Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation.

Glucose is a universal bioenergy source; however, its role in controlling protein interactions is unappreciated, as are its actions during differentiation-associated intracellular glucose elevation. Azido-glucose click chemistry identified glucose binding to a variety of RNA binding proteins (RBPs), including the DDX21 RNA helicase, which was found to be essential for epidermal differentiation. Glucose bound the ATP-binding domain of DDX21, altering protein conformation, inhibiting helicase activity, and dissociating DDX21 dimers. Glucose elevation during differentiation was associated with DDX21 re-localization from the nucleolus to the nucleoplasm where DDX21 assembled into larger protein complexes containing RNA splicing factors. DDX21 localized to specific SCUGSDGC motif in mRNA introns in a glucose-dependent manner and promoted the splicing of key pro-differentiation genes, including GRHL3, KLF4, OVOL1, and RBPJ. These findings uncover a biochemical mechanism of action for glucose in modulating the dimerization and function of an RNA helicase essential for tissue differentiation.

Enhanced DNA repair through droplet formation and p53 oscillations.

Living organisms are constantly exposed to DNA damage, and optimal repair is therefore crucial. A characteristic hallmark of the response is the formation of sub-compartments around the site of damage, known as foci. Following multiple DNA breaks, the transcription factor p53 exhibits oscillations in its nuclear concentration, but how this dynamics can affect the repair remains unknown. Here, we formulate a theory for foci formation through droplet condensation and discover how oscillations in p53, with its specific periodicity and amplitude, optimize the repair process by preventing Ostwald ripening and distributing protein material in space and time. Based on the theory predictions, we reveal experimentally that the oscillatory dynamics of p53 does enhance the repair efficiency. These results connect the dynamical signaling of p53 with the microscopic repair process and create a new paradigm for the interplay of complex dynamics and phase transitions in biology.

The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution.

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity1. In this study, we investigated the evolution of genomic signatures caused by endogenous and external mutagenic processes and their interplay with complex structural variants (SVs). We superimposed mutational signatures and phylogenetic analyses of matched serial tumours from patients with urothelial cancer to define the evolutionary dynamics of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas chemotherapy induces mutational bursts of hundreds of late subclonal mutations. Using a genome graph computational tool2, we observed frequent high copy-number circular amplicons characteristic of extrachromosomal DNA (ecDNA)-forming SVs. We characterized the distinct temporal patterns of APOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative to ecDNA biogenesis. We discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNA-forming SVs persisted and increased in complexity, incorporating additional DNA segments and contributing to the evolution of treatment resistance. Oxford Nanopore Technologies long-read whole-genome sequencing followed by de novo assembly mapped out CCND1 ecDNA structure. Experimental modelling of CCND1 ecDNA confirmed its role as a driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications.

Implementation of First-trimester Screening and Prevention of Preeclampsia: a Stepped Wedge Cluster-randomized Trial in Asia.

BACKGROUND: This trial aimed to assess the efficacy, acceptability and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia (PE) in Asia. METHODS: Between 1st August 2019 and 28th February 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from ten regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular six-week intervals, one cluster was randomized to transit from non-intervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm PE using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm PE ≥ 1 in 100, received low-dose aspirin from <16 weeks until 36 weeks. RESULTS: Overall, 88.04% (42,897/48,725) of women agreed to undergo first-trimester screening for preterm PE. Among those identified as high-risk in the intervention phase, 82.39% (2,919/3,543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm PE between the intervention and non-intervention phases (adjusted odds ratio [aOR] 1.59; 95% confidence interval [CI] 0.91 to 2.77). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm PE (aOR 0.59; 95%CI 0.37 to 0.92). Additionally, it correlated with 54%, 55% and 64% reduction in the incidence of PE with delivery at <34 weeks (aOR 0.46; 95%CI 0.23 to 0.93), spontaneous preterm birth <34 weeks (aOR 0.45; 95%CI 0.22 to 0.92) and perinatal death (aOR 0.34; 95%CI 0.12 to 0.91), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events. CONCLUSIONS: The implementation of the screen-and-prevent strategy for preterm PE is not associated with a significant reduction in the incidence of preterm PE. However, low-dose aspirin effectively reduces the incidence of preterm PE by 41% among high-risk women. The screen-and-prevent strategy for preterm PE is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm PE on a global scale.

