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Transcription factor EB (TFEB) mainly regulates the autophagy-lysosomal pathway, associated with many diseases, including cancer. However, the role of TFEB in pan-cancer has not been investigated systematically. In this study, we comprehensively analyzed TFEB targets under three stresses in Hela cells by cross-validation of RNA-seq and ChIP-seq. 1712 novel TFEB targets have not been reported in the Gene Set Enrichment Analysis and ChIP Enrichment Analysis databases. We further investigated their distributions and roles among the pan-cancer co-expression networks across 32 cancers constructed by multiscale embedded gene co-expression network analysis (MEGENA) based on the Cancer Genome Atlas (TCGA) cohort. Specifically, TFEB might serve as a hidden player with multifaceted functions in regulating pan-cancer risk factors, e.g. CXCL2 , PKMYT1  and BUB1 , associated with cell cycle and immunosuppression. TFEB might also regulate protective factors, e.g. CD79A , related to immune promotion in the tumor microenvironment. We further developed a Shiny app website to present the comprehensive regulatory targets of TFEB under various stimuli, intending to support further research on TFEB functions. Summarily, we provided references for the TFEB downstream targets responding to three stresses and the dual roles of TFEB and its targets in pan-cancer, which are promising anticancer targets that warrant further exploration., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Cancer.)

The exciting potential of harnessing the synergy between polysaccharides and bioactive components is attracting significant scientific interest. This research paves the way for the development of novel materials that can improve human health. Therefore, current research is conducted to explore the innovative use of chitosan, polyvinyl alcohol (PVA) complex (CHN-PVA), olive oil-stabilized Pickering emulsions (PEs), and films with multifaceted applications. The sonication stabilized Pickering emulsions (PEs at different pH values 3, 5, 7, 9, and 11) exhibited decrease in particle size compared to control PEs. The pH significantly impacted the zeta potential of PEs. Fourier-transform infrared spectroscopy (FTIR) confirmed the non-covalent linkages. The antibacterial activity of the PEs revealed greater efficacy against gram-positive bacteria than gram-negative bacteria. The CHN-PVA synergy greatly impacted the mechanical properties of films, resulting in tremendous increase of tensile strength and elongation at break compared to CHN film. The PEs efficiently delivered quercetin at neutral pH. The electro spraying of PEs significantly extended strawberry shelf life. Finally, the films exhibited promising properties of adsorbent and the results depicted that pH had a significant impact on methylene blue removal. Conclusively, this investigation underscores the potential of CHN-PVA films in food, health, and environmental fields., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neratinib (an active pharmaceutical ingredient [API]) is an irreversible pan-human epidermal growth factor receptor (HER) inhibitor used to treat HER2-positive breast cancer. The dosage form (marketed in the United States, China, Europe, and other regions) is a tablet for oral administration, and the brand product (NERLYNX) has patent protection for the crystalline neratinib maleate monohydrate form. This paper describes the product development using stable crystalline neratinib maleate anhydrous form, stability study, bioequivalence (BE) study of the products, and discussion of the adverse effects observed in the clinical study., (© 2024 John Wiley & Sons Ltd.)

Microalgae have emerged as promising photosynthetic microorganisms for biofabricating advanced tissue constructs, with improved oxygenation and reduced reactive oxygen species (ROS) production. However, their use in the engineering of human tissues has been limited due to their intrinsic growth requirements, which are not compatible with human cells. In this study, we first formulated alginate-gelatin (AlgGel) hydrogels with increasing densities of Chlorella vulgaris . Then, we characterised their mechanical properties and pore size. Finally, we evaluated their effects on cardiac spheroid (CS) pathophysiological response under control and ischemia/reperfusion (I/R) conditions. Our results showed that the addition of Chlorella did not affect AlgGel mechanical properties, while the mean pore size significantly decreased by 35% in the presence of the 10 7 cells ml -1 microalgae density. Under normoxic conditions, the addition of 10 7 Chlorella cells ml -1 significantly reduced CS viability starting from 14 d in. No changes in pore size nor CS viability were measured for hydrogels containing 10 5 and 10 6 Chlorella cells ml -1 . In our I/R model, all Chlorella -enriched hydrogels reduced cardiac cell sensitivity to hypoxic conditions with a corresponding reduction in ROS production, as well as protected against I/R-induced reduction in cell viability. Altogether, our results support a promising use of Chlorella -enriched Alg-Gel hydrogels for cardiovascular tissue engineering., (Creative Commons Attribution license.)

Malate is a key intermediate in the citric acid cycle, an enzymatic cascade that is central to cellular energy metabolism and that has been applied to make biofuel cells. To enable real-time sensing of malate levels, we have engineered a genetically encoded, protein-based fluorescent biosensor called Malon specifically responsive to malate by performing structure-based mutagenesis of the Cache-binding domain of the Citron GFP-based biosensor. Malon demonstrates high specificity and fluorescence activation in response to malate, and has been applied to monitor enzymatic reactions in vitro. Furthermore, we successfully incorporated Malon into redox polymer hydrogels and bacterial cells, enabling analysis of malate levels in these materials and living systems. These results show the potential for fluorescent biosensors in enzymatic cascade monitoring within biomaterials and present Malon as a novel tool for bioelectronic devices.

