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Cortical and cerebrovascular amyloid-β (Aβ) deposition is a hallmark of Alzheimer's disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) ε4 is a major genetic modulator of Aβ deposition and AD risk. Variants of the amyloid-β protein precursor (AβPP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and AβPP variants in cortical and cerebrovascular Aβ deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged ≥ 85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the ε4 allele with cortical (p = 4.91 × 10-17) and cerebrovascular (p = 9.87 × 10-11) Aβ deposition as well as with NIA-RI AD (p = 1.62 × 10-8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the AβPP locus. In single SNP or haplotype analyses there were no statistically significant AβPP locus associations with cortical or cerebrovascular Aβ deposition or with NIA-RI AD. We sequenced the promoter of the AβPP gene in 40 subjects with very high Aβ deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular Aβ depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE ε4 variant. Promoter mutations or common allelic variation in the AβPP gene do not have a major contribution to cortical or cerebrovascular Aβ deposition, or very late-onset AD in this Finnish population based study. [ABSTRACT FROM AUTHOR]

Background: Colchicine has been approved to reduce cardiovascular risk in patients with coronary heart disease on the basis of its potential benefits demonstrated in the COLCOT (Colchicine Cardiovascular Outcomes Trial) and LoDoCo2 (Low-Dose Colchicine 2) studies. Nevertheless, there are limited data available about the specific impact of colchicine on coronary plaques., Methods: This was a prospective, single-center, randomized, double-blind clinical trial. From May 3, 2021, until August 31, 2022, a total of 128 patients with acute coronary syndrome aged 18 to 80 years with lipid-rich plaque (lipid pool arc >90°) detected by optical coherence tomography were included. The subjects were randomly assigned in a 1:1 ratio to receive either colchicine (0.5 mg once daily) or placebo for 12 months. The primary end point was the change in the minimal fibrous cap thickness from baseline to the 12-month follow-up., Results: Among 128 patients, 52 in the colchicine group and 52 in the placebo group completed the study. The mean age of the 128 patients was 58.0±9.8 years, and 25.0% were female. Compared with placebo, colchicine therapy significantly increased the minimal fibrous cap thickness (51.9 [95% CI, 32.8 to 71.0] μm versus 87.2 [95% CI, 69.9 to 104.5] μm; difference, 34.2 [95% CI, 9.7 to 58.6] μm; P =0.006), and reduced average lipid arc (-25.2° [95% CI, -30.6° to -19.9°] versus -35.7° [95% CI, -40.5° to -30.8°]; difference, -10.5° [95% CI, -17.7° to -3.4°]; P =0.004), mean angular extension of macrophages (-8.9° [95% CI, -13.3° to -4.6°] versus -14.0° [95% CI, -18.0° to -10.0°]; difference, -6.0° [95% CI, -11.8° to -0.2°]; P =0.044), high-sensitivity C-reactive protein level (geometric mean ratio, 0.6 [95% CI, 0.4 to 1.0] versus 0.3 [95% CI, 0.2 to 0.5]; difference, 0.5 [95% CI, 0.3 to 1.0]; P =0.046), interleukin-6 level (geometric mean ratio, 0.8 [95% CI, 0.6 to 1.1] versus 0.5 [95% CI, 0.4 to 0.7]; difference, 0.6 [95% CI, 0.4 to 0.9]; P =0.025), and myeloperoxidase level (geometric mean ratio, 1.0 [95% CI, 0.8 to 1.2] versus 0.8 [95% CI, 0.7 to 0.9]; difference, 0.8 [95% CI, 0.6 to 1.0]; P =0.047)., Conclusions: Our findings suggested that colchicine resulted in favorable effects on coronary plaque stabilization at optical coherence tomography in patients with acute coronary syndrome., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04848857., Competing Interests: None.

Interleukin-2 (IL-2) has been used in cancer treatment for over 30 years. However, due to its high toxicity, new mutant variants have been developed. These variants retain some of the biological properties of the original molecule but offer other therapeutic advantages. At the Center of Molecular Immunology, the IL-2 no-alpha mutein, an IL-2 agonist with lower toxicity than wtIL-2, has been designed, produced, and is currently being evaluated in a Phase I/II clinical trial. The mutein is produced in E. coli as an insoluble material that must be refolded in vitro to yield a fully active protein. Controlled oxidation steps are essential in the purification process of recombinant proteins produced in E. coli to ensure the proper formation of the disulfide bonds in the molecules. In this case, the new purification process includes a copper-catalyzed air oxidation step to induce disulfide bond establishment. The optimal conditions of pH, copper, protein and detergent concentration for this step were determined through screening. The produced protein demonstrated a conserved 3D structure, higher purity, and greater biological activity than the obtained by established process without the oxidation step. Four batches were produced and evaluated, demonstrating the consistency of the new process., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Four new species of the genus Hendelia Czerny, 1903 collected from China, are described as new to science: H.latustigenis sp. nov. , H.macrocera sp. nov. , H.deltoides sp. nov. and H.flavida sp. nov. An updated key to the species of Hendelia from China is presented., Competing Interests: The authors have declared that no competing interests exist., (Shuai-Lai Yang, Xin-Ming Yin, Yu-Qiang Xi.)