Trapping biosynthetic acyl-enzyme intermediates with encoded 2,3-diaminopropionic acid.

Many enzymes catalyse reactions that proceed through covalent acyl-enzyme (ester or thioester) intermediates1. These enzymes include serine hydrolases2,3 (encoded by one per cent of human genes, and including serine proteases and thioesterases), cysteine proteases (including caspases), and many components of the ubiquitination machinery4,5. Their important acyl-enzyme intermediates are unstable, commonly having half-lives of minutes to hours6. In some cases, acyl-enzyme complexes can be stabilized using substrate analogues or active-site mutations but, although these approaches can provide valuable insight7-10, they often result in complexes that are substantially non-native. Here we develop a strategy for incorporating 2,3-diaminopropionic acid (DAP) into recombinant proteins, via expansion of the genetic code11. We show that replacing catalytic cysteine or serine residues of enzymes with DAP permits their first-step reaction with native substrates, allowing the efficient capture of acyl-enzyme complexes that are linked through a stable amide bond. For one of these enzymes, the thioesterase domain of valinomycin synthetase12, we elucidate the biosynthetic pathway by which it progressively oligomerizes tetradepsipeptidyl substrates to a dodecadepsipeptidyl intermediate, which it then cyclizes to produce valinomycin. By trapping the first and last acyl-thioesterase intermediates in the catalytic cycle as DAP conjugates, we provide structural insight into how conformational changes in thioesterase domains of such nonribosomal peptide synthetases control the oligomerization and cyclization of linear substrates. The encoding of DAP will facilitate the characterization of diverse acyl-enzyme complexes, and may be extended to capturing the native substrates of transiently acylated proteins of unknown function.

Heparan sulfate proteoglycans: Mediators of cellular and molecular Alzheimer's disease pathogenic factors via tunnelling nanotubes?

Neurological disorders impact around one billion individuals globally (15 % approx.), with significant implications for disability and mortality with their impact in Australia currently amounts to 6.8 million deaths annually. Heparan sulfate proteoglycans (HSPGs) are complex extracellular molecules implicated in promoting Tau fibril formation resulting in Tau tangles, a hallmark of Alzheimer's disease (AD). HSPG-Tau protein interactions contribute to various AD stages via aggregation, toxicity, and clearance, largely via interactions with the glypican 1 and syndecan 3 core proteins. The tunnelling nanotubes (TNTs) pathway is emerging as a facilitator of intercellular molecule transport, including Tau and Amyloid ß proteins, across extensive distances. While current TNT-associated evidence primarily stems from cancer models, their role in Tau propagation and its effects on recipient cells remain unclear. This review explores the interplay of TNTs, HSPGs, and AD-related factors and proposes that HSPGs influence TNT formation in neurodegenerative conditions such as AD.

Sec61 channel subunit Sbh1/Sec61ß promotes ER translocation of proteins with suboptimal targeting sequences and is fine-tuned by phosphorylation.

The highly conserved endoplasmic reticulum (ER) protein translocation channel contains one nonessential subunit, Sec61ß/Sbh1, whose function is poorly understood so far. Its intrinsically unstructured cytosolic domain makes transient contact with ER-targeting sequences in the cytosolic channel vestibule and contains multiple phosphorylation sites suggesting a potential for regulating ER protein import. In a microscopic screen, we show that 12% of a GFP-tagged secretory protein library depends on Sbh1 for translocation into the ER. Sbh1-dependent proteins had targeting sequences with less pronounced hydrophobicity and often no charge bias or an inverse charge bias which reduces their insertion efficiency into the Sec61 channel. We determined that mutating two N-terminal, proline-flanked phosphorylation sites in the Sbh1 cytosolic domain to alanine phenocopied the temperature-sensitivity of a yeast strain lacking SBH1 and its ortholog SBH2. The phosphorylation site mutations reduced translocation into the ER of a subset of Sbh1-dependent proteins, including enzymes whose concentration in the ER lumen is critical for ER proteostasis. In addition, we found that ER import of these proteins depended on the activity of the phospho-S/T-specific proline isomerase Ess1 (PIN1 in mammals). We conclude that Sbh1 promotes ER translocation of substrates with suboptimal targeting sequences and that its activity can be regulated by a conformational change induced by N-terminal phosphorylation.