Cellulose stabilized multiphase systems (CSMS) have garnered significant attention due to their ultra-stabilization mechanism and vast potential across different fields. CSMS have found valuable applications in scientific disciplines, including Food Science, Pharmaceutical Science, Material Science, and related fields, owing to their beneficial attributes such as sustainability, safety, renewability, and non-toxicity. Furthermore, MPS exhibit novel characteristics that enable multiple mechanisms to produce HIPEs, aerogels, and oleogels revealing undiscovered information. Therefore, to explore the undiscovered phenomena of MPS, molecular level insights using advanced simulation/computational approaches are essential. The molecular dynamics simulation (MDS), play a valuable role in analyzing the interactions of ternary interphase. The MDS have successfully quantified the interactions of MPS by generating, visualizing, and analyzing trajectories. Through MDS, researchers have explored CSMS at the molecular level and advanced their applications in 3D printing, packaging, preparation, drug delivery, encapsulation, biosensors, electronic devices, biomaterials, and energy conservation. This review highlights the remarkable advancements in CSMS over the past five years, along with contributions of MDS in evaluating the relationships that dictate the functionality and properties of CSMS. By integrating experimental and computational methods, we underscore the potential to innovate and optimize these multiphase systems for groundbreaking applications., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Shift work and artificial light at night disrupt the entrainment of endogenous circadian rhythms in physiology and behavior to the day-night cycle. We hypothesized that exposure to dim light at night (dLAN) disrupts feeding rhythms, leading to sex-specific changes in autonomic signaling and day-night heart rate and blood pressure rhythms. Compared to mice housed in 12-hour light/12-hour dark cycles, mice exposed to dLAN showed reduced amplitudes in day-night feeding, heart rate, and blood pressure rhythms. In female mice, dLAN reduced the amplitude of day-night cardiovascular rhythms by decreasing the relative sympathetic regulation at night, while in male mice, it did so by increasing the relative sympathetic regulation during the daytime. Time-restricted feeding to the dim light cycle reversed these autonomic changes in both sexes. We conclude that dLAN induces sex-specific changes in autonomic regulation of heart rate and blood pressure, and time-restricted feeding may represent a chronotherapeutic strategy to mitigate the cardiovascular impact of light at night., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Inborn errors of metabolism (IEM) such as lysosomal storage disorders (LSDs) are conditions caused by deficiency of one or more key enzymes, cofactors, or transporters involved in a specific metabolic pathway. Enzyme replacement therapy (ERT) provides an exogenous source of the affected enzyme and is one of the most effective treatment options for IEMs. In this paper, we review the first-in-human (FIH) protocols for ERT drug development programs supporting 20 Biologic License Applications (BLA) approved by the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) in the period of May 1994 to September 2023. We surveyed study design elements across these FIH protocols including study population, dosage form, dose selection, treatment duration, immunogenicity, biomarkers, and study follow-up. A total of 18 FIH trials from 20 BLAs were identified and of those, 72% (13/18) used single ascending dose (SAD) and/or multiple ascending dose (MAD) study design, 83% (15/18) had a primary objective of assessing the safety and tolerability, 72% (13/18) included clinical endpoint assessments, and 94% (17/18) included biomarker assessments as secondary or exploratory endpoints. Notably, the majority of ERT products tested the approved route of administration and the approved dose was tested in 83% (15/18) of FIH trials. At last, we offer considerations for the design of FIH studies., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Singlet oxygen generation has long been considered the key feature that allows genetically encoded fluorescent tags to produce polymeric contrast agents for electron microscopy. Optimization of the singlet oxygen sensitization quantum yield has not included the effects of electron-rich monomers on the sensitizer's photocycle. We report that at monomer concentrations employed for staining, quenching by electron transfer is the primary deactivation pathway for photoexcitations. A simple photochemical model including contributions from both processes reproduces the observed reaction rates and indicates that most of the product is driven by pathways that involve electron transfer with monomers─not by the sensitization of singlet oxygen. Realizing the importance of these competing reaction pathways offers a new paradigm to guide the development of genetically encodable tags and suggests opportunities to expand the materials scope and growth conditions for polymeric contrast agents (e.g., biocompatible monomers, O 2 poor environments).

This review explores the roles of the cholinergic system in the heart, comprising the neuronal and non-neuronal cholinergic systems. Both systems are essential for maintaining cardiac homeostasis by regulating the release of acetylcholine (ACh). A reduction in ACh release is associated with the early onset of cardiovascular diseases (CVDs), and increasing evidence supports the protective roles of ACh against CVD. We address the challenges and limitations of current strategies to elevate ACh levels, including vagus nerve stimulation and pharmacological interventions such as cholinesterase inhibitors. Additionally, we introduce alternative strategies to increase ACh in the heart, such as stem cell therapy, gene therapy, microRNAs, and nanoparticle drug delivery methods. These findings offer new insights into advanced treatments for regenerating the injured human heart., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

We report chemical vapor deposition (CVD) synthesis of two quasi-one-dimensional (quasi-1D) polymorphs of BiSCl, denoted by y-BiSCl and r-BiSCl. The length of the CVD samples can reach about 0.4 mm. Such quasi-1D samples of the two polymorphs can be readily separated into individual pieces for either characterization or application. The two polymorphs can be clearly differentiated by Raman spectroscopy. First-principles calculations and group analysis are used to assign each Raman peak to the corresponding vibrational mode. Ultraviolet-visible measurements on solution grown thin-film samples reveal that the two polymorphs exhibit significantly different band gaps of 2.08 eV (y-BiSCl) and 1.81 eV (r-BiSCl). First-principles calculation further shows that the interatomic chain binding energy is 18.1 meV/Å 2 , confirming that the van der Waals stacking determines the difference in their band gaps. Our findings highlight the possibility of realizing the desired functionalities in quasi-1D materials by controlling stacking orientation.

