Noncanonical usage of stop codons in ciliates expands proteins with structurally flexible Q-rich motifs.

Serine(S)/threonine(T)-glutamine(Q) cluster domains (SCDs), polyglutamine (polyQ) tracts and polyglutamine/asparagine (polyQ/N) tracts are Q-rich motifs found in many proteins. SCDs often are intrinsically disordered regions that mediate protein phosphorylation and protein-protein interactions. PolyQ and polyQ/N tracts are structurally flexible sequences that trigger protein aggregation. We report that due to their high percentages of STQ or STQN amino acid content, four SCDs and three prion-causing Q/N-rich motifs of yeast proteins possess autonomous protein expression-enhancing activities. Since these Q-rich motifs can endow proteins with structural and functional plasticity, we suggest that they represent useful toolkits for evolutionary novelty. Comparative Gene Ontology (GO) analyses of the near-complete proteomes of 26 representative model eukaryotes reveal that Q-rich motifs prevail in proteins involved in specialized biological processes, including Saccharomyces cerevisiae RNA-mediated transposition and pseudohyphal growth, Candida albicans filamentous growth, ciliate peptidyl-glutamic acid modification and microtubule-based movement, Tetrahymena thermophila xylan catabolism and meiosis, Dictyostelium discoideum development and sexual cycles, Plasmodium falciparum infection, and the nervous systems of Drosophila melanogaster, Mus musculus and Homo sapiens. We also show that Q-rich-motif proteins are expanded massively in 10 ciliates with reassigned TAAQ and TAGQ codons. Notably, the usage frequency of CAGQ is much lower in ciliates with reassigned TAAQ and TAGQ codons than in organisms with expanded and unstable Q runs (e.g. D. melanogaster and H. sapiens), indicating that the use of noncanonical stop codons in ciliates may have coevolved with codon usage biases to avoid triplet repeat disorders mediated by CAG/GTC replication slippage.

Intramedullary Nail vs. Plate Fixation for Pathological Humeral Shaft Fracture: An Updated Narrative Review and Meta-Analysis of Surgery-Related Factors.

(1) Background: Pathological humeral shaft fracture (PHSF) is a frequently observed clinical manifestation in the later stages of tumor metastasis. Surgical interventions are typically recommended to alleviate pain and restore functionality. Intramedullary nail fixation (INF) or plate fixation (PF) is currently recommended for the treatment of PHSF. However, there is still no standard for optimal surgical treatment. Thus, we conducted a meta-analysis comparing the clinical outcomes of INF with PF for PHSF treatment. (2) Methods: We conducted searches in databases, such as Scopus, EMBASE, and PubMed, for studies published prior to May 2023. In total, nine studies with 485 patients were reviewed. (3) Results: There were no significant differences noted in the incidence of fixation failure, local recurrence, wound complication or overall complication. However, the INF group demonstrated a significantly lower incidence of postoperative radial nerve palsy than the PF group (OR, 5.246; 95% CI, 1.548-17.774; p = 0.008). A subgroup analysis indicated that there were no statistically significant differences in fixation failure or local recurrence among subgroups categorized by the design of intramedullary nail. (4) Conclusions: Considering the short life expectancy of end-stage patients, the choice of surgical method depends on the patient's individual condition, fracture and lesion patterns, the surgeon's experience, and comprehensive discussion between the surgeon and patient.

The Complement System and C4b-Binding Protein: A Focus on the Promise of C4BPα as a Biomarker to Predict Clopidogrel Resistance.