Synergy of retinoic acid and BH3 mimetics in MYC(N)-driven embryonal nervous system tumours.

BACKGROUND: Certain paediatric nervous system malignancies have dismal prognoses. Retinoic acid (RA) is used in neuroblastoma treatment, and preclinical data indicate potential benefit in selected paediatric brain tumour entities. However, limited single-agent efficacy necessitates combination treatment approaches. METHODS: We performed drug sensitivity profiling of 76 clinically relevant drugs in combination with RA in 16 models (including patient-derived tumouroids) of the most common paediatric nervous system tumours. Drug responses were assessed by viability assays, high-content imaging, and apoptosis assays and RA relevant pathways by RNAseq from treated models and patient samples obtained through the precision oncology programme INFORM (n = 2288). Immunoprecipitation detected BCL-2 family interactions, and zebrafish embryo xenografts were used for in vivo efficacy testing. RESULTS: Group 3 medulloblastoma (MBG3) and neuroblastoma models were highly sensitive to RA treatment. RA induced differentiation and regulated apoptotic genes. RNAseq analysis revealed high expression of BCL2L1 in MBG3 and BCL2 in neuroblastomas. Co-treatments with RA and BCL-2/XL inhibitor navitoclax synergistically decreased viability at clinically achievable concentrations. The combination of RA with navitoclax disrupted the binding of BIM to BCL-XL in MBG3 and to BCL-2 in neuroblastoma, inducing apoptosis in vitro and in vivo. CONCLUSIONS: RA treatment primes MBG3 and NB cells for apoptosis, triggered by navitoclax cotreatment.

Local calcium chloride infusion after pulsed field ablation enhances acute efficacy of cardiac electroporation.

INTRODUCTION: Pulsed field ablation (PFA) has emerged as an innovative therapy for cardiac arrhythmias. Drawing parallels with PFA's application in solid tumors, calcium chloride (CaCl2) as an adjuvant therapy, known as calcium electroporation, may amplify PFA's apoptotic effects. We propose that PFA in the atrium could enhance calcium uptake through PFA-created pores, thereby increasing ablation efficacy even at reduced power levels by exploiting PFA's permeabilization effects. METHODS: We conducted in vivo ablations on the atria of seven pigs using low PFA power (250 V, 20 µs for 50 pulses at 200 ms intervals). Post-PFA, we randomly administered an infusion of either 200 mg/2 ml CaCl2 (calcium group) or saline (control) directly to the ablation site via the catheter tip. We evaluated reduction in electrogram voltage amplitude, electrocardiography (ECG) parameters, ablation lesion parameters, and histology after PFA. RESULTS: Nineteen lesions from control and calcium groups were examined. Control lesions showed no voltage decrease post-PFA, whereas calcium-treated lesions exhibited a significant voltage reduction. Gross pathology indicated marked differences in maximum lesion surface diameter, depth, and volume between the lesion groups. Histologically, calcium group lesions were characterized by a more severe acute PFA response with contraction band necrosis, myocytolysis and nuclear pyknosis in adjacent myocardium, in addition to microhemorrhages. CONCLUSION: Infusing calcium chloride locally after PFA markedly improves the immediate efficacy of electroporation in porcine atria. This study suggests that calcium electroporation could bolster PFA outcomes without higher energy levels, potentially diminishing associated risks. These preliminary findings warrant further research into the long-term efficacy and potential clinical application of calcium electroporation in PFA.

Developmental outcomes of children born through ICSI versus conventional IVF (cIVF) in couples with non-male factor infertility.