Introduction: To identify the differentially expressed genes of acute myeloid leukaemia (AML) and construct and verify a survival prognosis model combined with patient survival information., Methods: The TARGET database was searched to identify differentially expressed peripheral blood genes in children with AML and healthy children. A gene set functional analysis and pathway analysis were performed using gene ontology and the KEGG pathway. A prognostic model for children with AML was constructed using univariate Cox, LASSO Cox regression and multivariate Cox regression analyses. Time-dependent receiver operating characteristic (ROC) curves were adopted to assess the predictive capacity of the prognostic models., Results: In total, 1640 differentially expressed genes were screened (1119 upregulated and 521 downregulated genes). The differentially expressed genes were mainly involved in nutrient metabolism and cytochrome P450 metabolism. Six key genes related to the prognosis of AML, FAM157A, GPR78, IRX5, RP4-800G7.1, RP11-179H18.5 and RP11-61N20.3, were identified. Kaplan-Meier curves indicated that 3-year and 5-year overall survival was significantly higher in the low-risk group than in the high-risk group. The area under the ROC curve was 0.722. At different stages of AML, FAM157A and RP4-800G7.1 exhibited significant differences in expression. The expression levels of FAM157A were significantly decreased in AML, whereas the expression levels of GPR78, IRX5, RP4-800G7.1, RP11-179H18.5 and RP11-61N20.3 were significantly increased in AML., Conclusion: A prognosis-related gene model of AML was successfully constructed, and the expression levels of the model genes varied with AML stage., (© 2024 John Wiley & Sons Ltd.)

Objective: To investigate the clinical features, imaging findings, pathological phenotype, treatment and prognosis of unicentric Castleman disease in the children's neck, in order to improve the understanding of CD among Otolaryngology Head and Neck Surgery. Methods: Retrospective cross-sectional, observational study was undertaken in Kunming Children's Hospital, from the archival data between January July 2015 and June 2020. Only 6 cases of CD were identified after studying the histomorphological characteristics and neck mass diagnosed. The imaging and pathological features were summarized and the pathogenesis was discussed. Results: Among the 6 cases of Castleman disease, five were male and one was female. Histopathology: Five cases were hyaline vascular subtype, one was mixed type. The uniform clinicopathologic features seen in all hyaline vascular subtype of CD included atrophic germinal centre with lymphocyte depletion, concentric rings of small lymphocytes, increased vascularity and predominance of high endothelial vessels in interfollicular region. Twinning, in which two or more germinal centers are combined and surrounded by lymphocytes in the mantle zone was observed in two cases with lollipop pattern at the same time. All the cases underwent complete surgical resection, the median follow-up time was 48 months（26, 84）, both of them had good prognosis. Conclusion: Most cases of unicentric type CD in children are diagnosed late, which is clinical showed by painless lymphadenopathy. The most common pathological type is hyaline vascular. The overall prognosis of surgical treatment was good., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Type 2 diabetics have an increased prevalence of hypertension and nondipping blood pressure (BP), which worsen cardiovascular outcomes. Exenatide, a short acting glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes, also demonstrates blood pressure (BP)-lowering effects. However, the mechanisms behind this and the impact of administration timing on BP dipping remain unclear. We investigated the effects of exenatide intraperitoneal injected at light onset (ZT0) or dark onset (ZT12) in diabetic (db/db) mice and nondiabetic controls. Using radio-telemetry and BioDAQ cages, we continuously monitored BP and food intake. Db/db mice exhibited non-dipping BP and increased food intake. ZT0 exenatide administration restored BP dipping by specifically lowering light-phase BP, while ZT12 exenatide reversed dipping by lowering dark-phase BP. These effects correlated with altered food intake patterns, and importantly, were abolished when food access was removed. Additionally, urinary norepinephrine excretion, measured by HPLC, was significantly reduced 6 hours post-exenatide at both ZT0 and ZT12, suggesting sympathetic nervous system involvement. Notably, combining exenatide with either ganglionic blocker mecamylamine or α-blocker prazosin did not enhance BP reduction beyond the individual effects of each blocker. These findings reveal that exenatide, when administered at light onset, restores BP dipping in db/db mice by suppressing light-phase food intake and sympathetic activity. Importantly, the efficacy of exenatide is dependent on food availability and its timing relative to circadian rhythms, highlighting the potential for chronotherapy in optimizing GLP-1RA- based treatments for type 2 diabetes and hypertension., Article Highlights: Maintaining a normal blood pressure (BP) circadian rhythm is vital for cardiovascular health, but diabetes often disrupts this rhythm. The effect of exenatide, a GLP-1 receptor agonist (GLP-1RA), on BP rhythm in diabetes is uncertain.This study investigates the impact of exenatide administration timing on BP patterns in diabetic db/db mice.Findings indicate that exenatide given at the onset of rest restores normal BP dipping, while at the start of the active phase worsens BP rhythm by modulating food intake and sympathetic activity.Timing GLP-1 RA administration may optimize BP control and provide cardiovascular benefits for type 2 diabetes patients.

