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Abstract NME3 is a member of the nucleoside diphosphate kinase (NDPK) family localized on the mitochondrial outer membrane (MOM). Here, we report a role of NME3 in hypoxia-induced mitophagy dependent on its active site phosphohistidine but not the NDPK function. Mice carrying a knock-in mutation in the Nme3 gene disrupting NME3 active site histidine phosphorylation are vulnerable to ischemia/reperfusion-induced infarction and develop abnormalities in cerebellar function. Our mechanistic analysis reveals that hypoxia-induced phosphatidic acid (PA) on mitochondria is essential for mitophagy and the interaction of DRP1 with NME3. The PA binding function of MOM-localized NME3 is required for hypoxia-induced mitophagy. Further investigation demonstrates that the interaction with active NME3 prevents DRP1 susceptibility to MUL1-mediated ubiquitination, thereby allowing a sufficient amount of active DRP1 to mediate mitophagy. Furthermore, MUL1 overexpression suppresses hypoxia-induced mitophagy, which is reversed by co-expression of ubiquitin-resistant DRP1 mutant or histidine phosphorylatable NME3. Thus, the site-specific interaction with active NME3 provides DRP1 a microenvironment for stabilization to proceed the segregation process in mitophagy.

Tissue repair is significantly compromised in the aging human body resulting in critical disease conditions (such as myocardial infarction or Alzheimer’s disease) and imposing a tremendous burden on global health. Reprogramming approaches (partial or direct reprogramming) are considered fruitful in addressing this unmet medical need. However, the efficacy, cellular maturity and specific targeting are still major challenges of direct reprogramming. Here we describe novel approaches in direct reprogramming that address these challenges. Extracellular signaling pathways (Receptor tyrosine kinases, RTK and Receptor Serine/Theronine Kinase, RSTK) and epigenetic marks remain central in rewiring the cellular program to determine the cell fate. We propose that modern protein design technologies (AI-designed minibinders regulating RTKs/RSTK, epigenetic enzymes, or pioneer factors) have potential to solve the aforementioned challenges. An efficient transdifferentiation/direct reprogramming may in the future provide molecular strategies to collectively reduce aging, fibrosis, and degenerative diseases.

Abstract This study used DNA methyltransferase 3b (DNMT3b) knockout cells and the functional loss of DNMT3b mutation in immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) cells to understand how DNMT3b dysfunction causes genome instability. We demonstrated that R-loops contribute to DNA damages in DNMT3b knockout and ICF cells. More prominent DNA damage signal in DNMT3b knockout cells was due to the loss of DNMT3b expression and the acquirement of p53 mutation. Genome-wide ChIP-sequencing mapped DNA damage sites at satellite repetitive DNA sequences including (peri-)centromere regions. However, the steady-state levels of (peri-)centromeric R-loops were reduced in DNMT3b knockout and ICF cells. Our analysis indicates that XPG and XPF endonucleases-mediated cleavages remove (peri-)centromeric R-loops to generate DNA beaks, causing chromosome instability. DNMT3b dysfunctions clearly increase R-loops susceptibility to the cleavage process. Finally, we showed that DNA double-strand breaks (DSBs) in centromere are probably repaired by error-prone end-joining pathway in ICF cells. Thus, DNMT3 dysfunctions undermine the integrity of centromere by R-loop-mediated DNA damages and repair.

This aim of this research was to explore the appraisal of the use of smart alert bracelets by older adults diagnosed with dementia. Convenience sampling was adopted to recruit older adults with dementia in Yunlin County, Taiwan. A manual questionnaire survey was conducted, and SPSS 26.0 statistical software was used for analysis. The results of this study showed noticeable positive correlation results in the post-test for the modes “wearing device”, “degree of dementia”, and “field configuration”. Based on the experimental results, the following suggestions are provided: (1) in terms of statistical calculation, the statistical results were affected by changes in some participants; (2) as for the design of equipment, to be more suitable for adult use, the size and color of bracelets need to be optimized; (3) as for the problem of battery charging of the device, because the charging location of the device is not easy to find, it is better to extend device standby time; (4) regarding the selection of equipment, older adults with early-stage dementia could be concerned about the function of the wearable device, so it is recommended to provide a device designed with clear functions, such as a watch, so that older adults are more willing to wear it. Patients diagnosed with moderate and severe dementia should be advised to use concealed non-sensory devices, such as charms and cards, to better facilitate assistance from caregivers in wearing them; and (5) as for the device, in case of a loss event, in addition to mobile phone notifications, other light and sound device notifications can be added, allowing caregivers to pay more attention to information in real time. In summary, the feedback from caregivers and older adults suggests that if the device is to be used without charging, the overall design should be light and small, which is more suitable for service designs.