STUDY QUESTION: In non-male factor infertile couples, are there any differences in the developmental outcomes between children born through ICSI and conventional IVF (cIVF)? SUMMARY ANSWER: In this preliminary study, ICSI and cIVF seem to have a comparable effect on developmental outcomes after 12 months in children born to non-male factor infertile couples. WHAT IS KNOWN ALREADY: ICSI, an invasive technique, has raised concerns about potential developmental abnormalities in children. Limited data are available regarding the developmental outcomes of ICSI-conceived infants born to non-male factor infertile couples. STUDY DESIGN, SIZE, DURATION: This prospective cohort study involved a follow-up of all children aged 12 months or older who were born from pregnancies resulting from either ICSI or cIVF as part of a previous randomized controlled trial (RCT) (NCT03428919). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the original RCT, 1064 women were randomly assigned to the ICSI or cIVF groups (532 women for each group). Follow-up was conducted with 155 couples (195 children) in the ICSI group and 141 couples (185 children) in the cIVF group. The Vietnamese version of the Ages & Stages Third Edition Questionnaires (ASQ-3) and the Development Red Flags questionnaires were completed by the participants. A total of 141 (90.1%) women (177 children) in the ICSI group and 113 (80.1%) women (145 children) in the cIVF group returned fully completed questionnaires. The primary outcomes were the developmental outcomes based on responses to the ASQ-3 and the Red Flags questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age of children at follow-up was 19.5 ± 5.0 months in the ICSI group and 19.3 ± 5.5 months in the cIVF group. The mean height and weight of children in both groups were similar. The overall proportion of children with any abnormal ASQ-3 score did not differ significantly between the ICSI and cIVF groups (16.9% vs 13.1%, P = 0.34). The proportion of children with Red Flag signs was also comparable between the two groups (6.2% vs 9.2%, P = 0.36, ICSI vs cIVF, respectively). LIMITATIONS, REASONS FOR CAUTION: Despite a reasonably high follow-up response rate, there is a potential risk of sampling bias, and overall, the number of children with developmental abnormalities was very small. The study relied solely on questionnaires as screening tools, rather than incorporating additional behavioral observations or physical developmental tests; this may have affected the statistical power and the significance of between-group comparisons. WIDER IMPLICATIONS OF THE FINDINGS: The current findings contribute to the existing evidence and support the comparative safety of ICSI and cIVF regarding early childhood development. However, more extensive and prolonged follow-up data for these children are needed to draw definitive conclusions. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study, and no authors reported conflicting interests. TRIAL REGISTRATION NUMBER: NCT04866524 (clinicaltrials.gov).

Clinical characteristics and outcomes of patients with Herpes Simplex Encephalitis in Vietnam: a retrospective study.

BACKGROUND: Herpes simplex encephalitis (HSE) is an important central nervous infection with severe neurological sequelae. The aim of this study was to describe clinical characteristic and outcomes of patients with HSE in Vietnam. METHODS: This was a retrospective study of 66 patients with herpes simplex encephalitis who admitted to the National Hospital for Tropical Diseases, Hanoi, Vietnam from 2018 to 2021. The detection of herpes simplex virus (HSV) in cerebrospinal fluid was made by the real-time PCR assay. We reported the clinical manifestation on admission and evaluated clinical outcomes at the hospital discharge by modified Rankin Scale (mRS). Multivariate logistic regression analysis was used to analyze the independent risk factors of severe outcomes. RESULTS: Of the 66 patients with laboratory confirmed HSE, the median age was 53 years (IQR 38-60) and 44 patients (69.7%) were male. The most common manifestations included fever (100%), followed by the consciousness disorder (95.5%). Other neurological manifestation were seizures (36.4%), memory disorders (31.8%), language disorders (19.7%) and behavioral disorders (13.6%). Conventional magnetic resonance imaging (MRI) showed 93.8% patients with temporal lobe lesions, followed by abnormalities in insula (50%), frontal lobe (34.4%) and 48.4% of patients had bilateral lesions. At discharge, 19 patients (28.8%) completely recovered, 15 patients (22.7%) had mild sequelae, 28 patients (42.4%) had moderate to severe sequelae. Severe neurological sequelae were memory disorders (55.8%), movement disorders (53.5%), language disorders (30.2%). Multivariate logistic regression analysis showed that Glasgow score decrement at admission, seizures, and time duration from onset of symptoms to the start of Acyclovir treatment > 4 days were independent factors associated with severe outcomes in HSE patients. CONCLUSION: Glasgow score decrement, seizures and delay treatment with Acyclovir were associated with the poor outcome of patients with HSE.

Antiferromagnetism in GaS monolayer doped with TM-TM atom pairs (TM = V, Cr, Mn, and Fe).