Objective: To investigate the clinical phenotype of a family with branchio-oto syndrome （BOS） and to explore the genetic etiology of the syndrome in this family. Methods: Clinical data were collected from a child diagnosed with BOS and his family members. Genomic DNA was extracted from peripheral blood of the proband and his family members. Whole-exome sequencing was performed, and the mutation sites were verified and analyzed by Sanger sequencing. Results: The family consists of two generations with four members, three of whom exhibit the phenotype. Two members have hearing loss and bilateral preauricular fistulas and bilateral branchial cleft fistulas. One member has bilateral preauricular fistulas and bilateral branchial cleft fistulas. All of which were in line with the clinical diagnosis of gill ear syndrome, the inheritance mode of the family was autosomal dominant inheritance, genetic testing showed that all members of the family had c. 1744delC（p. L592Cfs*47） mutation in the EYA1 gene, while unaffected members have the wild-type allele at this locus. This mutation is a frameshift mutation, which results in the early appearance of the stop codon, and has not been reported so far. According to ACMG guidelines, the variant was preliminarily determined to be suspected pathogenic. Conclusion: The newly discovered EYA1c. 1744delC（p. L592Cfs*47） mutation in this family is the pathogenic mutant gene of the patients in this family, which further expands the mutation spectrum of EYA1 gene, gives us a new understanding of the disease, and provides an important reference for clinical diagnosis and genetic counseling., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms (AAs), a devastating vascular disease with a higher prevalence and fatality rate in men than in women. However, the mechanism by which androgen mediates AAs is largely unknown. Here, we found that male, not female, mice developed AAs when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (ARs) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and AAs. Furthermore, we demonstrated that administration of anti-PD-1 Ab and adoptive PD-1-deficient T cell transfer reinstated Aldo-salt-induced AAs in orchiectomized mice and that genetic deletion of PD-1 exacerbated AAs induced by a high-fat diet and angiotensin II (Ang II) in nonorchiectomized mice. Mechanistically, we discovered that the AR bound to the PD-1 promoter to suppress the expression of PD-1 in the spleen. Thus, our study unveils a mechanism by which androgen aggravates AAs by suppressing PD-1 expression in T cells. Moreover, our study suggests that some patients with cancer might benefit from screenings for AAs during immune checkpoint therapy.

The aim of this perspective is to promote the theory of salutogenesis as a novel approach to addressing ophthalmologic inflammatory conditions, illustrating several concepts in which it is based upon and how they can be applied to medical practice. This theory can better contextualize why patients with similar demographics and exposures are not uniform in their clinical presentations. Stressors in daily life can contribute to a state of ill-health and there are various factors that help alleviate their negative impact. These alleviating factors are significantly impaired in people with poor vision, one of the most common presentations of ophthalmologic conditions. Salutogenic principles can guide the treatment of eye conditions to be more respectful of patient autonomy amidst shifting expectations of the doctor-patient relationship. Being able to take ownership of their health and feeling that their cultural beliefs were considered improves compliance and subsequently gives more optimal outcomes. Population-level policy interventions could also utilize salutogenic principles to identify previously overlooked domains that can be addressed. We identified several papers about salutogenesis in an ophthalmological context and acknowledged the relatively few studies on this topic at present and offer directions in which we can explore further in subsequent studies.

Silk fibroin (SF) is a natural protein extracted from Bombyx mori silkworm thread. From its common use in the textile industry, it emerged as a biomaterial with promising biochemical and mechanical properties for applications in the field of tissue engineering and regenerative medicine. In this study, we evaluate for the first time the effects of SF on cardiac bioink formulations containing cardiac spheroids (CSs). First, we evaluate if the SF addition plays a role in the structural and elastic properties of hydrogels containing alginate (Alg) and gelatin (Gel). Then, we test the printability and durability of bioprinted SF-containing hydrogels. Finally, we evaluate whether the addition of SF controls cell viability and function of CSs in Alg-Gel hydrogels. Our findings show that the addition of 1% (w/v) SF to Alg-Gel hydrogels makes them more elastic without affecting cell viability. However, fractional shortening (FS%) of CSs in SF-Alg-Gel hydrogels increases without affecting their contraction frequency, suggesting an improvement in contractile function in the 3D cultures. Altogether, our findings support a promising pathway to bioengineer bioinks containing SF for cardiac applications, with the ability to control mechanical and cellular features in cardiac bioinks., (Creative Commons Attribution license.)

Background: In patients with embolic stroke of undetermined source (ESUS), occult atrial fibrillation (AF) has been implicated as a key source of cardioembolism. However, only a minority acquire implantable cardiac loop recorders (ILRs) to detect occult paroxysmal AF, partly due to financial cost and procedural inconvenience. Without the initiation of appropriate anticoagulation, these patients are at risk of increased ischemic stroke recurrence. Hence, cost-effective and accurate methods of predicting AF in ESUS patients are highly sought after., Objective: We aimed to incorporate clinical and echocardiography data into machine learning (ML) algorithms for AF prediction on ILRs in ESUS., Methods: This was a single-center cohort study that included 157 consecutive patients diagnosed with ESUS from October 2014 to October 2017 who had ILR evaluation. We developed four ML models, with hyperparameters tuned, to predict AF detection on an ILR., Results: The median age of the cohort was 67 (IQR 59-74) years old and the median monitoring duration was 1051 (IQR 478-1287) days. Of the 157 patients, 32 (20.4%) had occult AF detected on the ILR. Support vector machine predicted for AF with a 95% confidence interval area under the receiver operating characteristic curve (AUC) of 0.736-0.737, multilayer perceptron with an AUC of 0.697-0.708, XGBoost with an AUC of 0.697-0.697, and random forest with an AUC of 0.663-0.674. ML feature importance found that age, HDL-C, and admitting heart rate were important non-echocardiography variables, while peak mitral A-wave velocity and left atrial volume were important echocardiography parameters aiding this prediction., Conclusion: Machine learning modeling incorporating clinical and echocardiographic variables predicted AF in ESUS patients with moderate accuracy.

Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration., Competing Interests: Declaration of interests Y. Zhao, H.X., Y. Zhang, and D.Z. are co-inventors on a patent application related to the work in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

RNA synthetic biology tools have primarily been applied in E. coli ; however, many other bacteria are of industrial and clinical significance. Thus, the multicolor fluorogenic aptamer Pepper was evaluated in both Gram-positive and Gram-negative bacteria. Suitable HBC-Pepper dye pairs were identified that give blue, green, or red fluorescence signals in the E. coli , Bacillus subtilis , and Salmonella enterica serovar Typhimurium ( S . Typhimurium). Furthermore, we found that different RNA scaffolds have a drastic effect on in vivo fluorescence, which did not correlate with the in vitro folding efficiency. One such scaffold termed DF30-tRNA displays 199-fold greater fluorescence than the Pepper aptamer alone and permits simultaneous dual color imaging in live cells.

To improve the transient response, accuracy and robustness of trajectory tracking control for cable-driven continuum robots (CDCRs), a recursive integral terminal sliding mode control combined with an adaptive disturbance observer (ADO-RITSMC) is proposed. The recursive integral terminal sliding mode control (RITSMC) guarantees fast transient response and high tracking accuracy with a fast zero convergence of the tracking error without chattering. To attenuate the effect of uncertain dynamics, an adaptive disturbance observer (ADO) is constructed to derive uncertain dynamics. Particularly, an improved grey wolf optimizer (IGWO) is merged into the ADO to enhance the estimating accuracy of uncertain dynamic factors. Simulation and experiment results demonstrate the superiority of the ADO-RITSMC in enabling fast transient response, high accuracy and strong robustness of trajectory tracking control., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 ISA. Published by Elsevier Ltd. All rights reserved.)

Objectives: The objective of this study is to explore the clinical diagnosis and treatment of the congenital sternoclavicular sinus in the region of sternoclavicular joint, providing valuable insights for clinical practice in children., Methodology: A retrospective review of case notes was conducted for all patients treated for congenital sternoclavicular sinus at a tertiary care pediatric otolaryngology practice from January 2022 to September 2023.This review analyzed the clinical presentations, imaging examination, pathological examination, and treatment., Results: A total of 56 patients with congenital sternoclavicular sinus were included in the study, with a mean age of 4.10 ± 2.57 years old. Among these patients, the sinuses were located on the left side in 43 cases,on the right side in 12 cases,and bilaterally in one case.While two patients never experienced inflammation, 54 patients did, and 45 of them underwent incision and drainage before excision. Imaging examination, including ultrasonography and computerized tomography (CT) scans, revealed characteristics such as thickening of subcutaneous tissue,subcutaneous tubular structures or tubercles in front of the clavicle,and irregularly shaped lesions with clear borders and uneven internal low echo, Pathological examination confirmed that the sinuses were lined by squamous epithelium in all patients., Conclusions: The congenital sternoclavicular sinus may be a remnant of the fourth branchial cleft on the skin side.Complete resection of the sinus during the quiescent phase of inflammation is the recommended curative treatment to prevent recurrent infection., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Inborn errors of immunity (IEI) often lack specific disease models and personalized management. Signal transducer and activator of transcription (STAT)-1 gain of function (GoF) is such example of an IEI with diverse clinical phenotype with unclear pathomechanisms and unpredictable response to therapy. Limitations in obtaining fresh samples for functional testing and research further highlights the need for patient-specific ex vivo platforms., Objective: Using STAT1-GoF as an example IEI, we investigated the potential of patient-derived expanded potential stem cells (EPSC) as an ex vivo platform for disease modeling and personalized treatment., Methods: We generated EPSC derived from individual STAT1-GoF patients. STAT1 mutations were confirmed with Sanger sequencing. Functional testing including STAT1 phosphorylation/dephosphorylation and gene expression with or without Janus activating kinase inhibitors were performed. Functional tests were repeated on EPSC lines with GoF mutations repaired by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) editing., Results: EPSC were successfully reprogrammed from STAT1-GoF patients and expressed the same pluripotent makers as controls, with distinct morphologic differences. Patient-derived EPSC recapitulated the functional abnormalities of index STAT1-GoF patients with STAT1 hyperphosphorylation and increased expression of STAT1 and its downstream genes (IRF1, APOL6, and OAS1) after IFN-γ stimulation. Addition of ruxolitinib and baricitinib inhibited STAT1 hyperactivation in STAT1-GoF EPSC in a dose-dependent manner, which was not observed with tofacitinib. Corrected STAT1 phosphorylation and downstream gene expression were observed among repaired STAT1-GoF EPSC cell lines., Conclusion: This proof-of-concept study demonstrates the potential of our patient-derived EPSC platform to model STAT1-GoF. We propose this platform when researching, recapitulating, and repairing other IEI in the future., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aims: Giant cell arteritis (GCA) is the most common primary vasculitis in adults over 50 years of age. To facilitate early diagnosis and reduce harms from corticosteroids and temporal artery biopsies, fast-track pathways have been established. We review the benefits of the fast-track pathway set up in Waikato, Aotearoa New Zealand., Methods: Patients were collected prospectively as part of the fast-track pathway from 2014 to 2022. Their records were then reviewed retrospectively to collect data on clinical features, investigations and treatment., Results: There were 648 individual patients over the study period who had a colour Doppler ultrasound (CDUS) of the temporal arteries. There were 17 true positive CDUS, giving a sensitivity of 10.3% (95% confidence interval [CI] 6.3-15.5%) and specificity of 99.8% (95% CI 99.1-100%). Patients with GCA and a positive scan had significantly fewer steroids than those with GCA and a negative scan (p=0.0037). There were 376 patients discharged after a CDUS who did not have a diagnosis of GCA, resulting in reduced corticosteroid and temporal artery biopsy exposure., Conclusions: This is a real-life study that reflects the benefits of fast-track pathways in Aotearoa New Zealand to patients and healthcare systems. It also shows the effect of corticosteroids on positive CDUS, an important consideration when setting up an fast-track pathway., Competing Interests: Nil. Philippa van Dantzig has been employed part-time by the Waikato Hospital (Te Whatu Ora) for 12 months in a research position to carry out this research project among others, as well as perform a clinical role. There is no other specific funding towards the project., (© PMA.)