In recent years, the global population has increased significantly, resulting in elevated levels of pollution in waterways. Organic pollutants are a major source of water pollution in various parts of the world, with phenolic compounds being the most common hazardous pollutant. These compounds are released from industrial effluents, such as palm oil milling effluent (POME), and cause several environmental issues. Adsorption is known to be an efficient method for mitigating water contaminants, with the ability to eliminate phenolic contaminants even at low concentrations. Carbon-based materials have been reported to be effective composite adsorbents for phenol removal due to their excellent surface features and impressive sorption capability. However, the development of novel sorbents with higher specific sorption capabilities and faster contaminant removal rates is necessary. Graphene possesses exceptionally attractive chemical, thermal, mechanical, and optical properties, including higher chemical stability, thermal conductivity, current density, optical transmittance, and surface area. The unique features of graphene and its derivatives have gained significant attention in the application of sorbents for water decontamination. Recently, the emergence of graphene-based adsorbents with large surface areas and active surfaces has been proposed as a potential alternative to conventional sorbents. The aim of this article is to discuss novel synthesis approaches for producing graphene-based nanomaterials for the adsorptive uptake of organic pollutants from water, with a special focus on phenols associated with POME. Furthermore, this article explores adsorptive properties, experimental parameters for nanomaterial synthesis, isotherms and kinetic models, mechanisms of nanomaterial formation, and the ability of graphene-based materials as adsorbents of specific contaminants.

We present the first specification-compliant constant-time FPGA implementation of the Classic McEliece cryptosystem from the third-round of NIST’s Post-Quantum Cryptography standardization process. In particular, we present the first complete implementation including encapsulation and decapsulation modules as well as key generation with seed expansion. All the hardware modules are parametrizable, at compile time, with security level and performance parameters. As the most time consuming operation of Classic McEliece is the systemization of the public key matrix during key generation, we present and evaluate three new algorithms that can be used for systemization while complying with the specification: hybrid early-abort systemizer (HEA), single-pass early-abort systemizer (SPEA), and dual-pass earlyabort systemizer (DPEA). All of the designs outperform the prior systemizer designs for Classic McEliece by 2.2x to 2.6x in average runtime and by 1.7x to 2.4x in time-area efficiency. We show that our complete Classic McEliece design for example can perform key generation in 5.2 ms to 20 ms, encapsulation in 0.1 ms to 0.5 ms, and decapsulation in 0.7 ms to 1.5 ms for all security levels on an Xlilinx Artix 7 FPGA. The performance can be increased even further at the cost of resources by increasing the level of parallelization using the performance parameters of our design.

This paper introduces a key encapsulation mechanism ROLLO+ and presents a constant-time AVX2 implementation of it. ROLLO+ is a variant of ROLLO-I targeting IND-CPA security. The main difference between ROLLO+ and ROLLO-I is that the decoding algorithm of ROLLO+ is adapted from the decoding algorithm of ROLLO-I. Our implementation of ROLLO+-I-128, one of the level-1 parameter sets of ROLLO+, takes 851823 Skylake cycles for key generation, 30361 Skylake cycles for encapsulation, and 673666 Skylake cycles for decapsulation. Compared to the state-of-the-art implementation of ROLLO-I-128 by Aguilar-Melchor et al., which is claimed to be constant-time but actually is not, our implementation achieves a 12.9x speedup for key generation, a 10.6x speedup for encapsulation, and a 14.5x speedup for decapsulation. Compared to the state-of-the-art implementation of the level-1 parameter set of BIKE by Chen, Chou, and Krausz, our key generation time is 1.4x as slow, but our encapsulation time is 3.8x as fast, and our decapsulation time is 2.4x as fast.

Background: Gallstone disease (GD) is associated with a high risk of cardiovascular disease. However, it is unknown whether GD contributes to atrial fibrillation (AF). We aimed to investigate the association between GD and AF.Methods: We performed a population-based cohort study using data from the Taiwan National Health Insurance Research Database between 2001 and 2011. A GD cohort of 230,076 patients was compared with a control cohort consisting of an equal number of patients matched for age, sex, cardiovascular and gastrointestinal comorbidities.Results: In total, 5,992 (49.8/10,000 person-years) patients with GD and 5,804 (44.5/10,000 person-years) controls developed AF. GD increased AF risk with a hazard ratio (HR) of 1.20 [95% confidence interval (CI), 1.16–1.25]. In patients with GD but without cholecystectomy, the HR of AF reached 1.57 (95% CI = 1.50–1.63). After cholecystectomy, the HR of AF significantly decreased to 0.85 (95% CI = 0.81–0.90). Among the three age groups with GD (

We present the first Cortex-M4 implementation of the NISTPQC signature finalist Rainbow. We target the Giant Gecko EFM32GG11B which comes with 512 kB of RAM which can easily accommodate the keys of RainbowI. We present fast constant-time bitsliced F16 multiplication allowing multiplication of 32 field elements in 32 clock cycles. Additionally, we introduce a new way of computing the public map P in the verification procedure allowing vastly faster signature verification. Both the signing and verification procedures of our implementation are by far the fastest among the NISTPQC signature finalists. Signing of rainbowIclassic requires roughly 957 000 clock cycles which is 4× faster than the state of the art Dilithium2 implementation and 45× faster than Falcon-512. Verification needs about 239 000 cycles which is 5× and 2× faster respectively. The cost of signing can be further decreased by 20% when storing the secret key in a bitsliced representation.