Background: Intrahepatic cholangiocarcinoma (ICC) is a highly desmoplastic tumor with poor prognosis even after curative resection. We investigated the associations between the composition of the ICC stroma and immune cell infiltration and aimed to develop a stromal-immune signature to predict prognosis in surgically treated ICC., Patients and Methods: We recruited 359 ICC patients and performed immunohistochemistry to detect α-smooth muscle actin (α-SMA), CD3, CD4, CD8, Foxp3, CD68, and CD66b. Aniline was used to stain collagen deposition. Survival analyses were performed to detect prognostic values of these markers. Recursive partitioning for a discrete-time survival tree was applied to define a stromal-immune signature with distinct prognostic value. We delineated an integrated stromal-immune signature based on immune cell subpopulations and stromal composition to distinguish subgroups with different recurrence-free survival (RFS) and overall survival (OS) time., Results: We defined four major patterns of ICC stroma composition according to the distributions of α-SMA and collagen: dormant (α-SMAlow/collagenhigh), fibrogenic (α-SMAhigh/collagenhigh), inert (α-SMAlow/collagenlow), and fibrolytic (α-SMAhigh/collagenlow). The stroma types were characterized by distinct patterns of infiltration by immune cells. We divided patients into six classes. Class I, characterized by high CD8 expression and dormant stroma, displayed the longest RFS and OS, whereas Class VI, characterized by low CD8 expression and high CD66b expression, displayed the shortest RFS and OS. The integrated stromal-immune signature was consolidated in a validation cohort., Conclusion: We developed and validated a stromal-immune signature to predict prognosis in surgically treated ICC. These findings provide new insights into the stromal-immune response to ICC.

Tumor-associated inflammation drives cancer progression and therapy resistance, often linked to the infiltration of monocyte-derived tumor-associated macrophages (TAMs), which are associated with poor prognosis in various cancers. To advance immunotherapies, testing on immunocompetent pre-clinical models of human tissue is crucial. We have developed an in vitro model of microvascular networks with tumor spheroids or patient tissues to assess monocyte trafficking into tumors and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via CCL7 and CCL2, mediated by CSF-1R. Additionally, a multispecific antibody targeting CSF-1R, CCR2, and neutralizing TGF-β (CSF1R/CCR2/TGF-β Ab) repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and blocks monocyte migration. This antibody also inhibits monocyte recruitment in patient-specific vascularized tumor models. In summary, this vascularized tumor model recapitulates the monocyte recruitment cascade, enabling functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roger D. Kamm reports financial support was provided by National Institutes of Health. Huu Tuan Nguyen reports financial support was provided by Swiss National Science Foundation, Switzerland. Roger D. Kamm reports financial support was provided by Marengo Therapeutics. Roger D. Kamm reports a relationship with AIM Biotech that includes: board membership. Roger D. Kamm reports a relationship with Amgen Inc that includes: funding grants. Roger D. Kamm reports a relationship with Boehringer Ingelheim GmbH that includes: funding grants. Roger D. Kamm reports a relationship with Novartis AG that includes: funding grants. Roger D. Kamm reports a relationship with Roche that includes: funding grants. Roger D. Kamm reports a relationship with Takeda Pharmaceutical Company Limited that includes: funding grants. Roger D. Kamm reports a relationship with Eisai Co Ltd that includes: funding grants. Roger D. Kamm reports a relationship with Merck KGaA that includes: funding grants. Roger D. Kamm reports a relationship with Visterra Inc that includes: funding grants. Roger D. Kamm reports a relationship with Daiichi Sankyo Co Ltd that includes: funding grants. Roger D. Kamm reports a relationship with AbbVie Inc that includes: funding grants. Roger Kamm, Huu Tuan Nguyen, Sharon Wei Ling Lee has patent Fluidic platforms for perfusable vascularized tissues with infiltrates pending to Massachusetts Institute of Technology. Andreas Loew holds stocks and options in Marengo Therapeutics., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Achieving both high efficiency and high stability in blue thermally activated delayed fluorescence organic light-emitting diodes (TADF-OLEDs) is challenging for practical displays and lighting. Here, we have successfully developed a series of sky-blue to pure-blue emitting donor-acceptor (D-A) type TADF materials featuring a four-coordinated boron with 2,2'-(pyridine-2,6-diyl)diphenolate (dppy) ligands, i.e. 1-8. Synergistic engineering of substituents on the phenyl bridge as well as the electronic properties and the attached positions of heteroatom N-donors not only enables fine-tuning of the emission colors, but also modulates the nature and energies of their triplet excited states that are important for the reverse intersystem crossing (RISC). Particularly for the compound with two methyl substituents on the phenyl bridge (compound 8), RISC is significantly facilitated through the vibronic coupling of the energetically close-lying triplet charge transfer ( 3 CT) and the triplet local excited ( 3 LE) states, when compared to analogue 7. Efficient sky-blue to pure-blue OLEDs with electroluminescence peaks ( λ EL ) at 460-492 nm have been obtained, in which ca . five-fold higher external quantum efficiencies (EQEs) of 18.9% have been demonstrated by 8 than that by 7. Moreover, ca . thirty times longer device operational half-lifetimes (LT 50 ) of 9113 hours for 8 than that for 7 as well as satisfactory LT 50 reaching 26 643 hours for 6 at an initial luminance of 100 cd m -2 have also been demonstrated. To the best of our knowledge, these results represent one of the best high-performance blue OLEDs based on tetracoordinated boron TADF emitters. Moreover, the design strategy presented here has provided an attractive strategy for enhancing the device performance of blue TADF-OLEDs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Sanghuangprous vaninii is a medicinal macrofungus cultivated extensively in China. Both the mycelia and fruiting bodies of S. vaninii have remarkable therapeutic properties, but it remains unclear whether the mycelia may serve as a substitute for the fruiting bodies. Furthermore, S. vaninii is a perennial fungus with therapeutic components that vary significantly depending on the growing year of the fruiting bodies. Hence, it is critical to select an appropriate harvest stage for S. vaninii fruiting bodies for a specific purpose. With the aid of Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), metabolomics based on ultra-high performance liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-QQQ-MS) was used to preliminarily determine 81 key active metabolites and 157 active pharmaceutical metabolites in S. vaninii responsible for resistance to the six major diseases. To evaluate the substitutability of the mycelia and fruiting bodies of S. vaninii and to select an appropriate harvest stage for the fruiting bodies of S. vaninii , we analyzed the metabolite differences, especially active metabolite differences, among the mycelia and fruiting bodies during three different harvest stages (1-year-old, 2-year-old, and 3-year-old). Moreover, we also determined the most prominent and crucial metabolites in each sample of S. vaninii . These results suggested that the mycelia show promise as a substitute for the fruiting bodies of S. vaninii and that extending the growth year does not necessarily lead to higher accumulation levels of active metabolites in the S. vaninii fruiting bodies. This study provided a theoretical basis for developing and using S. vaninii ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qi, Guo, Xu, Hou, Liu, Guo, Xu, Yang and Yu.)