Aim: Giant cell arteritis (GCA) is the most common primary vasculitis in adults over 50 years of age. Our primary objective was to assess the incidence and prevalence of GCA in Waikato in a bid to deepen our understanding of the epidemiology of GCA in Aotearoa New Zealand., Methods: From January 2014 to December 2022, cases of GCA were identified prospectively and retrospectively through temporal artery ultrasound request lists and temporal artery biopsy histology reports. Using electronic health records, data were collected retrospectively on patient demographics and clinical features. These were used to calculate the incidence, prevalence and standardised mortality ratio (SMR) of GCA in Waikato., Results: There were 214 patients diagnosed with GCA over the 9-year period. The majority of patients were European (93.9%, 201/214) with Māori patients being significantly younger than European patients. The mean annual incidence of clinical GCA was 14.7 per 100,000 people over 50 years (95% confidence interval [CI] 12.7-16.6). The SMR was 1.18 (95% CI 0.83-1.52)., Conclusion: This is the largest study to date on the epidemiology of GCA in Aotearoa New Zealand. The incidence of GCA is comparable to other studies performed in Aotearoa New Zealand and appears to be stable over time. GCA is uncommon in Māori, Pacific Islander and Asian ethnic groups., Competing Interests: None. Philippa van Dantzig has been employed part-time by the Waikato Hospital (Te Whatu Ora) for 12 months in a research position to carry out this research project among others, as well as perform a clinical role. There is no other specific funding towards the project., (© PMA.)

Trafficability gives tracked vehicles adaptability, stability, and propulsion for various purposes, including deep-sea research in rough terrain. Terrain characteristics affect tracked vehicle mobility. This paper investigates the soil mechanical interaction dynamics between rubber-tracked vehicles and sedimental soils through controlled laboratory-simulated experiments. Focusing on Bentonite and Diatom sedimental soils, which possess distinct shear properties from typical land soils, the study employs innovative user-written subroutines to characterize mechanical models linked to the RecurDyn simulation environment. The experiment is centered around a dual-tracked crawler, which in itself represents a fully independent vehicle. A new three-dimensional multi-body dynamic simulation model of the tracked vehicle is developed, integrating the moist terrain's mechanical model. Simulations assess the vehicle's trafficability and performance, revealing optimal slip ratios for maximum traction force. Additionally, a mathematical model evaluates the vehicle's tractive trafficability based on slip ratio and primary design parameters. The study offers valuable insights and a practical simulation modeling approach for assessing trafficability, predicting locomotion, optimizing design, and controlling the motion of tracked vehicles across diverse moist terrain conditions. The focus is on the critical factors influencing the mobility of tracked vehicles, precisely the sinkage speed and its relationship with pressure. The study introduces a rubber-tracked vehicle, pressure, and moisture sensors to monitor pressure sinkage and moisture, evaluating cohesive soils (Bentonite/Diatom) in combination with sand and gravel mixtures. Findings reveal that higher moisture content in Bentonite correlates with increased track slippage and sinkage, contrasting with Diatom's notable compaction and sinkage characteristics. This research enhances precision in terrain assessment, improves tracked vehicle design, and advances terrain mechanics comprehension for off-road exploration, offering valuable insights for vehicle design practices and exploration endeavors.

Transcatheter pulmonary valve replacement (TPVR), also known as percutaneous pulmonary valve implantation, refers to a minimally invasive technique that replaces the pulmonary valve by delivering an artificial pulmonary prosthesis through a catheter into the diseased pulmonary valve under the guidance of X-ray and/or echocardiogram while the heart is still beating not arrested. In recent years, TPVR has achieved remarkable progress in device development, evidence-based medicine proof and clinical experience. To update the knowledge of TPVR in a timely fashion, and according to the latest research and further facilitate the standardized and healthy development of TPVR in Asia, we have updated this consensus statement. After systematical review of the relevant literature with an in-depth analysis of eight main issues, we finally established eight core viewpoints, including indication recommendation, device selection, perioperative evaluation, procedure precautions, and prevention and treatment of complications., (© 2024 Wiley Periodicals LLC.)