This paper introduces a new key space for CSIDH and a new algorithm for constant-time evaluation of the CSIDH group action. The key space is not useful with previous algorithms, and the algorithm is not useful with previous key spaces, but combining the new key space with the new algorithm produces speed records for constant-time CSIDH. For example, for CSIDH-512 with a 256-bit key space, the best previous constant-time results used 789000 multiplications and more than 200 million Skylake cycles; this paper uses 438006 multiplications and 125.53 million cycles.

This paper presents a constant-time implementation of Classic McEliece for ARM Cortex-M4. Specifically, our target platform is stm32f4-Discovery, a development board on which the amount of SRAM is not even large enough to hold the public key of the smallest parameter sets of Classic McEliece. Fortunately, the flash memory is large enough, so we use it to store the public key. For the level-1 parameter sets mceliece348864 and mceliece348864f, our implementation takes 582 199 cycles for encapsulation and 2 706 681 cycles for decapsulation. Compared to the level-1 parameter set of FrodoKEM, our encapsulation time is more than 80 times faster, and our decapsulation time is more than 17 times faster. For the level-3 parameter sets mceliece460896 and mceliece460896f, our implementation takes 1 081 335 cycles for encapsulation and 6 535 186 cycles for decapsulation. In addition, our implementation is also able to carry out key generation for the level-1 parameter sets and decapsulation for level-5 parameter sets on the board.

BIKE is a key encapsulation mechanism that entered the third round of the NIST post-quantum cryptography standardization process. This paper presents two constant-time implementations for BIKE, one tailored for the Intel Haswell and one tailored for the ARM Cortex-M4. Our Haswell implementation is much faster than the avx2 implementation written by the BIKE team: for bikel1, the level-1 parameter set, we achieve a 1.39x speedup for decapsulation (which is the slowest operation) and a 1.33x speedup for the sum of all operations. For bikel3, the level-3 parameter set, we achieve a 1.5x speedup for decapsulation and a 1.46x speedup for the sum of all operations. Our M4 implementation is more than two times faster than the non-constant-time implementation portable written by the BIKE team. The speedups are achieved by both algorithm-level and instruction-level optimizations.

As global economy takes off, we have a universalization of Manufacture and transfer of goods being made in other places. However, this practice results in some operational issues formultinational companies which are not able to transfer their know- how and supply chain practices for their overseas offices, due either to local legislation, lack of customized software to local rules and even transfer delays of the product. One of the most critical issues that emerges is the contractual obligations for keeping sla?? and state mandatory deadlines, which may result in penalties. The go-to solution for that issue is to organize and keep a local safety stock, although that is problematic in itself, due to short shelf life, maintenance cost and demand fluctuations. In addition, many man hours were used for planning the local safety stock. In a case study, an AI technique was used, called fuzzy logic, to deal with these issues. The technique described in this article for the real system was able to mimic the discretionary behavior of the operator responsible for the safety stock, performing ideal planning for acquisitions.

Cancer stem cells, in contrast to their more differentiated daughter cells, can endure genotoxic insults, escape apoptosis, and cause tumor recurrence. Understanding how normal adult stem cells survive and go to quiescence may help identify druggable pathways that cancer stem cells have co-opted. In this study, we utilize a genetically tractable model for stem cell survival in the Drosophila gonad to screen drug candidates and probe chemical-genetic interactions. Our study employs three levels of small molecule screening: (1) a medium-throughput primary screen in male germline stem cells (GSCs), (2) a secondary screen with irradiation and protein-constrained food in female GSCs, and (3) a tertiary screen in breast cancer organoids in vitro. Herein, we uncover a series of small molecule drug candidates that may sensitize cancer stem cells to apoptosis. Further, we have assessed these small molecules for chemical-genetic interactions in the germline and identified the NF-κB pathway as an essential and druggable pathway in GSC quiescence and viability. Our study demonstrates the power of the Drosophila stem cell niche as a model system for targeted drug discovery.

Introduction: The external appearance of auricle varies between ethnic groups. However, there have been no studies on external ear morphometry correlating soft biometrics of the same individual. Therefore, a morphometric databank for the same appears to offer useful data to doctors and computer engineers working with documentation system. Aim: To correlate the external ear parameters (Total ear height, Lobular width and Lobular height) with biometric parameters (Height, Head circumference and shoulder breadth) of individuals of different Ethnic Group and to correlate the linear measurements of the external ear within individuals of different ethnic groups. Materials and Methods: From four of Asian ethnic group, 160 students aged between 19 and 25 volunteered for the study. The races include Malaysians, Malaysian Chinese (Chinese residing in Malaysia); Indians; and Malaysian Indian (Indians residing in Malaysia). Linear measurements of ear pinna, Height, Head circumference, and Shoulder breadth of every participant were measured. The data were analysed using SPSS software, through one-way ANOVA and non-parametric Pearson’s coefficient. Results: Except Indian males there was significant correlation existing between height of individuals and total ear height (Malaysian Male r=0.507, p