The increasing accessibility of commercial and private space travel necessitates a profound understanding of its impact on human health. The NASA Open Science Data Repository (OSDR) provides transparent and FAIR access to biological studies, notably the SpaceX Inspiration4 (I4) mission, which amassed extensive data from civilian astronauts. This dataset encompasses omics and clinical assays, facilitating comprehensive research on space-induced biological responses. These data allow for multi-modal, longitudinal assessments, bridging the gap between human and model organism studies. Crucially, community-driven data standards established by NASA's OSDR Analysis Working Groups empower artificial intelligence and machine learning to glean invaluable insights, guiding future mission planning and health risk mitigation. This article presents a concise guide to access and analyze I4 data in OSDR, including programmatic access through GLOpenAPI. This pioneering effort establishes a precedent for post-mission health monitoring programs within space agencies, propelling research in the burgeoning field of commercial space travel's impact on human physiology., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

China's aging population has witnessed a surge in widowed older adults, raising concerns about their mental health. Losing a spouse is a profoundly distressing experience with enduring effects on well-being. Despite the proverbial belief in time's healing power, existing studies often neglect the potential decline in depressive symptoms during widowhood. Drawing data from the 2015 and 2018 China Health and Retirement Longitudinal Study, this study delved into the impact of widowhood duration on depression among 8370 older adults and uncovered significantly higher depression scores among widowed individuals, particularly in the initial three years. This study revealed that widowhood contributes to heightened depression levels even after accounting for sociodemographic factors. Although the depressive impact lessens over time, it persists beyond three years, underscoring the need for heightened awareness and support for this vulnerable population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The tumor microbiome has been characterized in several malignancies; however, no previous studies have investigated its role in intrahepatic cholangiocarcinoma (ICC). Hence, we explored the tumor microbiome and its association with prognosis in ICC., Methods: One hundred and twenty-one ICC tumor samples and 89 adjacent normal tissues were profiled by 16S rRNA sequencing. Microbial differences between tumor and adjacent nontumoral liver tissues were assessed. Tumor microbial composition was then evaluated to detect its association with prognosis. Finally, a risk score calculated by the tumor microbiota was accessed by the least absolute shrinkage and selector operator method (Lasso) to predict prognosis of ICC., Results: The tumor microbiome displayed a greater diversity than that in adjacent nontumoral liver tissues. Tumor samples were characterized by a higher abundance of Firmicutes, Actinobacteria, Bacteroidetes, and Acidobacteriota. Higher tumor microbial α diversity was associated with lymph node metastasis and predicted shortened overall survival (OS) and recurrence-free survival (RFS). A total of 11 bacteria were selected to generate the risk score by Lasso. This score showed potential in predicting OS, and was an independent risk factor for OS., Conclusion: In conclusion, our study characterized the tumor microbiome and revealed its role in predicting prognosis in ICC., (© 2024. Japanese Society of Gastroenterology.)

Background: Artificial intelligence has the potential to dramatically alter health care by enhancing how we diagnose and treat disease. One promising artificial intelligence model is ChatGPT, a general-purpose large language model trained by OpenAI. ChatGPT has shown human-level performance on several professional and academic benchmarks. We sought to evaluate its performance on surgical knowledge questions and assess the stability of this performance on repeat queries., Methods: We evaluated the performance of ChatGPT-4 on questions from the Surgical Council on Resident Education question bank and a second commonly used surgical knowledge assessment, referred to as Data-B. Questions were entered in 2 formats: open-ended and multiple-choice. ChatGPT outputs were assessed for accuracy and insights by surgeon evaluators. We categorized reasons for model errors and the stability of performance on repeat queries., Results: A total of 167 Surgical Council on Resident Education and 112 Data-B questions were presented to the ChatGPT interface. ChatGPT correctly answered 71.3% and 67.9% of multiple choice and 47.9% and 66.1% of open-ended questions for Surgical Council on Resident Education and Data-B, respectively. For both open-ended and multiple-choice questions, approximately two-thirds of ChatGPT responses contained nonobvious insights. Common reasons for incorrect responses included inaccurate information in a complex question (n = 16, 36.4%), inaccurate information in a fact-based question (n = 11, 25.0%), and accurate information with circumstantial discrepancy (n = 6, 13.6%). Upon repeat query, the answer selected by ChatGPT varied for 36.4% of questions answered incorrectly on the first query; the response accuracy changed for 6/16 (37.5%) questions., Conclusion: Consistent with findings in other academic and professional domains, we demonstrate near or above human-level performance of ChatGPT on surgical knowledge questions from 2 widely used question banks. ChatGPT performed better on multiple-choice than open-ended questions, prompting questions regarding its potential for clinical application. Unique to this study, we demonstrate inconsistency in ChatGPT responses on repeat queries. This finding warrants future consideration including efforts at training large language models to provide the safe and consistent responses required for clinical application. Despite near or above human-level performance on question banks and given these observations, it is unclear whether large language models such as ChatGPT are able to safely assist clinicians in providing care., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Maintaining genomic stability is a prerequisite for proliferating NPCs to ensure genetic fidelity. Though histone arginine methylation has been shown to play important roles in safeguarding genomic stability, the underlying mechanism during brain development is not fully understood. Protein arginine N-methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that plays a role in transcriptional regulation. Here, we identify PRMT5 as a key regulator of DNA repair in response to double-strand breaks (DSBs) during NPC proliferation. Prmt5 F/F ; Emx1-Cre (cKO-Emx1) mice show a distinctive microcephaly phenotype, with partial loss of the dorsal medial cerebral cortex and complete loss of the corpus callosum and hippocampus. This phenotype is resulted from DSBs accumulation in the medial dorsal cortex followed by cell apoptosis. Both RNA sequencing and in vitro DNA repair analyses reveal that PRMT5 is required for DNA homologous recombination (HR) repair. PRMT5 specifically catalyzes H3R2me2s in proliferating NPCs in the developing mouse brain to enhance HR-related gene expression during DNA repair. Finally, overexpression of BRCA1 significantly rescues DSBs accumulation and cell apoptosis in PRMT5-deficient NSCs. Taken together, our results show that PRMT5 maintains genomic stability by regulating histone arginine methylation in proliferating NPCs., (© 2024. The Author(s).)