The complement system plays a dual role in the body, either as a first-line defense barrier when balanced between activation and inhibition or as a potential driver of complement-associated injury or diseases when unbalanced or over-activated. C4b-binding protein (C4BP) was the first circulating complement regulatory protein identified and it functions as an important complement inhibitor. C4BP can suppress the over-activation of complement components and prevent the complement system from attacking the host cells through the binding of complement cleavage products C4b and C3b, working in concert as a cofactor for factor I in the degradation of C4b and C3b, and consequently preventing or reducing the assembly of C3 convertase and C5 convertase, respectively. C4BP, particularly C4BP α-chain (C4BPα), exerts its unique inhibitory effects on complement activation and opsonization, systemic inflammation, and platelet activation and aggregation. It has long been acknowledged that crosstalk or interplay exists between the complement system and platelets. Our unpublished preliminary data suggest that circulating C4BPα exerts its antiplatelet effects through inhibition of both complement activity levels and complement-induced platelet reactivity. Plasma C4BPα levels appear to be significantly higher in patients sensitive to, rather than resistant to, clopidogrel, and we suggest that a plasma C4BPα measurement could be used to predict clopidogrel resistance in the clinical settings.

Early identification of delayed wound healing in complex diabetic foot ulcers treated with a dermal regeneration template: a novel clinical target and its risk factors.

BACKGROUND: The dermal regeneration template (DRT), a tissue-engineered skin substitute composing a permanent dermal matrix and an upper temporary silicone layer that serves as the epidermis, has demonstrated efficacy in treating uncomplicated diabetic foot ulcers (DFUs). Our institution has obtained good outcomes with DRT in patients with more complicated DFUs. Because of its chronicity, the authors are working to identify a clinical target that anticipates delayed healing early in the treatment in addition to determining the risk factors linked to this endpoint to increase prevention. MATERIALS AND METHODS: This retrospective single-center study analyzed patients with DFUs who underwent wound reconstruction using DRT between 2016 and 2021. The patients were categorized into poor or good graft-take groups based on their DRT status on the 21st day after the application. Their relationship with complete healing (CH) rate at day 180 was analyzed. Variables were collected for risk factors for poor graft take at day 21. Independent risk factors were identified after multivariable analysis. The causes of poor graft take were also reported. RESULTS: This study examined 80 patients (38 and 42 patients in the poor and good graft-take groups, respectively). On day 180, the CH rate was 86.3% overall, but the poor graft-take group had a significantly lower CH rate (76.3 vs. 95.2%, P =0.021) than the good graft-take group. Our analysis identified four independent risk factors: transcutaneous oxygen pressure less than 30 mmHg (odds ratio, 154.14), off-loading device usage (0.03), diabetic neuropathy (6.51), and toe wound (0.20). The most frequent cause of poor graft take was infection (44.7%), followed by vascular compromise (21.1%) and hematoma (15.8%). CONCLUSION: Our study introduces the novel concept of poor graft take at day 21 associated with delayed wound healing. Four independent risk factors were identified, which allows physicians to arrange interventions to mitigate their effects or select patients more precisely. DRT represents a viable alternative to address DFUs, even in complicated wounds. A subsequent split-thickness skin graft is not always necessary to achieve CH.

First Observation of Negative Capacitance in Molecular Ferroelectric Thin Films.

On the path of persisting Moore's Law, one of the biggest obstacles is the "Boltzmann tyranny," which defines the lower limit of power consumption of individual transistors. Negative capacitance (NC) in ferroelectrics could provide a solution and has garnered significant attention in the fields of nanoelectronics, materials science, and solid-state physics. Molecular ferroelectrics, as an integral part of ferroelectrics, have developed rapidly in terms of both performance and functionality, with their inherent advantages such as easy fabrication, mechanical flexibility, low processing temperature, and structural tunability. However, studies on the NC in molecular ferroelectrics are limited. In this study, the focus is centered on the fabricated high-quality thin films of trimethylchloromethyl ammonium trichlorocadmium(II), and a pioneering investigation on their NC responses is conducted. The findings demonstrate that the NC exhibited by molecular ferroelectrics is comparable to that of conventional HfO2 -based ferroelectrics. This underscores the potential of molecular material systems for next-generation electronic devices.

Wireless Deep Brain Stimulation by Ultrasound-Responsive Molecular Piezoelectric Nanogenerators.