Immune cells protect us against infection and cancer cells, as well as functioning during healing processes to support tissue repairing and regeneration. These behaviors require that upon stimulation from immune activation the appropriate subsets of immune cells are generated. In addition to activation-induced signaling cascades, metabolic reprogramming (profound changes in metabolic pathways) also provides a novel form of regulation to control the formation of desirable immune responses. Immune cells encounter various nutrient compositions by circulating in bloodstream and infiltrating into peripheral tissues; therefore, proper engagement of metabolic pathways is critical to fulfill the metabolic demands of immune cells. Metabolic pathways are tightly regulated mainly via mitochondrial dynamics and the activities of the tricarboxylic acid cycle and the electron transport chain. In this review, we will discuss how metabolic reprogramming influences activation, effector functions, and lineage polarization in T cells, with a particular focus on mitochondria-regulated metabolic checkpoints. Additionally, we will further explore how in various diseases deregulation and manipulation of mitochondrial regulation can occur and be exploited. Furthermore, we will discuss how this knowledge can facilitate the design of immunotherapies.

This note tries to provide a patch work for the paper of Chang Dye and Chuang (published in Yugoslav Journal of Operational Research 2002, number 1, 73-84). Their paper contains an important finding of smoothly connected property that can very dramatically simplify the solution procedure of many inventory models with ramp type demand and trapezoidal type demand. Our improvement will arouse attention of the researchers and help them apply their important findings in the pending research projects.

This paper presents a grammar and semantic corpus based similarity algorithm for natural language sentences. Natural language, in opposition to “artificial language”, such as computer programming languages, is the language used by the general public for daily communication. Traditional information retrieval approaches, such as vector models, LSA, HAL, or even the ontology-based approaches that extend to include concept similarity comparison instead of cooccurrence terms/words, may not always determine the perfect matching while there is no obvious relation or concept overlap between two natural language sentences. This paper proposes a sentence similarity algorithm that takes advantage of corpus-based ontology and grammatical rules to overcome the addressed problems. Experiments on two famous benchmarks demonstrate that the proposed algorithm has a significant performance improvement in sentences/short-texts with arbitrary syntax and structure.

Abstract Background Prokaryotic ubiquitin-like protein (Pup), the firstly identified post-translational protein modifier in prokaryotes, is an important signal for the selective degradation of proteins. Recently, large-scale proteomics technology has been applied to identify a large number of pupylated proteins. The development of a database for managing pupylated proteins and pupylation sites is important for further analyses. Description A database named PupDB is constructed by collecting experimentally identified pupylated proteins and pupylation sites from published studies and integrating the information of pupylated proteins with corresponding structures and functional annotations. PupDB is a web-based database with tools for browses and searches of pupylated proteins and interactive displays of protein structures and pupylation sites. Conclusions The structured and searchable database PupDB is expected to provide a useful resource for further analyzing the substrate specificity, identifying pupylated proteins in other organisms and developing computational tools for predicting pupylation sites. PupDB is freely available at http://cwtung.kmu.edu.tw/pupdb.

Abstract Background Accurate prediction of peptide immunogenicity and characterization of relation between peptide sequences and peptide immunogenicity will be greatly helpful for vaccine designs and understanding of the immune system. In contrast to the prediction of antigen processing and presentation pathway, the prediction of subsequent T-cell reactivity is a much harder topic. Previous studies of identifying T-cell receptor (TCR) recognition positions were based on small-scale analyses using only a few peptides and concluded different recognition positions such as positions 4, 6 and 8 of peptides with length 9. Large-scale analyses are necessary to better characterize the effect of peptide sequence variations on T-cell reactivity and design predictors of a peptide's T-cell reactivity (and thus immunogenicity). The identification and characterization of important positions influencing T-cell reactivity will provide insights into the underlying mechanism of immunogenicity. Results This work establishes a large dataset by collecting immunogenicity data from three major immunology databases. In order to consider the effect of MHC restriction, peptides are classified by their associated MHC alleles. Subsequently, a computational method (named POPISK) using support vector machine with a weighted degree string kernel is proposed to predict T-cell reactivity and identify important recognition positions. POPISK yields a mean 10-fold cross-validation accuracy of 68% in predicting T-cell reactivity of HLA-A2-binding peptides. POPISK is capable of predicting immunogenicity with scores that can also correctly predict the change in T-cell reactivity related to point mutations in epitopes reported in previous studies using crystal structures. Thorough analyses of the prediction results identify the important positions 4, 6, 8 and 9, and yield insights into the molecular basis for TCR recognition. Finally, we relate this finding to physicochemical properties and structural features of the MHC-peptide-TCR interaction. Conclusions A computational method POPISK is proposed to predict immunogenicity with scores which are useful for predicting immunogenicity changes made by single-residue modifications. The web server of POPISK is freely available at http://iclab.life.nctu.edu.tw/POPISK.