Background: Several factors are associated with increased postoperative complications after appendectomies. However, few studies combined these potential factors for comprehensive prediction of surgical outcomes. Whether high-risk patients benefit from a shorter waiting time for surgery remains unclear. This study aimed to explore the impact of surgical waiting time and potential risk factors on postoperative complications., Methods: A total of 1343 patients diagnosed with acute appendicitis requiring an emergent appendectomy were included from 2013 to 2018. The preoperative risk factors associated with postoperative complications were selected and the probability of postoperative complications was calculated by multivariate logistic regression model. Patients were divided into four groups based on the risk (high & low) and time to surgery (> 12 & ≤12 hours). The odds ratios for complications were evaluated between groups., Results: The selected risk factors included age, neutrophil-lymphocyte ratio, systemic inflammatory response syndrome and abdominal pain duration. Compared with low-risk patients with time to surgery ≤12 hours, high-risk patients with time to surgery > 12 hours had significant increased overall postoperative complication rate (16.85% vs. 8.16%, p = 0.002) and a trend toward increased surgical site infection rate (10.99% vs. 6.46%, p = 0.058). When operated within 12 hours, there was no difference in outcomes between high- and low-risk patients. On the other hand, time to surgery > 12 hours did not increase complication rate in low-risk patients., Conclusions: The surgical outcome may be affected by preoperative factors and time to surgery. It is suggested that high-risk patients receive appendectomy within 12 hours to avoid increased postoperative complications., (© 2024. The Author(s).)

In the present research, we produce a coherent account of the storage and retrieval processes in short- and long-term event memory, and long-term knowledge, that produce response accuracy and response time in a wide variety of conditions in our studies of recognition memory. Two to nine pictures are studied sequentially followed by a target or foil test picture in four conditions used in Nosofsky et al. Journal of Experimental Psychology: Learning, Memory, and Cognition, 47, 316-342, (2021) and in our new paradigm: VM: target and foil responses to a given stimulus change from trial to trial; CM: the responses do not change from trial to trial; AN: every trial uses new stimuli; MIXED: combinations of VM, CN, and AN occur on each trial. In the new paradigm a given picture is equally often tested as old or new, but only in CM is the response key the same and learnable. Our model has components that have appeared in a variety of prior accounts, including learning and familiarity, but are given support by our demonstration that accuracy and response time data from a large variety of conditions can be predicted by these processes acting together, with parameter values that largely are unchanged. A longer version of this article, containing information not found here due to space, is available online  https://doi.org/10.31234/osf.io/h8msp .The avalibility of the data (supplement materials), info and link is attached at the end section ( https://psyarxiv.com/h8msp .)., (© 2024. The Psychonomic Society, Inc.)

A new class of thermally activated delayed fluorescence (TADF) pyridine-/pyrazine-containing tetradentate C^C^N^N gold(III) complexes have been designed and synthesized. Displaying photoluminescence quantum yields (PLQYs) of up to 0.77 in solid-state thin films, these complexes showed at-least a six-fold increase in the radiative decay rate constant ( k r ) in toluene upon increasing temperature from 210 to 360 K. Using variable-temperature (VT) ultrafast transient absorption (TA) spectroscopy, the reverse intersystem crossing (RISC) processes were directly observed and the activation parameters were determined, in line with the results of the Boltzmann two-level model fittings, in which the energy separation values between the lowest-lying singlet excited state (S 1 ) and the lowest-lying triplet excited state (T 1 ), Δ E (S 1 -T 1 ), of these complexes were estimated to be in the range of 0.16-0.18 eV. Through strategic modification of the position of the electron-donating - t Bu substituent in the cyclometalating ligand, the permanent dipole moments (PDMs) of these tetradentate gold(III) emitters could be manipulated to enhance their horizontal alignment in the emitting layer of organic light-emitting devices (OLEDs). Consequently, the resulting vacuum-deposited OLEDs demonstrated a 30% increase in the theoretical out-coupling efficiency ( η out ), as well as promising electroluminescence (EL) performance with maximum external quantum efficiencies (EQEs) of up to 15.7%.

A new species of Malakichthys is described based on six specimens collected from deepwaters off southwestern Taiwan, northwestern Pacific Ocean. The new species, M. formosus sp. nov., exhibits distinct morphological characters, primarily characterized by the absence of chin spines, distinguishing it from other congeners with the exception of M. levis and M. mochizuki. It differs from the two species by having more lateral-line scales, a shorter distance between the snout and dorsal-fin origin, a shallower head, fewer scale rows below the lateral line, and the structure of the first anal-fin pterygiophore. Eight species are now recognized in Malakichthys.

Aim: Functional disability is a widespread challenge faced by the older population in China, where those with functional disabilities demand greater healthcare and geriatric services. This study performs a longitudinal analysis examining the effects of physiological conditions, intra-, and extra-individual factors, and life-course socioeconomic status risk factors on the disability levels and change rates of functional disability trajectories in old age., Methods: Data for this study came from the four waves of the China Health and Retirement Longitudinal Survey. A latent growth model was used to analyze the functional disability of 5044 older adults aged 60 and over in 2011 who survived to 2018., Results: Pathologies are closely associated with functional disability trajectories, and higher numbers of comorbidities relate to more disabilities. Risk factors and intra- and extra-individual factors affect functional disability trajectories and work through independent and shared mechanisms. The effects of risk factors can be traced to childhood conditions, and higher childhood and adulthood socioeconomic status is related to fewer functional disabilities., Conclusion: Functional disability trajectories are dynamic processes related to pathologies, intra-, and extra-individual factors, and life-course risk factors, and thus prevention and control measures should focus on both childhood and adulthood. Promoting working in later life and improving childhood socioeconomic status deserve prompt attention. Geriatr Gerontol Int 2023; 23: 817-829., (© 2023 Japan Geriatrics Society.)