Comparative pharmacokinetics (PK) studies have efficiently served as the bridge between autoinjectors and prefilled syringes given the underlying principles that comparable exposure could translate to comparable efficacy and safety. This article discusses approaches used to address uncertainties associated with the observation of noncomparable PK leading to the successful introduction of new autoinjector devices for monoclonal antibody and Fc-fusion protein products. Information from seven case examples suggests a knowledge gap that warrants attention in autoinjector development., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

In classic pancreatic transplantation, the splenic artery and vein are ligated at the tail of the pancreas graft. This leads to slowed blood flow in the splenic vein and may cause thrombosis and graft loss. In this study, a patient received a pancreas after kidney transplantation. A modified surgical technique was used in the pancreatic graft preparation. The donor splenic artery and vein were anastomosed end to end at the tail of the pancreas. The splenic artery near the anastomosis was partially ligated, and an effective diameter of 2 mm was reserved to limit arterial blood pressure and flow. The patient recovered very well. Contrasted computed tomography scans on days 11 and 88 after pancreas transplantation indicated sufficient backflow of the splenic vein. We believe that this procedure may avoid the risk of splenic vein thrombosis after pancreas transplantation. This modified technique has not been reported in clinical cases previously and may help reduce the risk of thrombosis after pancreas transplantation., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Intravenous or subcutaneous routes of administration (ROAs) are common dosing routes for therapeutic proteins. Eleven therapeutic proteins with approval for one ROA have subsequently received approval for a second ROA. The clinical programs supporting the second ROA consistently leveraged data from the first ROA and included studies that characterized the pharmacokinetics (PKs) of the drug administered by the new ROA to identify an appropriate dosage regimen. The selected dosing regimen was then further evaluated in clinical trials designed with various primary end points. All programs implemented model-informed drug development approaches to ensure that the selected regimens would achieve comparable systemic exposures (PK-based bridging) or pharmacodynamic (PD) responses (PD-based bridging) as the reference ROA. To support the approval of a second ROA, these programs either demonstrated noninferiority in PK, PD, and/or clinical end points for the second ROA, or established efficacy and safety through a comparison to a placebo treatment. The accumulative examples showed that clinical trials which provided the primary evidence to support approvals of the second ROA generally demonstrated noninferiority in the systemic exposures regardless of being specified as an end point or not in the study protocols. The experience to date supports the use of PK- and PD-based bridging approaches not only in the selection of dosing regimens for a second ROA to be tested in clinical studies, but also for providing evidence of effectiveness to support approval, when appropriate., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

The recently discovered plastic/ductile inorganic thermoelectric (TE) materials open a new avenue for the fabrication of high-efficiently flexible TE devices, which can utilize the small temperature difference between human body and environment to generate electricity. However, the maximum power factor (PF) of current plastic/ductile TE materials is usually around or less than 10 µW cm -1 K -2 , much lower than the classic brittle TE materials. In this work, a record-high PF of 18.0 µW cm -1 K -2 at 375 K in plastic/ductile bulk SnSe 2 -based crystals is reported, superior to all the plastic inorganic TE materials and flexible organic TE materials reported before. The origin of such high PF is from the modulation of material's stacking forms and polymorph crystal structures via simultaneously doping Cl/Br at Se-site and intercalating Cu inside the van der Waals gap, leading to the significantly enhanced carrier concentrations and mobilities. An in-plane fully flexible TE device made of the plastic/ductile SnSe 2 -based crystals is successfully developed to show a record-high normalized maximum power density to 0.18 W m -1 under a temperature difference of 30 K. This work indicates that the plastic/ductile material can realize high TE power factor to achieve large output electric power density in flexible TE technology., (© 2023 Wiley-VCH GmbH.)

In this study, we describe the first real-time live cell assay for compound accumulation and permeability in both Gram positive and Gram negative bacteria. The assay utilizes a novel fluorogenic tagging strategy that permits direct visualization of compound accumulation dynamics in the cytoplasm of live cells, unobscured by washing or other processing steps. Quantitative differences could be reproducibly measured by flow cytometry at compound concentrations below the limit of detection for MS-based approaches. We establish the fluorogenic assay in E. coli and B. subtilis and compare the intracellular accumulation of two antibiotics, ciprofloxacin and ampicillin, with related pharmacophores in these bacteria.

Importance: The prevalence of multidrug-resistant Staphylococcus aureus is of global concern, and vaccines are urgently needed. The iron-regulated surface determinant protein B (IsdB) of S. aureus was investigated as a vaccine candidate because of its essential role in bacterial iron acquisition but failed in clinical trials despite strong immunogenicity. Here, we reveal an unexpected second function for IsdB in pathogen-host interaction: the bacterial fitness factor IsdB triggers a strong inflammatory response in innate immune cells via Toll-like receptor 4 and the inflammasome, thus acting as a novel pathogen-associated molecular pattern of S. aureus . Our discovery contributes to a better understanding of how S. aureus modulates the immune response, which is necessary for vaccine development against the sophisticated pathogen., Competing Interests: The authors declare no conflict of interest.