Abstract Background Bladder cancer is the sixth most common cancer in the world and the incidence is particularly high in southwestern Taiwan. Previous studies have identified several tumor-related genes that are hypermethylated in bladder cancer; however the DNA methylation profile of bladder cancer in Taiwan is not fully understood. Methods In this study, we compared the DNA methylation profile of multiple tumor suppressor genes (APC, DAPK, E-cadherin, hMLH1, IRF8, p14, p15, RASSF1A, SFRP1 and SOCS-1) in bladder cancer patients from different Chinese sub-populations including Taiwan (104 cases), Hong Kong (82 cases) and China (24 cases) by MSP. Two normal human urothelium were also included as control. To investigate the diagnostic potential of using DNA methylation in non-invasive detection of bladder cancer, degree of methylation of DAPK, IRF8, p14, RASSF1A and SFRP1 was also accessed by quantitative MSP in urine samples from thirty bladder cancer patients and nineteen non-cancer controls. Results There were distinct DNA methylation epigenotypes among the different sub-populations. Further, samples from Taiwan and China demonstrated a bimodal distribution suggesting that CpG island methylator phentotype (CIMP) is presented in bladder cancer. Moreover, the number of methylated genes in samples from Taiwan and Hong Kong were significantly correlated with histological grade (P < 0.01) and pathological stage (P < 0.01). Regarding the samples from Taiwan, methylation of SFRP1, IRF8, APC and RASSF1A were significantly associated with increased tumor grade, stage. Methylation of RASSF1A was associated with tumor recurrence. Patients with methylation of APC or RASSF1A were also significantly associated with shorter recurrence-free survival. For methylation detection in voided urine samples of cancer patients, the sensitivity and specificity of using any of the methylated genes (IRF8, p14 or sFRP1) by qMSP was 86.7% and 94.7%. Conclusions Our results indicate that there are distinct methylation epigenotypes among different Chinese sub-populations. These profiles demonstrate gradual increases with cancer progression. Finally, detection of gene methylation in voided urine with these distinct DNA methylation markers is more sensitive than urine cytology.

Abstract The study examined the effects of a norepinephrine transporter (NET) inhibitor reboxetine (RBX) on an attentional performance test. Adult SD rats trained with five-choice serial reaction time task (5-CSRTT) were administered with RBX (0, 3.0 and 10 mg/kg) in the testing day. Alpha-1 adrenergic receptor antagonist PRA and alpha-2 adrenergic receptor antagonist RX821002 were used to clarify the RBX effect. Results revealed that rat received RBX at 10 mg/kg had an increase in the percentage of the correct response and decreases in the numbers of premature response. Alpha-1 adrenergic receptor antagonist Prazosin (PRA) at 0.1 mg/kg reversed the RBX augmented correct responding rate. However, alpha-2 adrenergic receptor antagonist RX821002 at 0.05 and 0.1 mg/kg dose dependently reversed the RBX reduced impulsive responding. Our results suggested that RBX as a norepinephrine transporter inhibitor can be beneficial in both attentional accuracy and response control and alpha-1 and alpha-2 adrenergic receptors might be involved differently.

Abstract Background Analyzing gene expression data by assessing the significance of pre-defined gene sets, rather than individual genes, has become a main approach in microarray data analysis and this has promisingly derive new biological interpretations of microarray data. However, the detection power of conventional gene list or gene set-based approaches is limited on highly heterogeneous samples, such as tumors. Results We developed a novel method, the regulatory event-based Gene Set Analysis (eGSA), which considers not only the consistently changed genes but also every gene regulation (event) of each sample to overcome the detection limit. In comparison with conventional methods, eGSA can detect functional changes in heterogeneous samples more precisely and robustly. Furthermore, by utilizing eGSA, we successfully revealed novel functional characteristics and potential mechanisms of very early hepatocellular carcinoma (HCC). Conclusion Our study creates a novel scheme to directly target the major cellular functional changes in heterogeneous samples. All potential regulatory routines of a functional change can be further analyzed by the regulatory event frequency. We also provide a case study on early HCCs and reveal a novel insight at the initial stage of hepatocarcinogenesis. eGSA therefore accelerates and refines the interpretation of heterogeneous genomic data sets in the absence of gene-phenotype correlations.

Abstract Background Ubiquitylation plays an important role in regulating protein functions. Recently, experimental methods were developed toward effective identification of ubiquitylation sites. To efficiently explore more undiscovered ubiquitylation sites, this study aims to develop an accurate sequence-based prediction method to identify promising ubiquitylation sites. Results We established an ubiquitylation dataset consisting of 157 ubiquitylation sites and 3676 putative non-ubiquitylation sites extracted from 105 proteins in the UbiProt database. This study first evaluates promising sequence-based features and classifiers for the prediction of ubiquitylation sites by assessing three kinds of features (amino acid identity, evolutionary information, and physicochemical property) and three classifiers (support vector machine, k-nearest neighbor, and NaïveBayes). Results show that the set of used 531 physicochemical properties and support vector machine (SVM) are the best kind of features and classifier respectively that their combination has a prediction accuracy of 72.19% using leave-one-out cross-validation. Consequently, an informative physicochemical property mining algorithm (IPMA) is proposed to select an informative subset of 531 physicochemical properties. A prediction system UbiPred was implemented by using an SVM with the feature set of 31 informative physicochemical properties selected by IPMA, which can improve the accuracy from 72.19% to 84.44%. To further analyze the informative physicochemical properties, a decision tree method C5.0 was used to acquire if-then rule-based knowledge of predicting ubiquitylation sites. UbiPred can screen promising ubiquitylation sites from putative non-ubiquitylation sites using prediction scores. By applying UbiPred, 23 promising ubiquitylation sites were identified from an independent dataset of 3424 putative non-ubiquitylation sites, which were also validated by using the obtained prediction rules. Conclusion We have proposed an algorithm IPMA for mining informative physicochemical properties from protein sequences to build an SVM-based prediction system UbiPred. UbiPred can predict ubiquitylation sites accompanied with a prediction score each to help biologists in identifying promising sites for experimental verification. UbiPred has been implemented as a web server and is available at http://iclab.life.nctu.edu.tw/ubipred.