Green extractive methods accompanied by resource conservation through process optimization are important in working towards sustainable processes. In the present paper, rutin was extracted from the leaf of female Carica papaya Linn using microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), sequential microwave ultrasound-assisted extraction (MUAE), and sequential ultrasound microwave-assisted extraction (UMAE) methods. Subsequently, the effect of extraction parameters on rutin yield were analyzed and compared. In addition, the extraction efficiency and energy consumption of the extraction processes were measured and discussed. In the present study, solid-liquid (S/L) ratio was determined to be the most significant extraction variable. Under optimized conditions, MUAE and UMAE were determined to yield the highest amount of rutin extracted at 18.46 ± 0.64 mg/g and 18.43 ± 0.81 mg/g, respectively. However, MUAE was determined to be the least resource efficient method as it consumed the highest amount of energy due to its relatively long extraction time. UAE was determined to be the most efficient in resource utilization as it required the least amount of energy for every mg/g of yield extracted, while the yield obtained was, nonetheless, comparatively high. The optimal condition obtained for UAE was 20 min of ultrasonic extraction time (T U ), 20 % of ethanol mixture concentration (C), 710 μm of particle size (S), and 1:650 wt/wt of solid-liquid (S/L) ratio (R)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Asian cultivated rice has been domesticated from ancestors of the wild rice species Oryza rufipogon . During this process, important changes have occurred in many agronomic traits, such as plant height, grain shattering, and panicle shape, and the yield has also greatly increased. However, many favored traits (e.g., stress resistance) have been lost. The genome of O. longistaminata is of the same AA type as O. sativa , harboring many genes conferring resistance to biotic and abiotic stresses, and it is considered as a potential gene pool for genetic improvement of O. sativa . In this review, we summarize the basic research on O. longistaminata , including its resistance to biotic and abiotic stresses, its rhizome traits, and other traits that are of potential application value, such as bacterial blight resistance, drought resistance, heat tolerance, self-incompatibility, nitrogen efficiency, and high yield. Furthermore, we present the current applied research progress on perennial rice breeding based on the rhizome trait of O. longistaminata . Lastly, the possibility of de novo domestication of O. longistaminata is discussed. We expect this article to provide information to enhance the basic research of O. longistaminata and accelerate the genetic improvement of cultivated rice.

The EGFR and TGFβ signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFβ could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFβRII. The TGFβ "trap" fused to the light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity. Functional neutralization of TGFβ by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer-cell activation, while suppressing VEGF secretion. In addition, BCA101 inhibited differentiation of naïve CD4+ T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFβ "trap." TGFβ in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFβRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after dose cessation. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR-expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy., Significance: The bifunctional mAb fusion design of BCA101 targets it to the tumor microenvironment where it inhibits EGFR and neutralizes TGFβ to induce immune activation and to suppress tumor growth., (©2023 The Authors; Published by the American Association for Cancer Research.)

The COVID-19 pandemic has caused a large number of diseases worldwide. There are few vaccines to constrain this disease and the value of them is high. In this sense, the antigens of the vaccine platform Soberana, the receptor binding domain from SARS-CoV-2 Spike protein, both the monomeric (mRBD) and dimeric (dRBD) forms, have been developed. This study encompassed several analyses by different techniques like circular dichroism (CD), fluorescence spectroscopy (FS) and Gel Filtration- High Performance Liquid ChLC of mRBD and dRBD. Monomer and dimer exhibited similar far-UV CD spectral characteristics with 54% of β-sheet content. Similar conformational features according to near-UV CD and FS studies were observed in both RBD. Stress stability studies by far-UV CD, FS, biological activity and GF-HPLC at 37 °C showed that mRBD is very stable. On the other hand, dRBD fluorescent emission showed a shift towards higher wavelengths as the incubation time increases, suggesting exposition of tryptophan residues, unlike what happens with mRBD. Biological activity outcome confirms these results. GF-HPLC profiles showed that in mRBD, the product of molecular stress are dimers and does not increase over time. However, dRBD showed dimer fragmentation as the main degradation species. This study reveals the usefulness of CD techniques for the analysis of degradation of RBD molecules as well as showed the difference in stability of both RBD molecules. Besides, our work provides useful insights into the production of a key protein used in diagnosis and therapeutics to fight COVID-19 pandemia., (© 2023. The Author(s).)

A new species of Okamejei is described based on two adult males collected from deep waters in the South China Sea. The new species, Okamejei picta sp. nov., is readily distinguished from most other congeners in having densely scattered black spots on dorsal disc. Okamejei hollandi and O. mengae is quite similar to the new species by their spot patterns on dorsal disc, but the new species differs from the former by a combination of characters: a yellowish brown dorsal surface densely covered with small, circular to irregular-shaped black spots; blotches on dorsal disc indistinct; posterior ocellus absent; ventral disc white; disc length 45.0-47.7% TL; distance between cloaca to caudal-fin tip 53.6-55.1% TL; trunk centra 31; total basal radials 73-76, morphology of clasper terminal skeleton, and lacking component funnel at the clasper end.