In this work, structural modification at Ga sites of the gallium sulfide (GaS) monolayer is explored to create new two-dimensional (2D) materials towards spintronic applications. GaS monolayer is a non-magnetic indirect-gap semiconductor material with an energy gap of 2.38 (3.27) eV as calculated using the PBE(HSE06) functional. Half-metallicity is induced in this 2D material by creating a single Ga vacancy, where S atoms around the defect site produce mainly the magnetic properties with a total magnetic moment of 1.00µB. In contrast, the non-magnetic nature is preserved under the effects of a pair of Ga vacancies, which metallize the monolayer. V, Mn, and Fe doping leads to the emergence of the diluted magnetic semiconductor nature, while doping with Cr creates a new 2D half-metallic material from the GaS monolayer. In these cases, total magnetic moments between 2.00 and 5.00µB are obtained and the 3d orbital of transition metal (TM) impurities mainly induces the system magnetism. In addition, the effects of doping with a pair of TM (pTM) atoms are also investigated, in which the antiferromagnetism is found to be stable rather than the ferromagnetism to follow the Pauli exclusion principle. Significant magnetization of the GaS monolayer is also achieved with zero total magnetic moment because of the structural mirror-symmetry. pV-, pMn-, and pFe-doped systems are antiferromagnetic semiconductor materials with energy gaps of 1.06, 1.90, and 1.84 eV, respectively. Meanwhile, the monolayer is metallized by doping with a pCr pair. The results presented herein indicate that the defective and doped GaS monolayers are prospective 2D candidates for spintronic applications - which are hindered for the pristine GaS monolayer because of the absence of intrinsic magnetism.

A systematic investigation of chromium and vanadium impurities in a Janus Ga2SO monolayer towards spintronic applications.

Transition metals (TMs) have been employed as efficient sources of magnetism in non-magnetic two-dimensional (2D) materials. In this work, doping with chromium (Cr) and vanadium (V) is proposed to induce feature-rich electronic and magnetic properties in a Janus Ga2SO monolayer towards spintronic applications. The Ga2SO monolayer is a 2D semiconductor material with an energy gap of 1.30 (2.12) eV obtained from PBE(HSE06)-based calculations. Considering the structural asymmetry, different vacancy and doping sites are considered. A single Ga vacancy and pair of Ga vacancies magnetize the monolayer with total magnetic moments between 0.69 and 3.13µB, where the half-metallic nature is induced by the single Ga1 vacancy (that bound to the S atom). In these cases, the magnetism is originated mainly from S and O atoms closest to the vacancy sites. Depending on the doping site, either half-metallicity or diluted magnetic semiconductor natures are obtained by doping with Cr and V atoms with total magnetic moments of 3.00 and 2.00µB, respectively. Herein, 3d TM impurities produce mainly the system magnetism. When substituting a pair of Ga atoms, TM atoms exhibit the antiparallel spin alignment to follow the Pauli exclusion principle, retaining the novel electronic characteristics induced by a single TM dopant. Except for the case of doping with a pair of V atoms, total magnetic moments of 2.00 and 1.00µB are obtained by doping with a pair or Cr atoms and Cr/V co-doping, respectively. The non-zero magnetic moment is derived from the different interactions of each TM atom with its neighboring atoms, which will also be studied by Bader charge analysis. Our results introduce new promising 2D spintronic candidates, which are made by structural modifications at Ga sites of a non-magnetic Janus Ga2SO monolayer.

Rich essential properties of silicon-substituted graphene nanoribbons: a comprehensive computational study.

The diverse structural, electronic, and magnetic properties of silicon (Si)-substituted armchair and zigzag graphene nanoribbons (AGNRs and ZGNRs) were investigated using spin-polarized density functional theory (DFT) calculations. Pristine AGNRs belong to a nonmagnetic semiconductor with a direct bandgap of 1.63/1.92 eV determined by PBE/HSE06 functionals. Under various Si substitutions, nonmagnetic bandgaps were tuned at 1.49/1.87, 1.06/1.84, 0.81/1.45, 1.04/1.71, 0.89/1.05, and 2.38/3.0 eV (PBE/HSE06) in the single Si edge-, single Si non-edge-, double Si ortho-, double Si meta-, double Si para-, and 100% Si-substituted AGNR configurations, respectively. Meanwhile, pristine ZGNRs displayed antiferromagnetic semiconducting behavior with a spin degenerate bandgap of 0.52/0.81 eV (PBE/HSE06) and becomes a ferromagnetic semimetal in the single Si configurations or an unusual ferromagnetic semiconductor in the 100% Si configuration. Under the developed first-principles theoretical framework, the formation of quasi π (C-2pz and Si-3pz) and quasi σ (C-2s, -2pxy and Si-3s and -3pxy) bands was identified in the Si-substituted configurations. These quasi π and quasi σ bands showed weak separation, resulting in weak quasi sp2 hybridization in Si-C bonds, in which the identified hybridization mechanism was a strong evidence for the formation of stable planar 1D structures in the Si-substituted configurations. Our complete revelation of the essential properties of Si-substituted GNRs can provide a complete understanding of their chemically doped 1D materials for various practical applications.