Abstract Background Gene Ontology (GO) annotation, which describes the function of genes and gene products across species, has recently been used to predict protein subcellular and subnuclear localization. Existing GO-based prediction methods for protein subcellular localization use the known accession numbers of query proteins to obtain their annotated GO terms. An accurate prediction method for predicting subcellular localization of novel proteins without known accession numbers, using only the input sequence, is worth developing. Results This study proposes an efficient sequence-based method (named ProLoc-GO) by mining informative GO terms for predicting protein subcellular localization. For each protein, BLAST is used to obtain a homology with a known accession number to the protein for retrieving the GO annotation. A large number n of all annotated GO terms that have ever appeared are then obtained from a large set of training proteins. A novel genetic algorithm based method (named GOmining) combined with a classifier of support vector machine (SVM) is proposed to simultaneously identify a small number m out of the n GO terms as input features to SVM, where m <

Abstract Background The identification of specific gene expression signature for distinguishing sample groups is a dominant field in cancer research. Although a number of tools have been developed to identify optimal gene expression signatures, the number of signature genes obtained is often overly large to be applied clinically. Furthermore, experimental verification is sometimes limited by the availability of wet-lab materials such as antibodies and reagents. A tool to evaluate the discrimination power of candidate genes is therefore in high demand by clinical researchers. Results Signature Evaluation Tool (SET) is a Java-based tool adopting the Golub's weighted voting algorithm as well as incorporating the visual presentation of prediction strength for each array sample. SET provides a flexible and easy-to-follow platform to evaluate the discrimination power of a gene signature. Here, we demonstrated the application of SET for several purposes: (1) for signatures consisting of a large number of genes, SET offers the ability to rapidly narrow down the number of genes; (2) for a given signature (from third party analyses or user-defined), SET can re-evaluate and re-adjust its discrimination power by selecting/de-selecting genes repeatedly; (3) for multiple microarray datasets, SET can evaluate the classification capability of a signature among datasets; and (4) by providing a module to visualize the prediction strength for each sample, SET allows users to re-evaluate the discrimination power on mis-grouped or less-certain samples. Information obtained from the above applications could be useful in prognostic analyses or clinical management decisions. Conclusion Here we present SET to evaluate and visualize the sample-discrimination ability of a given gene expression signature. This tool provides a filtration function for signature identification and lies between clinical analyses and class prediction (or feature selection) tools. The simplicity, flexibility and brevity of SET could make it an invaluable tool for marker identification in clinical research.

The manipulation of single atom within the metallic kernel of nanoclusters has attracted considerable attention due to its potentials to elucidate kernel-based structure-property relationships at the single-atom level. Herein, new-designed chiral bialkynyl ligands, have been chosen as protective agents to isolate two pairs of 8-electron superatomic silver nanoclusters, R/S-Ag39 and R/S-Ag40. X-ray diffraction analysis reveals that Ag39 and Ag40 with the same number of chiral ligands, possess a closely analogous silver skeleton but a single-atomic difference. The incorporation of an extra Ag 40th atom into Ag40 evokes two significant changes of structure and property compared to Ag39: (i) a reduction in the symmetry of the entire nanocluster, resulting in an enhancement of kernel-related asymmetry g-factor; (ii) a regulation of the transitions (1P → 1D and Ligand (π)  → 1D) of excited state, leading to a second near-infrared (NIR-II, 1000-1700 nm) phosphorescent emission red-shift from 1088 to 1150 nm. This work not only provides vital insights into the relationship between structures and ground/excited states chiroptical activities at the single-atom level, but also presents bialkynyl as a promising stabilizing agent for building superatomic metal nanoclusters., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Coinage metal nanoclusters (NCs), comprising a few to several hundred atoms, are prized for their size-dependent properties crucial in catalysis, sensing, and biomedicine. However, their practical application is often hindered by stability and reactivity challenges. Thiacalixarene, a macrocyclic ligand, shows promise in stabilizing silver, copper, and bimetallic NCs, enhancing their structural integrity and chemical stability. This investigation delves into the unique properties of thiacalix[4]arene and their role in bolstering NC stability, catalytic efficiency, and sensing capabilities. The current challenges and future prospects are critically evaluated, underscoring the transformative impact of thiacalix[4]arene in nanoscience. This review aims to broaden the utilization of atomically precise coinage metal NCs, unlocking new avenues across scientific and industrial applications., (© 2024 Wiley‐VCH GmbH.)