A new class of thermally activated delayed fluorescence (TADF) tetradentate C ∧ C ∧ N ∧ N ligand-containing gold(III) complexes containing acridinyl moieties has been designed and synthesized. These complexes exhibit orange-red to deep-red emission with photoluminescence quantum yields (PLQYs) of up to 0.76 in solid-state thin films. Short excited-state lifetimes of ≤2.0 μs and large radiative decay rate constants ( k r ) in the order of 10 5 s -1 have also been found in the complexes. High-performance solution-processed and vacuum-deposited organic light-emitting devices (OLEDs) based on these complexes have been fabricated, demonstrating high maximum external quantum efficiencies (EQEs) of 12.2 and 12.7%, respectively, which are among the best values ever reported for red-emitting gold(III)-based OLEDs. In addition, satisfactory operational half-lifetime (LT 50 ) values of up to 34,058 h have been attained in these red-emitting devices. It is found that the operational stability is strongly dependent on the choice of functional groups on the acridinyl moieties, of which the incorporation of -O- and -S- linkers can effectively prolong the LT 50 value by an order of magnitude. The TADF properties of the complexes are substantiated by the hypsochromic shift in emission energies and the remarkable enhancement in the emission intensity upon increasing temperature. The TADF properties have also been supported by temperature-dependent ultrafast transient absorption studies, with the direct observation of reverse intersystem crossing (RISC) and the determination of the activation parameters for the very first time, together with their excited-state dynamics.

Incurable bacterial infection and intractable multidrug resistance remain critical challenges in public health. A prevalent approach against bacterial infection is phototherapy including photothermal and photodynamic therapy, which is unfortunately limited by low penetration depth of light accompanied with inevitable hyperthermia and phototoxicity damaging healthy tissues. Thus, eco-friendly strategy with biocompatibility and high antimicrobial efficacy against bacteria is urgently desired. Herein, we propose and develop an oxygen-vacancy-rich MoO x in situ on fluorine-free Mo 2 C MXene with unique neural-network-like structure, namely MoO x @Mo 2 C nanonetworks, in which their desirable antibacterial effectiveness originates from bacteria-capturing ability and robust reactive oxygen species (ROS) generation under precise ultrasound (US) irradiation. The high-performance, broad-spectrum microbicidal activity of MoO x @Mo 2 C nanonetworks without damaging normal tissues is validated based on systematic in vitro and in vivo assessments. Additionally, RNA sequencing analysis illuminates that the underlying bactericidal mechanism is attributed to the chaotic homeostasis and disruptive peptide metabolisms on bacteria instigated by MoO x @Mo 2 C nanonetworks under US stimulation. Considering antibacterial efficiency and a high degree of biosafety, we envision that the MoO x @Mo 2 C nanonetworks can serve as a distinct antimicrobial nanosystem to fight against diverse pathogenic bacteria, especially eradicating multidrug-resistant bacteria-induced deep tissue infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Monoclonal antibodies (mAbs) and their derivatives are the fastest expanding category of pharmaceuticals. Efficient screening and generation of appropriate therapeutic human antibodies are important and urgent issues in the field of medicine. The successful in vitro biopanning method for antibody screening largely depends on the highly diverse, reliable and humanized CDR library. To rapidly obtain potent human antibodies, we designed and constructed a highly diverse synthetic human single-chain variable fragment (scFv) antibody library greater than a giga in size by phage display. Herein, the novel TIM-3-neutralizing antibodies with immunomodulatory functions derived from this library serve as an example to demonstrate the library's potential for biomedical applications., Methods: The library was designed with high stability scaffolds and six complementarity determining regions (CDRs) tailored to mimic human composition. The engineered antibody sequences were optimized for codon usage and subjected to synthesis. The six CDRs with variable length CDR-H3s were individually subjected to β-lactamase selection and then recombined for library construction. Five therapeutic target antigens were used for human antibody generation via phage library biopanning. TIM-3 antibody activity was verified by immunoactivity assays., Results: We have designed and constructed a highly diverse synthetic human scFv library named DSyn-1 (DCB Synthetic-1) containing 2.5 × 10 10 phage clones. Three selected TIM-3-recognizing antibodies DCBT3-4, DCBT3-19, and DCBT3-22 showed significant inhibition activity by TIM-3 reporter assays at nanomolar ranges and binding affinities in sub-nanomolar ranges. Furthermore, clone DCBT3-22 was exceptionally superior with good physicochemical property and a purity of more than 98% without aggregation., Conclusion: The promising results illustrate not only the potential of the DSyn-1 library for biomedical research applications, but also the therapeutic potential of the three novel fully human TIM-3-neutralizing antibodies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Lok, Lin, Lai, Wu, Hu, Liao, Ho, Chou, Hsu, Lo and Chern.)

Importance: BRAF variants are associated with tumor progression; however, the prevalence of BRAF variant subtypes and their association with disease characteristics, prognosis, and targeted therapy response in patients with intrahepatic cholangiocarcinoma (ICC) are largely unknown., Objective: To explore the association of BRAF variant subtypes with disease characteristics, prognosis, and targeted therapy response in patients with ICC., Design, Setting, and Participants: In this cohort study, 1175 patients who underwent curative resection for ICC from January 1, 2009, through December 31, 2017, were evaluated at a single hospital in China. Whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify BRAF variants. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using Cox proportional hazards regression. Associations between BRAF variants and targeted therapy response were tested in 6 BRAF-variant, patient-derived organoid lines and in 3 of the patient donors of those lines. Data were analyzed from June 1, 2021, to March 15, 2022., Interventions: Hepatectomy in patients with ICC., Main Outcomes and Measures: The association of BRAF variant subtypes with OS and DFS., Results: Of 1175 patients with ICC, the mean (SD) age was 59.4 (10.4) years and 701 (59.7%) were men. A total of 20 different subtypes of BRAF somatic variance affecting 49 patients (4.2%) were identified; V600E was the most frequent allele in this cohort, accounting for 27% of the identified BRAF variants, followed by K601E (14%), D594G (12%), and N581S (6%). Compared with patients with non-V600E BRAF variants, patients with BRAF V600E variants were more likely to have large tumor size (10 of 13 [77%] vs 12 of 36 [33%]; P = .007), multiple tumors (7 of 13 [54%] vs 8 of 36 [22%]; P = .04), and more vascular/bile duct invasion (7 of 13 [54%] vs 8 of 36 [22%]; P = .04). Multivariate analysis revealed that BRAF V600E variants, but not overall BRAF variants or non-V600E BRAF variants, were associated with poor OS (hazard ratio [HR], 1.87; 95% CI, 1.05-3.33; P = .03) and DFS (HR, 1.66; 95% CI, 1.03-2.97; P = .04). There were also broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors., Conclusions and Relevance: The findings of this cohort study suggest that there are broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors. Identifying and classifying BRAF variants may be able to help guide precise treatment for patients with ICC.