A theoretical screening of phytochemical constituents from Millettia brandisiana as inhibitors against acetylcholinesterase.

Alzheimer's disease is one of the causes associated with the early stages of dementia. Nowadays, the main treatment available is to inhibit the actions of the acetylcholinesterase (AChE) enzyme, which has been identified as responsible for the disease. In this study, computational methods were used to examine the structure and therapeutic ability of chemical compounds extracted from Millettia brandisiana natural products against AChE. This plant is commonly known as a traditional medicine in Vietnam and Thailand for the treatment of several diseases. Furthermore, machine learning helped us narrow down the choice of 85 substances for further studies by molecular docking and molecular dynamics simulations to gain deeper insights into the interactions between inhibitors and disease proteins. Of the five top-choice substances, γ-dimethylallyloxy-5,7,2,5-tetramethoxyisoflavone emerges as a promising substance due to its large free binding energy to AChE and the high thermodynamic stability of the resulting complex.

Synthesis and biological evaluation of 2'-hydroxychalcone derivatives as AMPK activators.

A series of 2'-hydroxychalcone derivatives with various substituents on B-ring were synthesized and evaluated for AMP-activated protein kinase (AMPK) activation activity in podocyte cells. The results displayed that hydroxy, methoxy and methylenedioxy groups on B-ring could enhance the activitiy better than O-saturated alkyl, O-unsaturated alkyl or other alkoxy groups. Compounds 27 and 29 possess the highest fold change of 2.48 and 2.73, respectively, which were higher than those of reference compound (8) (1.28) and metformin (1.88). Compounds 27 and 29 were then subjected to a concentration-response study to obtain the EC50 values of 2.0 and 4.8 µM, respectively and MTT assays also showed that cell viability was not influenced by the exposure of podocytes to compounds 27 and 29 at concentrations up to 50 µM. In addition, compound 27 was proved to activate AMPK via calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß)-dependent pathway without affecting intracellular calcium levels. The computational study showed that the potent compounds exhibited stronger ligand-binding strength to CaMKKß, particularly compounds 27 (-8.4 kcal/mol) and 29 (-8.0 kcal/mol), compared to compound 8 (-7.5 kcal/mol). Fragment molecular orbital (FMO) calculation demonstrated that compound 27 was superior to compound 29 due to the presence of methyl group, which amplified the binding by hydrophobic interactions. Therefore, compound 27 would represent a promising AMPK activator for further investigation of the treatment of diabetes and diabetic nephropathy.

Apparent diffusion coefficient histogram in the differentiation of benign and malignant testicular tumors.