The established capability of anion templates in precisely manipulating the size, geometry, and function of metal clusters is well acknowledged. However, the development of a systematic methodology for orchestrating the assembly of silver clusters, particularly those encompassing multiple distinct types of anion templates, remains elusive due to the formidable synthetic challenge. In this work, we report two novel silver clusters, Ag57 and Ag72, using two and three different anion templates, respectively. Ag57 features a gyroscope-like monovalent cation with an Ag 3 triangle core sandwiched by one [SiW 9 O 34 ] 10- and a triad of Cl - anion templates. By intentionally introducing the third anion template, SO 4 2- , the structure is expanded to the unprecedented Ag72 (with 15 silver atoms epitaxially grown on top of Ag57) resembling a tumbler, inside of which two Ag 3 layers are laminated by one [SiW 9 O 34 ] 10- , seven Cl - and one SO 4 2- anion templates in parallel with respect to longitudinal orientation. It is noteworthy that Ag72 exhibits remarkable structural complexity and represents a pioneering achievement as the first silver cluster incorporating three distinct types of anion templates. In addition, Ag72 demonstrates a significant advantage over Ag57, particular in terms of applications such as luminescent thermometers and remote laser ignition. This work not only broadens the horizon for precise control of the silver cluster structures through the integration of multiple types of hetero-anions but also lays a solid foundation for potential optical applications in the future., (© 2024 Wiley-VCH GmbH.)

Immobilizing molecular catalysts on electro-conductive supports (for example, multi-walled carbon nanotubes, CNTs) represent a promising way to well-defined catalyst/support interfaces, which has shown appreciable performance for catalytic transformation. However, their full potential is far from achieved due to insufficient utilization of the intrinsic activity for each immobilized molecular catalyst, especially at loadings that should allow decent current densities. In the present work, we discover host-guest interaction between tetra-crown ether substituted cobalt phthalocyanine and metal ions, for example K + ions, not only eliminate catalyst aggregation at immobilization procedures but also reinforce catalyst/support interactions by additional electrostatic attractions under operational conditions. Through simple dip-coating procedures, a successful single molecular dispersion is achieved. Such a catalyst/electrode interface is stable and can selectively catalyze CO 2 -to-CO conversion with Faradaic efficiency over 96%. Importantly, this interface maintains an almost unchanged turnover frequency (TOF) across all loading conditions, implying a full utilization of the intrinsic activity of supported molecular catalysts. Therefore, a simultaneous achievement of high TOF and high current density (TOF of 111 s -1 at 38 mA cm -2 ) is achieved, in an aqueous H-type electrolyzer at an overpotential of 570 mV., (© 2024 Wiley-VCH GmbH.)

Extrachromosomal, circular DNA (ecDNA) is a prevalent oncogenic alteration in cancer genomes, often associated with aggressive tumor behavior and poor patient outcome. While previous studies proposed a chromatin-based mobile enhancer model for ecDNA-driven oncogenesis, its precise mechanism and impact remains unclear across diverse cancer types. Our study, utilizing advanced multi-omics profiling, epigenetic editing, and imaging approaches in three cancer models, reveals that ecDNA hubs are an integrated part of nuclear condensates and exhibit cancer-type specific chromatin connectivity. Epigenetic silencing of the ecDNA-specific regulatory modules or chemically disrupting liquid-liquid phase separation breaks down ecDNA hubs, displaces MED1 co-activator binding, inhibits oncogenic transcription, and promotes cell death. These findings substantiate the trans -activator function of ecDNA and underscore a structural mechanism driving oncogenesis. This refined understanding expands our views of oncogene regulation and opens potential avenues for novel therapeutic strategies in cancer treatment.

Transition metal carbyne complexes are of fundamental importance in carbon-carbon bond formation, alkyne metathesis, and alkyne coupling reactions. Most reported iron carbyne complexes are stabilized by incorporating heteroatoms. Here we show the synthesis of bioinspired FeMo heterobimetallic carbyne complexes by the conversion of C 2 H 2 through a diverse series of intermediates. Key reactions discovered include the reduction of a μ-η 2 :η 2 -C 2 H 2 ligand with a hydride to produce a vinyl ligand (μ-η 1 :η 2 -CH = CH 2 ), tautomerization of the vinyl ligand to a carbyne (μ-CCH 3 ), and protonation of either the vinyl or the carbyne compound to form a hydrido carbyne heterobimetallic complex. Mechanistic studies unveil the pivotal role of H 2 O as a proton shuttle, facilitating the proton transfer that converts the vinyl group to a bridging carbyne., (© 2024. The Author(s).)