Oct4 is essential to maintain pluripotency and has a pivotal role in establishing the germline. Its DNA-binding POU domain was recently found to bind motifs with methylated CpG elements normally associated with epigenetic silencing. However, the mode of binding and the consequences of this capability has remained unclear. Here, we show that Oct4 binds to a compact palindromic DNA element with a methylated CpG core (CpGpal) in alternative states of pluripotency and during cellular reprogramming towards induced pluripotent stem cells (iPSCs). During cellular reprogramming, typical Oct4 bound enhancers are uniformly demethylated, with the prominent exception of the CpGpal sites where DNA methylation is often maintained. We demonstrate that Oct4 cooperatively binds the CpGpal element as a homodimer, which contrasts with the ectoderm-expressed POU factor Brn2. Indeed, binding to CpGpal is Oct4-specific as other POU factors expressed in somatic cells avoid this element. Binding assays combined with structural analyses and molecular dynamic simulations show that dimeric Oct4-binding to CpGpal is driven by the POU-homeodomain whilst the POU-specific domain is detached from DNA. Collectively, we report that Oct4 exerts parts of its regulatory function in the context of methylated DNA through a DNA recognition mechanism that solely relies on its homeodomain., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The milk-eye catshark Apristurus nakayai Iglésias, 2012 was known from three specimens in the southwestern Pacific Ocean. Six specimens were recently collected from the South China Sea. It belongs to the brunneus group, and superficially resembles A. platyrhynchus Tanaka, 1909. Apristurus nakayai differs from A. platyrhynchus by the following characters: iris shiny white when fresh; body brownish black to black; second dorsal-fin insertion above or slightly in front of the anal-fin insertion; denticles absent inside mouth; and maturing at about 400 mm TL in both sexes. The occurrence of Apristurus nakayai from the South China Sea represents the first record in the northern Hemisphere, and a substantial distributional range extension (ca. 4665 km).

A new series of robust C^C^N carbazolylgold(III) complexes is designed and synthesized through the introduction of inert and sterically bulky oligophenyl substituents on the pyridyl moiety of the cyclometalating ligand. High photoluminescence quantum yields of up to 96% are recorded with these complexes doped in solid-state thin films, and short excited-state lifetimes of 0.3 μs or less in the solid state at room temperature are found. Promising electroluminescence (EL) performances are shown by the vacuum-deposited organic light-emitting devices (OLEDs) based on this series of gold(III) complexes. High external quantum efficiencies of up to 19.5% with efficiency roll-offs of down to 10% at a practical luminance brightness level of 1000 cd m -2 are achieved. More importantly, record-long operational lifetimes (LT 50 ) of up to 470,700 h at 100 cd m -2 are realized, which is currently the highest value among all classes of gold(III) complexes with tridentate pincer ligands. Particularly, by introducing a sterically bulky terphenyl moiety on the reactive site of the pyridine ring, the LT 50 value is shown to attain ∼7 times longer half-lifetime than that based on the unsubstituted complex. These unprecedented EL performances and the simple synthetic route in a mercury-free fashion make them promising emitting materials for practical OLEDs toward commercialization.

During laparoscopic surgery, surgical gauze is usually inserted into the body cavity to help achieve hemostasis. Retention of surgical gauze in the body cavity may necessitate reoperation and increase surgical risk. Using deep learning technology, this study aimed to propose a neural network model for gauze detection from the surgical video to record the presence of the gauze. The model was trained by the training group using YOLO (You Only Look Once)v5x6, then applied to the testing group. Positive predicted value (PPV), sensitivity, and mean average precision (mAP) were calculated. Furthermore, a timeline of gauze presence in the video was drawn by the model as well as human annotation to evaluate the accuracy. After the model was well-trained, the PPV, sensitivity, and mAP in the testing group were 0.920, 0.828, and 0.881, respectively. The inference time was 11.3 ms per image. The average accuracy of the model adding a marking and filtering process was 0.899. In conclusion, surgical gauze can be successfully detected using deep learning in the surgical video. Our model provided a fast detection of surgical gauze, allowing further real-time gauze tracing in laparoscopic surgery that may help surgeons recall the location of the missing gauze., (© 2022. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Objective: To explore relationships between mental health climate, positive mental health, sense of belonging, and depression among a U.S. national sample of Black college students. Participants: 1303 Black undergraduate and graduate students from 15 colleges and universities throughout the U.S. Methods: Data were from the 2018-2019 Healthy Minds Study. Analysis included hierarchical regression models. Results : A more positive perception of mental health climate and higher levels of both positive mental health and sense of belonging were significantly associated with lower levels of depression. Significant interactions existed between positive mental health and climate and sense of belonging and climate with buffering effects being most pronounced for students reporting high levels of positive mental health. Conclusion: Black college students' perceptions of an institution's mental health climate are associated with psychological outcomes. College health stakeholders should consider the buffering effects of protective factors on mental health when designing initiatives for Black college students.

Background: The development of healthy relationships and connections is of fundamental importance to adolescent well-being. The use of social media plays a vital role in the lives of young Canadians, yet the association between different types of social media use and the quality of relationships and connections remains unknown, and most existing analyses on this topic are based on modest and non-representative samples., Data and Methods: Using 2017/2018 reports from the nationally representative Health Behaviour in School-aged Children study (n=17,149; ages 11 to 15 years), the strength, consistency and significance of associations was examined between intensive (frequent use to connect with other people) and problematic (use that depicts addictive qualities) social media use and available measures of adolescent relationships and connections., Results: Overall, intensive use (online communication with others almost all of the time) and problematic use (potential addiction to social media) were more common in girls than boys (38% of girls versus 30% of boys and 7.7% of girls versus 5.2% of boys, respectively), with prevalence levels that rose with age. Intensive use was associated with more positive social relationships with friends, especially among girls (relative risk [RR] = 1.40 [95% confidence interval (CI) 1.28 - 1.54]), while problematic use was consistently and negatively associated with strong relationships and connections in all groups in the study. Notably, problematic use was negatively associated with strong family relationships in boys (RR = 0.58 [95% CI 0.42 to 0.79]) and girls (RR=0.48 [95% CI 0.36 to 0.63])., Interpretation: Intensive use of social media has the potential to strengthen relationships and connections in adolescents. However, when social media use becomes addictive or "problematic", it is highly correlated with weaker relationships and a sense of social disconnection. Public health initiatives related to social media use should consider how different types of social media use have the potential to impact on different aspects of health.