Purpose: This retrospective study assessed the value of histogram parameters of the apparent diffusion coefficient (ADC) map (HA) in differentiating between benign and malignant testicular tumors. We compared the diagnostic performance of two different volume-of-interest (VOI) placement methods: VOI 1, the entire tumor; VOI 2, the tumor excluding its cystic, calcified, hemorrhagic, and necrotic portions. Materials and methods: We retrospectively evaluated 45 patients with testicular tumors examined with scrotal contrast-enhanced magnetic resonance imaging. These patients underwent surgery with the pathological result of seven benign and 39 malignant tumors. We calculated the HA parameters, including mean, median, maximum, minimum, kurtosis, skewness, entropy, standard deviation (SD), mean of positive pixels, and uniformity of positive pixels by the two different VOI segmentation methods. We compared these parameters using the chi-square test, Mann-Whitney U test, and area under the receiver operating characteristic curve (AUC) to determine their optimal cut-off, sensitivity (Se), and specificity (Sp). Result: This study included 45 patients with 46 testicular lesions (seven benign and 39 malignant tumors), one of which had bilateral testicular seminoma. With the VOI 1 method, benign lesions had significantly lower maximum ADC (p = 0.002), ADC skewness (p = 0.017), and ADC variance (p = 0.000) than malignant lesions. In contrast, their minimum ADC was significantly higher ADC (p = 0.000). With the VOI 2 method, the benign lesions had significantly higher ADC SD (p = 0.048) and maximum ADC (p = 0.015) than malignant lesions. In contrast, their minimum ADC was significantly lower (p = 0.000). With the VOI 1 method, maximum ADC, ADC variance, and ADC skewness performed well in differentiating benign and malignant testicular lesions with cut-offs (Se, Sp, AUC) of 1846.000 (74.4%, 100%, 0.883), 39198.387 (79.5%, 85.7%, 0.868), and 0.893 (48.7%, 100%, 0.758). Conclusion: The HA parameters showed value in differentiating benign and malignant testicular neoplasms. The entire tumor VOI placement method was preferable to the VOI placement method excluding cystic, calcified, hemorrhagic, and necrotic portions in measuring HA parameters. Using this VOI segmentation, maximum ADC performed best in discriminating benign and malignant testicular lesions, followed by ADC variance and skewness.

Dual-energy computed tomography in supporting prostatic artery embolization for benign prostatic hyperplasia.

Objective: Our study aims to evaluate the value of 256-slice dual-energy computed tomography (DECT) in supporting prostatic artery embolization (PAE) under digital subtraction angiography (DSA) for benign prostatic hyperplasia (BPH). Methods: The study was conducted on 88 patients who underwent PAE to treat BPH from January 2022 to November 2023. Of these, 38 patients who had PAE without DECT were placed in group 1, while the other 50 patients with pre-interventional DECT were assigned to group 2. The results of DECT imaging of the prostate artery (PA) were compared with the results of DSA imaging. Test for statistically significant differences between the variables of the two research groups using the T - student test and Mann-Whitney test algorithms with p < 0.05 corresponding to a 95% confidence interval. The data were analyzed according to medical statistical methods using SPSS 20.0 software. Results: DECT can detect the PA origin in 96.1% of cases, identify atherosclerosis at the root of the artery with a sensitivity of 66.7% and a specificity of 89.5%, and present anastomosis with a sensitivity of 72.7% and a specificity of 72.2%. There is no statistically significant difference in PA diameter on DECT compared to DSA with 95% confidence. Group 2 used DECT for 3D rendering of the PA before PAE had procedure time reduced by 25.8%, fluoroscopy time reduced by 23.2%, dose-area product (DAP) reduced by 25.6%, contrast medium volume reduced by 33.1% compared to group 1 not using DECT, statistically significant with 95% confidence. Conclusion: DECT is a valuable method for planning before PAE to treat BPH. 3D rendering DECT of PA provides anatomical information that minimizes procedure time, fluoroscopy time, dose-area product, and contrast medium volume.

Prenatal diagnosis of autosomal recessive renal tubular dysgenesis caused by variants in the ACE gene: Two fetuses with anhydramnios.

INTRODUCTION: Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare genetic disorder with a very high mortality rate. The typical symptoms of the disease during pregnancy are oligohydramnios, anhydramnios, and nearly all affected fetuses die after birth or have a stillbirth in late gestation, which can adversely increase maternal risks. METHODS: Oligohydramnios/anhydramnios can make both amniocentesis for diagnostic testing and morphological evaluation via ultrasound more difficult. In cases of oligohydramnios/anhydramnios suspicious for urinary tract anomalies, amnioinfusion is a meaningful technique that facilitates sampling of amniotic fluid for genetic diagnosis. RESULTS: We report two cases of fetuses with anhydramnios and invisible urinary bladder. Clinical exome sequencing from amniotic fluid revealed a biparentally inherited homozygous pathogenic nonsense ACE variant c.2503G 〉 T [p.Glu853Ter] in proband 1 and a biparentally inherited homozygous pathogenic nonsense ACE variant c.2992C 〉 T [p.Gln998Ter] in proband 2. The prognosis was poor and the patients elected to terminate the pregnancies. Additional post-mortem histopathological examination from the renal tissue of the second fetus showed renal tubular hypoplasia. CONCLUSION: To our knowledge for the first time, we describe the prenatal diagnosis of ARRTD in Vietnam, and highlight the benefit of detecting ACE variants associated with ARRTD in fetuses with oligohydramnios/anhydramnios through amnioinfusion and amniocentesis, which improves genotype-phenotype correlations and provides valuable information for reproductive counseling.