Implantable neural stimulation devices are becoming prevalent in bioelectronic medicine for the precise treatment of various clinical diseases. Nevertheless, the limited lifespan and buckling size of the implanted devices remain significant obstacles for chronic clinical application. In this study, we developed an ultrasound-driven battery-free neurostimulator based on a high-performance mini-sized nanogenerator and demonstrated its successful application for the deep-brain-stimulation (DBS) therapy of Parkinson's disease in a rat model. This soft piezoelectric-triboelectric hybrid nanogenerators (PTNG) are made of porous thin-films of molecular piezoelectric materials, which have great advantages of facile, scalable, low-temperature, and flexible processing. Without any bucky accessory control circuits, the subcutaneously implanted soft PTNG can function as a wirelessly powered neurostimulator, allowing for the adjustment of stimulation parameters through external programmable ultrasound pulses. This DBS electroceutical application of energy-harvesting thin-film devices based on molecular piezoelectric materials provides valuable insight into the development of a soft high-performance bioelectronic device.

Current Management and Volar Locking Plate Fixation with Bone Cement Augmentation for Elderly Distal Radius Fractures-An Updated Narrative Review.

Distal radius fractures (DRFs) are the most common among all kinds of fractures with an increase in incidence due to the rapidly expanded size of the elderly population in the past decades. Both non-surgical and surgical treatments can be applied for this common injury. Nowadays, more and more elderly patients with DRFs undergo surgical treatments to restore pre-injury activity levels faster. However, optimal treatment for geriatric DRFs is still debated, and careful evaluation and selection of patients are warranted considering clinical and functional outcomes, and complications following surgical treatments. Furthermore, osteoporosis is a predominant factor in elderly DRFs mostly deriving from a low-energy trauma, so many treatment modalities are developed to enhance better bone healing. Among various options for bone augmentation, bone cement is one of the most widely used measures. Bone cement such as calcium phosphate theoretically improves fracture stability and healing, but whether the elderly patients with DRFs can significantly benefit from surgical fixation with bone cement augmentation (BCA) remains controversial. Hence, in the present review, the latest literature regarding current concepts of management and evidence about volar locking plate fixation (VLPF) with BCA for elderly DRFs was searched in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science; out of >1000 articles, full texts of 48 and 6 articles were then examined and analyzed separately for management and VLPF with BCA for elderly DRFs. We aim to provide the readers with updates concerning the above issues.

Post-Operative Greater Tuberosity Resorption or Malreduction Is Associated with Poor Prognostic Outcomes in Patients with Proximal Humeral Fractures Treated Operatively-A Single-Center Retrospective Cohort Study.

(1) Background: Proximal humerus fractures can be a debilitating condition if not properly treated. These fracture patterns are varied and differ in every patient. Functional outcomes may be determined by the integrity of the shoulder girdle involving the rotator cuff insertion. The post-operative resorption or malreduction of the greater tuberosity (GT) is an important factor contributing to the poor functional outcome of a patient. Thus, we intend to evaluate the cause-and-effect relationship between GT complications and clinical prognosis and outcomes. (2) Methods: A single-center retrospective comparative study was performed to evaluate the functional outcomes of patients undergoing operative fixation for this injury. A total of 387 consecutive cases treated operatively from 2019-2021 were included for analysis. (3) Results: 94 cases fulfilled our criteria for analysis. A matched-group comparison of 19 patients each was performed to compare demographics, post-operative fracture characteristics and clinical outcomes. (4) Conclusions: The resorption or malreduction of the GT contributes greatly to the prognostic outcome in patients treated with open reduction and internal fixation (ORIF) surgery. In our demographic study, obesity is another contributing factor affecting the parameters of post-operative reduction in proximal humerus fractures. Appropriate surgical planning and post-operative multidisciplinary care must be taken into consideration to attain a satisfactory prognostic outcome.

How host ER membrane chaperones and morphogenic proteins support virus infection.

