V2O2(PO4)2F to enhance both the electrochemical sodium storage and material air stability. The optimized Na0.67Ni0.23Mn0.67V0.1O2@5wt %Na3V2O2(PO4)2F exhibited a high discharge capacity of 176 mA h g-1 within the 1.5-4.1 V range at a low current density of 17 mA g-1. At an increased current density of 850 mA g-1 within the same voltage window, it still delivered a substantial initial discharge capacity of 112 mAh g-1. These findings validate the significant enhancement of ion diffusion capabilities and rate performance in the P2-type Na0.67Ni0.33Mn0.67O2 material conferred by the composite cathode.

PABPC1L Induces IDO1 to Promote Tryptophan Metabolism and Immune Suppression in Renal Cell Carcinoma.

The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance despite having extensive T-cell infiltration. Elucidation of the mechanisms underlying immune evasion could help identify therapeutic strategies to boost the efficacy of immune checkpoint blockade (ICB) in RCC. This study uncovered a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine 2,3-dioxygenase 1 (IDO1), a prospective target for immunotherapy. PABPC1L was markedly upregulated in RCC, and high PABPC1L expression correlated with unfavorable prognosis and resistance to ICB. PABPC1L bolstered tryptophan metabolism by upregulating IDO1, inducing T-cell dysfunction and Treg infiltration. PABPC1L enhanced the stability of JAK2 mRNA, leading to increased JAK2-STAT1 signaling that induced IDO1 expression. Additionally, PABPC1L-induced activation of the JAK2-STAT1 axis created a positive feedback loop to promote PABPC1L transcription. Conversely, loss of PABPC1L diminished IDO1 expression, mitigated cytotoxic T-cell suppression, and enhanced responsiveness to anti-PD-1 therapy in patient-derived xenograft models. These findings reveal the crucial role of PABPC1L in facilitating immune evasion in RCC and indicate that inhibiting PABPC1L could be a potential immunotherapeutic approach in combination with ICB to improve patient outcomes. SIGNIFICANCE: PABPC1L functions as a key factor in renal cell carcinoma immune evasion, enhancing IDO1 and impeding T-cell function, and represents a potential target to enhance the efficacy of immune checkpoint blockade therapy.

Social integration as a mediator of the association between housing tenure and health inequalities among China's migrants: A housing discrimination perspective.

Due to the housing affordability crisis and institutional discrimination embedded in China's housing system, which refers to the unequal rights between homeowners and renters, migrant renters face greater social exclusion and health inequalities compared to migrant homeowners. Although housing tenure is considered an important determinant of health, along with other socioeconomic factors, the pathways underlying the association between housing tenure and health remain overlooked. Using data from the 2017 China Migrants Dynamic Survey of 62,268 participants, this study examined the mediating effects of social integration between housing tenure and self-rated health, and whether housing affordability moderated the mediating effects. Simple mediation models showed that social integration partly mediated the association between housing tenure and self-rated health. Moderated mediation models revealed that housing affordability moderated the association between housing tenure and social integration, and did not moderate the association between social integration and self-rated health. Compared with migrants living in affordable housing, the mediating effect of social integration was significantly smaller among migrants living in unaffordable housing. The results add knowledge to previous literature by uncovering the underlying mechanisms between housing tenure and health and linking housing studies to social inequalities in health. Our study suggested that diminishing housing discrimination and improving housing affordability could not only be beneficial for migrants' health but also be helpful to narrowing the health inequalities among migrants.

Assessing the importance of primary care diagnoses in the UK Biobank.

The UK Biobank has made general practitioner (GP) data (censoring date 2016-2017) available for approximately 45% of the cohort, whilst hospital inpatient and death registry (referred to as "HES/Death") data are available cohort-wide through 2018-2022 depending on whether the data comes from England, Wales or Scotland. We assessed the importance of case ascertainment via different data sources in UKB for three diseases that are usually first diagnosed in primary care: Parkinson's disease (PD), type 2 diabetes (T2D), and all-cause dementia. Including GP data at least doubled the number of incident cases in the subset of the cohort with primary care data (e.g. from 619 to 1390 for dementia). Among the 786 dementia cases that were only captured in the GP data before the GP censoring date, only 421 (54%) were subsequently recorded in HES. Therefore, estimates of the absolute incidence or risk-stratified incidence are misleadingly low when based only on the HES/Death data. For incident cases present in both HES/Death and GP data during the full follow-up period (i.e. until the HES censoring date), the median time difference between an incident diagnosis of dementia being recorded in GP and HES/Death was 2.25 years (i.e. recorded 2.25 years earlier in the GP records). Similar lag periods were also observed for PD (median 2.31 years earlier) and T2D (median 2.82 years earlier). For participants with an incident GP diagnosis, only 65.6% of dementia cases, 69.0% of PD cases, and 58.5% of T2D cases had their diagnosis recorded in HES/Death within 7 years since GP diagnosis. The effect estimates (hazard ratios, HR) of established risk factors for the three health outcomes mostly remain in the same direction and with a similar strength of association when cases are ascertained either using HES only or further adding GP data. The confidence intervals of the HR became narrower when adding GP data, due to the increased statistical power from the additional cases. In conclusion, it is desirable to extend both the coverage and follow-up period of GP data to allow researchers to maximise case ascertainment of chronic health conditions in the UK.