Voice disorder discrimination using vowel acoustic measures in female speakers.

BACKGROUND: Sustained vowels are important vocal tasks that have been investigated in discriminating voice disorders using acoustic analysis. To date, no study has combined vowel acoustic measures only that evaluate major aspects of the pathological voice signals in voice disorder discrimination. AIMS: To investigate the value of vowel acoustic measures that quantify glottal noise, signal stability, signal periodicity, spectral slope and overall voice quality in discriminating female speakers with and without voice disorders. METHODS & PROCEDURES: Sustained vowel /ɑ/ samples were extracted from 133 voice-disordered female patients and 97 non-voice disordered female speakers and were signal typed prior to analysis. Praat software was used to measure harmonics-to-noise ratio (HNR), glottal-to-noise excitation ratio (GNE), the standard deviation of fundamental frequency (F0SD) and cepstral peak prominence (CPPp); and the Analysis of Dysphonia in Speech and Voice (ADSV) program was used to measure CPPadsv, low/high spectral ratio (LH) and the cepstral/spectral index of dysphonia (CSID). Outcome measures included sensitivity, specificity, and discrimination accuracy. OUTCOMES & RESULTS: As individual acoustic measures, only spectral-based measures showed good (CPPadsv) and acceptable (CSID) discrimination results. The HNR, GNE and CPPp measures had acceptable sensitivity but poor or non-acceptable specificity and discrimination accuracy. Logistic regression models with all Praat measures (F0SD, HNR, GNE, CPPp) plus ADSV measures (CPPadsv, LH or CSID) provided excellent sensitivity, good-to-excellent specificity and excellent discrimination accuracy. ROC analysis for all individual measures showed that CPPadsv, CSID, CPPp, GNE and F0SD had the highest area under the curve (AUC) values. CONCLUSIONS & IMPLICATIONS: A combination of acoustic measures that evaluate the major aspects of vocal dysfunction resulted in good to excellent voice discrimination outcomes. Individual acoustic measures had lower discrimination ability than combined measures. The findings implied that acoustic measures extracted from a prolonged vowel were useful in voice disorder discrimination. WHAT THIS PAPER ADDS: What is already known on this subject Acoustic measures hold great value in discriminating voice disorders from normal voices. However, no study has evaluated discrimination values of a combination of sustained vowel acoustic measures that quantify additive noise, signal stability, signal periodicity, spectral slope and overall voice quality in single-gender cohorts. Previous studies have not used signal typing (the classification of the acoustic signals) for time-based measures, impacting the reliability of discrimination. What this study adds to the existing knowledge This study was the first to implement signal typing to include sustained vowel samples of Types 1 and 2 signals for discrimination statistics. We showed that a combination of vocal acoustic measures using time- and spectral-based extraction from the sustained /ɑ/ vowel evaluating additive noise, signal stability, signal periodicity, spectral slope and overall voice quality resulted in good to excellent sensitivity, specificity and discrimination accuracy. As individual measures, traditional time-based measures such as HNR had rather limited discrimination values whilst spectral-based measures provided higher discrimination values. Measures that are sensitive to signal types have low discrimination ability. What are the potential or actual clinical implications of this work? The sustained vowel /ɑ/ is a relevant, universal vocal task for clinical application using acoustic measures to discriminate female speakers with and without voice disorders if signal typing is implemented. Clinical voice assessment using vowels may not be effective if relying solely on time-based measurements. Spectral-based measures perform better in voice disorder discrimination given their insensitivity to signal types. The most effective voice disorder discrimination could only be obtained using a combination of acoustic measures that quantify major phenomena in the signals of disordered voices. Using measures extracted from both programs, Praat and ADSV, is useful given that specific settings in a program may impact on discrimination accuracy.