The multi-functional endoplasmic reticulum (ER) is exploited by viruses to cause infection. Morphologically, this organelle is a highly interconnected membranous network consisting of sheets and tubules whose levels are dynamic, changing in response to cellular conditions. Functionally, the ER is responsible for protein synthesis, folding, secretion and degradation, as well as Ca2+ homeostasis and lipid biosynthesis, with each event catalyzed by defined ER factors. Strikingly, these ER host factors are hijacked by viruses to support different infection steps, including entry, translation, replication, assembly and egress. Although the full repertoire of these ER factors that are hijacked is unknown, recent studies have uncovered several ER membrane machineries that are exploited by viruses - ranging from polyomavirus to flavivirus and coronavirus - to facilitate different steps of their life cycle. These discoveries should provide better understanding of virus infection mechanisms, potentially leading to the development of more effective anti-viral therapies.

Enhanced metabolic activation of and platelet response to clopidogrel in T cell-deficient mice through induction of Cyp2c and Cyp3a and inhibition of Ces1.

BACKGROUND: T cells and platelets reciprocally coordinate mutual functions through crosstalk or interaction. However, it is not known whether metabolic activation of and platelet response to clopidogrel could be changed if T cells were deficient or impaired in some cases and, if any, how it would work. OBJECTIVES: The objective of this study was to dissect the potential changes in platelet responses to and metabolic activation of clopidogrel in the case of T cell deficiency and to elucidate their mechanisms involved. METHODS: BALB/c athymic nude mice or euthymic mice (controls) pretreated with cyclosporine A (CsA), thymosin α1 (Tα1), or their combination were used to investigate the changes in ADP-induced platelet activation and aggregation, systemic exposure of clopidogrel and its metabolites, and mRNA/protein expression and activity levels of clopidogrel-metabolizing enzymes in the liver, respectively. RESULTS: Nude mice exhibited significantly enhanced antiplatelet effects of clopidogrel due to increased formation of clopidogrel active metabolite in the liver, where the enzyme activity levels of Cyp2c and Cyp3a were significantly elevated compared with control mice. Furthermore, the effects of CsA pretreatment on the metabolism of clopidogrel in euthymic mice were identical to those seen in athymic mice. As expected, concomitant use of Tα1 reversed all the observed effects of CsA on clopidogrel metabolism and relevant metabolic enzymes. CONCLUSIONS: T cell deficiency or suppression enhances the antiplatelet effects of clopidogrel due to the boosted metabolic activation of clopidogrel in the liver through a dramatic induction of Cyp2c and Cyp3a in mice, suggesting that the metabolism of substrate drugs of Cyp2c and Cyp3a may be enhanced by T cell impairment.

The First Demonstration of Strain-Controlled Periodic Ferroelectric Domains with Superior Piezoelectric Response in Molecular Materials.

Achieving a periodic domain structure in ferroelectric materials to tailor the macroscopic properties or realize new functions has always been a hot topic. However, methods to construct periodic domain structures, such as epitaxial growth, direct writing by scanning tips, and the patterned electrode method, are difficult or inefficient to implement in emerging molecular ferroelectrics, which have the advantages of lightweight, flexibility, biocompatibility, etc. An efficient method for constructing and controlling periodic domain structures is urgently needed to facilitate the development of molecular ferroelectrics in nanoelectronic devices. In this work, it is demonstrated that large-area, periodic and controllable needle-like domain structures can be achieved in thin films of the molecular ferroelectric trimethylchloromethyl ammonium trichlorocadmium (TMCM-CdCl3 ) upon the application of tensile strain. The domain evolution under various tensile strains can be clearly observed, and such processes are accordingly identified. Furthermore, the domain wall exhibits a superior piezoelectric response, with up to fivefold enhancement compared to that of the pristine samples. Such large-area tunable periodic domain structure and abnormally strong piezoresponse are not only of great interests in fundamental studies, but also highly important in the future applications in functional molecular materials.