Plastic pollution is worsening the living conditions on Earth, primarily due to the toxicity and stability of non-biodegradable plastics (NBPs). Photocatalytic cracking of NBPs is emerging as a promising way to cleave inert C-C bonds and abstract the carbon atoms from these wastes into valuable chemicals and fuels. However, controlling these processes is a huge challenge, ascribed to the complicated reactions of various NBPs. Herein, we summarize recent advances in the CO 2 and carbon-radical-mediated photocatalytic cracking of NBPs, with an emphasis on the pivotal intermediates. The CO 2 -mediated cracking proceeded with indiscriminate C-H/C-C bond cleavage of NBPs and tandem photoreduction of CO 2 , while carbon-radical-mediated cracking was realized by the prior activation of C-H bonds for selective C-C bond cleavage of NBPs. Catalytic generation and conversion of different intermediates greatly depend on the kinds of active species and the structure of photocatalysts under irradiation. Meanwhile, the fate of a specific intermediate is compared with small molecule activation to reveal the key problems in the cracking of NBPs. Finally, the challenges and potential directions are discussed to improve the overall efficiency in the photocatalytic cracking of NBPs., (© 2024 Wiley-VCH GmbH.)

Background: A causal connection between oxidative stress and inflammation in diabetes, along with its associated renal and cardiovascular complications, has been established. Sixteen prescribed potentially renoprotective Chinese herbal medicines for diabetic kidney disease (PRCHMDKD), which are scientific Chinese medicine (botanical drug) and categorized into five classes (clearing heat, nourishing yin, dampness dispelling, tonifying qi, and harmonizing formulas), exhibit shared antioxidative properties and target multiple oxidative stress pathways. However, the time-response, cumulative effects, and safety (hyperkalemia risk) of these sixteen PRCHMDKD on cardiorenal and survival outcomes in patients with overall and advanced DKD remain unresolved., Methods: This retrospective cohort study analyzed national health insurance claims data in 2000-2017. Four statistical methods, including Cox proportional hazards models, complementary restricted mean survival time (RMST), propensity score matching, and competing risk analysis for end-stage renal disease (ESRD), were employed to investigate this relationship. The study included 43,480 PRCHMDKD users and an equal number of matched nonusers within the overall DKD patient population. For advanced DKD patients, the cohort comprised 1,422 PRCHMDKD users and an equivalent number of matched nonusers., Results: PRCHMDKD use in overall and advanced, respectively, DKD patients was associated with time-dependent reductions in adjusted hazard ratios for ESRD (0.66; 95% CI, 0.61-0.70 vs. 0.81; 0.65-0.99), all-cause mortality (0.48; 0.47-0.49 vs. 0.59; 0.50-0.70), and cardiovascular mortality (0.50; 0.48-0.53 vs. 0.61; 0.45-0.82). Significant differences in RMST were observed in overall and advanced, respectively, DKD patients, favoring PRCHMDKD use: 0.31 years (95% CI, 0.24-0.38) vs. 0.61 years (0.13-1.10) for ESRD, 2.71 years (2.60-2.82) vs. 1.50 years (1.03-1.98) for all-cause mortality, and 1.18 years (1.09-1.28) vs. 0.59 years (0.22-0.95) for cardiovascular mortality. Additionally, hyperkalemia risk did not increase. These findings remained consistent despite multiple sensitivity analyses. Notably, the cumulative effects of utilizing at least four or five classes and multiple botanical drugs from the sixteen PRCHMDKD provided enhanced renoprotection for patients with both overall and advanced DKD. This suggests that there is involvement of multiple targets within the oxidative stress pathways associated with DKD., Conclusion: This real-world study suggests that using these sixteen PRCHMDKD provides time-dependent cardiorenal and survival benefits while ensuring safety for DKD patients., 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 Chen, Tung, Yu and Chen.)

Herein is the first example of photocatalytic cross-coupling of alkenes with aldehydes by a single catalyst without an external photosensitizer and any additives. Irradiation of the aromatic aldehyde and cobaloxime catalyst results in the formation of an acyl radical, which undergoes radical addition with alkene or indole and subsequently β-H elimination to afford alkenyl ketone. The reaction features cheap and readily available raw materials, a broad substrate scope, and mild conditions, even for late-stage derivatization of bioactive compounds.

Represented herein is the first 1,3-difunctionalization of alkenes via photocatalysis. A single cobaloxime is used to carry out two catalytic cycles in which cobaloxime is used not only as a photocatalyst to initiate the reaction but also as a metal catalyst for the β-H elimination process. Electron-deficient alkenes, electron-rich alkenes, and unactivated alkenes could be directly converted to 1,3-bisphosphorylated products, even unsymmetric 1,3-bisphosphorylated products, with only H 2 as a byproduct under extremely mild reaction conditions.

Expanding the diversity of multi-macrocyclic nanocarbons, particularly those with all-benzene scaffolds, represents intriguing yet challenging synthetic tasks. Complementary to the existing synthetic approaches, here we report an efficient and modular post-functionalization strategy that employs iridium-catalyzed C-H borylation of the highly strained meta-cycloparaphenylenes (mCPPs) and an mCPP-derived catenane. Based on the functionalized macrocyclic synthons, a number of novel all-benzene topological structures including linear and cyclic chains, polycatenane, and pretzelane have been successfully prepared and characterized, thereby showcasing the synthetic utility and potential of the post-functionalization strategy., (© 2024 Wiley-VCH GmbH.)