This article analyzes the relationship between various forms of intimate partner violence (IPV) and unmet need for family planning (FP) in South Asia. The data were obtained from the latest wave of the Demographic and Health Survey in Afghanistan, India, Maldives, Nepal, and Pakistan. Binary logistic regression analyses show mixed results, with a significant association between at least one type of IPV and unmet need for FP in all countries under study, except Maldives. There were also contrasting findings on the IPV-unmet need nexus, with a positive sign in some but negative sign in others. Women who experienced physical violence were associated with a higher odds of having an unmet need in Pakistan, but the opposite was true in Afghanistan and Nepal. The odds of having an unmet need were higher among Indian women who experienced IPV (sexual and emotional). In Afghanistan, women who experienced IPV (physical and emotional) have lower odds of having an unmet need. However, the interaction analysis of IPV (physical and sexual) and partners' controlling behavior showed a positive association with unmet need. Policymakers need to develop policies and strategies to prevent IPV and reduce unmet need for FP, in line with the Sustainable Development Goals.

Background: Ramucirumab is indicated for salvage treatment after failure of first-line treatment for metastatic colorectal cancer (mCRC). However, the application of ramucirumab at later-line treatment in real-world practice has not received much discussion., Methods: In this retrospective study, we enrolled 70 patients with mCRC who received ramucirumab plus chemotherapy at National Taiwan University Hospital between 2018 and 2019., Results: Compared with those who received third- or later-line ramucirumab treatment, patients who received second-line ramucirumab treatment had significantly longer median time to treatment discontinuation (mTTD; 6.7 vs 3.6 months, P = .004) and median overall survival (mOS; not reached vs 7.6 months, P = .009). Multivariate analyses revealed that second-line ramucirumab and triplet chemotherapy backbone were the only independent predictive factors for long mTTD and mOS. Patients who received ramucirumab with triplet chemotherapy had a significantly longer mOS than did patients who received ramucirumab with doublet chemotherapy (not reached vs 5.6 months, P = .002). Among those receiving second-line ramucirumab treatment, combination with triplet chemotherapy led to a longer mTTD than did combination with doublet chemotherapy, but the difference was non-significant (not reached vs 4.4 months, P = .108). By contrast, in patients receiving fourth- or later-line ramucirumab, combination with triplet chemotherapy led to significantly longer mTTD than did combination with doublet chemotherapy (8.0 vs 2.9 months, P = .032)., Conclusion: Ramucirumab plus triplet chemotherapy may be an alternative regimen in patients with mCRC, particularly as a later-line treatment modality., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The longnose houndshark, Iago garricki Fourmanoir & Rivaton 1979, was described based on five specimens collected from Vanuatu. Five additional specimens were recently collected from the waters off Dongsha Atoll, South China Sea. A redescription of this species is provided based on the holotype, non-types collected near the type locality and off Dongsha Atoll. The species is characterized by eye length larger than gill slit height; first dorsal-fin origin not reaching a vertical line through pectoral-fin base; head length 20.2-22.2% TL; preoral length 7.2-8.3% TL; upper labial furrow 2.2-3.4% TL; lateral teeth with 1-3 small cusplets on lateral side basally; diplospondylous centra 53-61; precaudal centra 94-102; and total centra 149-157. The specimens collected from the South China Sea represent the northernmost distributional record of this species.

Rationale: Diabetic retinopathy (DR) is a major complication of diabetes mellitus causing significant vision loss. DR is a multifactorial disease involving changes in retinal microvasculature and neuronal layers, and aberrations in vascular endothelial growth factors (VEGF) and inflammatory pathways. Despite the success of anti-VEGF therapy, many DR patients do not respond well to the treatment, emphasizing the involvement of other molecular players in neuronal and vascular aberrations in DR. Methods: We employed advanced mass spectrometry-based proteome profiling to obtain a global snapshot of altered protein abundances in vitreous humor from patients with proliferative DR (PDR) in comparison to individuals with epiretinal membrane without active DR or other retinal vascular complications. Global proteome correlation map and protein-protein interaction networks were used to probe into the functional inclination of proteins and aberrated molecular networks in PDR vitreous. In addition, peptide-centric analysis of the proteome data was carried out to identify proteolytic processing, primarily ectodomain shedding events in PDR vitreous. Functional validation experiments were performed using preclinical models of ocular angiogenesis. Results: The vitreous proteome landscape revealed distinct dysregulations in several metabolic, signaling, and immune networks in PDR. Systematic analysis of altered proteins uncovered specific impairment in ectodomain shedding of several transmembrane proteins playing critical roles in neurodegeneration and angiogenesis, pointing to defects in their regulating sheddases, particularly ADAM10, which emerged as the predominant sheddase. We confirmed that ADAM10 protease activity was reduced in animal models of ocular angiogenesis and established that activation of ADAM10 can suppress endothelial cell activation and angiogenesis. Furthermore, we identified the impaired ADAM10-AXL axis as a driver of retinal angiogenesis. Conclusion: We demonstrate restoration of aberrant ectodomain shedding as an effective strategy for treating PDR and propose ADAM10 as an attractive therapeutic target. In all, our study uncovered impaired ectodomain shedding as a prominent feature of PDR, opening new possibilities for advancement in the DR therapeutic space., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)