HPV is a cargo for the COPI sorting complex during virus entry.

During entry, human papillomavirus (HPV) traffics from the cell surface to the endosome and then to the trans-Golgi network (TGN) and Golgi apparatus. HPV must transit across the TGN/Golgi and exit these compartments to reach the nucleus to cause infection, although how these steps are accomplished is unclear. Combining cellular fractionation, unbiased proteomics, and gene knockdown strategies, we identified the coat protein complex I (COPI), a highly conserved protein complex that facilitates retrograde trafficking of cellular cargos, as a host factor required for HPV infection. Upon TGN/Golgi arrival, the cytoplasmic segment of HPV L2 binds directly to COPI. COPI depletion causes the accumulation of HPV in the TGN/Golgi, resembling the fate of a COPI binding-defective L2 mutant. We propose that the L2-COPI interaction drives HPV trafficking through the TGN and Golgi stacks during virus entry. This shows that an incoming virus is a cargo of the COPI complex.

Choline and trimethylamine N-oxide impair metabolic activation of and platelet response to clopidogrel through activation of the NOX/ROS/Nrf2/CES1 pathway.

BACKGROUND: Trimethylamine N-oxide (TMAO), a gut microbe-generated metabolite, elicits thrombotic events by enhancing platelet reactivity; however, no studies have reported the effects of TMAO on the metabolism of and response to clopidogrel. OBJECTIVES: To determine whether choline and TMAO could significantly impair metabolic activation of and platelet response to clopidogrel in choline- or TMAO-fed mice and the mechanisms involved. METHODS: Male mice were fed with vehicle control (Ctrl), TMAO, choline alone or in combination with 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 for 14 days and then treated with Ctrl or a single oral dose of clopidogrel. Plasma TMAO, protein levels of clopidogrel-metabolizing enzymes in the liver, plasma concentrations of clopidogrel and its metabolites, and adenosine diphosphate-induced platelet aggregation and activation were measured. In addition, HepG2 cells were treated with Ctrl or TMAO alone or in combination with N-acetyl-L-cysteine, ML385, or apocynin, and CES1, reactive oxygen species (ROS), and Nrf2 protein levels were measured, respectively. RESULTS: TMAO significantly increased Ces1 protein expression and activity and clopidogrel hydrolysis in the liver as well as intracellular ROS and CES1 levels and Nrf2 nucleus translocation in HepG2 cells but decreased the formation of clopidogrel active metabolite and impaired platelet response to clopidogrel. Furthermore, concomitant use of 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 effectively reversed choline- or TMAO-induced impairment of inhibition of platelet aggregation by clopidogrel in mice, respectively. CONCLUSIONS: Choline and TMAO impair the metabolic activation of and platelet response to clopidogrel through the activation of the NOX-dependent ROS/Nrf2/CES1 pathway, suggesting novel strategies for overcoming clopidogrel resistance from bench to bedside.

Fascia defect closure versus non-closure in minimal invasive direct inguinal hernia mesh repair: a systematic review and meta-analysis of real-world evidence.

PURPOSE: Laparoscopic and robotic inguinal hernia mesh repair are both common surgical procedures worldwide. Postoperative hernia recurrence and seroma formation are important concerns. In ventral hernia, primary defect closure in laparoscopic surgery reduces the recurrence rate. However, there is no synthetic evidence of direct inguinal hernia defect closure versus non-closure in minimal invasive surgery. Therefore, this study investigated the efficacy of defect closure in patients undergoing minimal invasive direct inguinal hernia mesh repair. METHODS: Eligible studies were identified through a search of PubMed, Embase, Cochrane Library, and CINAHL from their inception until March 2022. Studies examining defect closure in laparoscopic direct inguinal hernia repair were included, and a meta-analysis was performed using the random-effect model. Sensitivity analyses were performed by removing one study at a time. The primary outcomes were hernia recurrence and seroma formation. Acute and chronic postoperative pain, operation time, and length of hospital stay were the secondary outcomes. RESULTS: Five nonrandomized studies and one randomized controlled trial were included. Pooled analysis revealed defect closure might reduce the hernia recurrence rate (risk difference, - 0.02; 95% confidence interval [CI] - 0.04 to - 0.00; p = 0.02). The result of seroma formation (odds ratio, 0.49; 95% CI 0.17-1.46; p = 0.20) showed no significant difference. Moreover, no significant differences were observed in acute postoperative pain, chronic pain, length of hospital stay, and operation time. CONCLUSIONS: Our study indicated defect closure seems to be an option to reduce the direct inguinal hernia recurrence rate. No significant benefits were shown in seroma formation and other secondary outcomes. Our study was mostly based on nonrandomized studies and underestimated the effect of defect closure; thus, further high-quality studies are required to draw definitive conclusions.

Vicagrel is hydrolyzed by Raf kinase inhibitor protein in human intestine.

As an analog of clopidogrel and prasugrel, vicagrel is completely hydrolyzed to intermediate thiolactone metabolite 2-oxo-clopidogrel (also the precursor of active thiol metabolite H4) in human intestine, predominantly by AADAC and CES2; however, other unknown vicagrel hydrolases remain to be identified. In this study, recombinant human Raf kinase inhibitor protein (rhRKIP) and pooled human intestinal S9 (HIS9) fractions and microsome (HIM) preparations were used as the different enzyme sources; prasugrel as a probe drug for RKIP (a positive control), vicagrel as a substrate drug of interest, and the rate of the formation of thiolactone metabolites 2-oxo-clopidogrel and R95913 as metrics of hydrolase activity examined, respectively. In addition, an IC50 value of inhibition of rhRKIP-catalyzed vicagrel hydrolysis by locostatin was measured, and five classical esterase inhibitors with distinct esterase selectivity were used to dissect the involvement of multiple hydrolases in vicagrel hydrolysis. The results showed that rhRKIP hydrolyzed vicagrel in vitro, with the values of Km , Vmax , and CLint measured as 20.04 ± 1.99 µM, 434.60 ± 12.46 nM/min/mg protein, and 21.69 ± 0.28 ml/min/mg protein, respectively, and that an IC50 value of locostatin was estimated as 1.24 ± 0.04 mM for rhRKIP. In addition to locostatin, eserine and vinblastine strongly suppressed vicagrel hydrolysis in HIM. It is concluded that RKIP can catalyze the hydrolysis of vicagrel in the human intestine, and that vicagrel can be hydrolyzed by multiple hydrolases, such as RKIP, AADAC, and CES2, concomitantly.

Patterning and doping of transition metals in tungsten dichalcogenides.

Substitutional transition metal doping in two-dimensional (2D) layered dichalcogenides is of fundamental importance in manipulating their electrical, excitonic, magnetic, and catalytic properties through the variation of the d-electron population. Yet, most doping strategies are spatially global, with dopants embedded concurrently during the synthesis. Here, we report an area-selective doping scheme for W-based dichalcogenide single layers, in which pre-patterned graphene is used as a reaction mask in the high-temperature substitution of the W sublattice. The chemical inertness of the thin graphene layer can effectively differentiate the spatial doping reaction, allowing for local manipulation of the host 2D materials. Using graphene as a mask is also beneficial in the sense that it also acts as an insertion layer between the contact metal and the doped channel, capable of depinning the Fermi level for low contact resistivity. Tracing doping by means of chalcogen labelling, deliberate Cr embedment is found to become energetically favorable in the presence of chalcogen deficiency, assisting the substitution of the W sublattice in the devised chemical vapor doping scheme. Atomic characterization using scanning transmission electron microscopy (STEM) shows that the dopant concentration is controllable and varies linearly with the reaction time in the current doping approach. Using the same method, other transition metal atoms such as Mo, V, and Fe can also be doped in the patterned area.