Introduction: Psychological evaluation is required by insurance companies in the United States prior to proceeding with a spinal cord stimulation or a dorsal root ganglion stimulation trial. Since January 2017, we implemented a Multidisciplinary Team Conference for Neuromodulation in our center to facilitate the collaboration between pain physicians and psychologists and to optimize screening of neuromodulation candidates. This study aims to report the impact of this team conference on improvement of neuromodulation outcome in our center., Methods: Appropriateness of neuromodulation were discussed in the team conference after initial visit with the pain specialist and psychological evaluation. For this study, we prospectively and retrospectively collected data on neuromodulation candidates who went through the team conference and those who did not as controls., Results: We discussed 461 patients in the team conference sessions from January 2017 to July 2023. Out of these, a spinal cord stimulator or a dorsal root ganglion stimulator trial was performed in 164 patients with 80.5% (132 cases) trial success rate leading to 140 implants. Out of these implants, 26 (18.6%) explanted and 21 (15%) required revision in 41 (29.3%) patients. We performed neuraxial neuromodulation trial for 70 patients without going through the team conference from January 2016 to July 2023 with a trial success rate of 45.7% (32 cases). In this group, 7 (21.9%) and 6 (18.8%) patients underwent explant and revision. The differences between the groups were statistically significant for trial success rate (odds ratio of 4.9 with p -value of <0.01) but not for explant (odds ratio of 0.8 with p -value of 0.627) or revision (odds ratio of 0.8 with p -value of 0.595)., Conclusion: Implementing Multidisciplinary Team Conference increased trial success rate in our center. Team conference provides therapeutic benefit for patients, and also provides the opportunity for an educational discussion for trainees., 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., (© 2024 Salmasi, Rasouli, Kao, Ottestad, Terkawi, Morris, Qian, Coleman, Talavera, Poupore-King, Slater and Leong.)

Objective: Manufacturing changes occur commonly throughout stages of biologics development and may result in product quality attribute changes. As changes in critical quality attributes have the potential to affect clinical safety and efficacy of products, it is imperative to ensure the quality and clinical performance before introducing the after-change products. Thus, we embarked on this project to understand what data have supported the manufacturing changes for licensed products with pre- and post-approval changes., Methods: We surveyed the manufacturing changes of 85 monoclonal antibodies and 10 Fc fusion proteins approved by the Food and Drug Administration as of December 25, 2021. After collecting the type and timing of changes for these products, we investigated the approaches that provided supporting data for the changes. The source documents included reports submitted by applicants and FDA's regulatory reviews., Results: Analytical comparability was assessed to support all identified manufacturing changes. Supporting clinical data were available in 92% of these manufacturing changes; including data from pharmacokinetic comparability studies alone (3%), other studies on efficacy or safety (70%) and a combination of both (19%). Clinical pharmacokinetic comparability data contributed to supporting substantial changes, such as host cell type or master cell bank changes, concentration or formulation changes, and changes from pre-filled syringes to autoinjectors, especially when introduced after completing pivotal studies., Conclusion: Our comprehensive retrospective analysis provides an understanding of the regulatory experience and industry practice, which could facilitate developing appropriate comparability approaches to support manufacturing changes in the future., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In minimally invasive thoracoscopic surgery, for solitary pulmonary nodules (SPNs) far from the pleura, it is difficult to resected by only relying on imaging data, and effective preoperative localization can significantly improve the success rate of surgery. Therefore, preoperative localization is particularly important for accurate resection. Here, we compare the value of a novel Lung-pro-guided localization technique with Hook-wire localization in video-assisted thoracoscopic surgery., Method: In this study, 70 patients who underwent CT-guided Hook-wire localization and Lung-pro guided surgical marker localization before VATS-based SPNs resection between May 2020 and March 2021 were analyzed, and the clinical efficacy and complication rate of the two groups were compared., Result: Thirty-five patients underwent Lung-pro guided surgical marker localization, and 35 patients underwent CT-guided Hook-wire localization. The localization success rates were 94.3% and 88.6%, respectively (p = 0.673). Compared with the puncture group, the locating time in the Lung-pro group was significantly shorter (p = 0.000), and the wedge resection time was slightly shorter than that in the puncture group (P = 0.035). There were no significant differences in the success rate of localization, localization complications, intraoperative blood loss, postoperative hospital stay, and the number of staplers used., Conclusion: The above studies show that the Lung-pro guided surgical marker localization and the CT-guided Hook-wire localization have shown good safety and effectiveness. However, the Lung-pro guided surgical marker localization may show more safety than the Hook-wire and can improve the patient's perioperative experience., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Brassica rapa (B. rapa) roots are attracting increased attention from nutritionists and health-conscious customers because of their remarkable performance in supplying necessary nutrients. Polysaccharides are major biologically active substances in B. rapa roots, which come in a variety of monosaccharides with different molar ratios and glycosidic bond types. Depending on the source, extraction, separation, and purification methods of B. rapa roots polysaccharides (BRP); different structural features, and pharmacological activities are elucidated. Polysaccharides from B. rapa roots possess a range of nutritional, biological, and health-enhancing characteristics, including anti-hypoxic, antifatigue, immunomodulatory, hypoglycemic, anti-tumor, and antioxidant activities. This paper reviewed extraction and purification methods, structural features, and biological activities as well as correlations between the structural and functional characteristics of polysaccharides from the B. rapa roots. Ultimately, this work will serve as useful reference for understanding the connections between polysaccharide structure and biological activity and developing novel BRP-based functional foods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Engineered RNAs have applications in diverse fields from biomedical to environmental. In many cases, the folding of the RNA is critical to its function. Here we describe a strategy to improve the response time of a riboswitch-based fluorescent biosensor. Systematic mutagenesis was performed to either make transpose or transition base pair mutants or introduce orthogonal base pairs. Both natural and unnatural base pair mutants were found to improve the biosensor response time without compromising fold turn-on or ligand affinity. These strategies can be transferred to improve the performance of other RNA-based tools.

Two challenges facing machine learning tasks in materials science are data set construction and descriptor design. Graph neural networks circumvent the need for empirical descriptors by encoding geometric information in graphs. Large language models have shown promise for database construction via text extraction. Here, we apply OpenAI's Generative Pre-trained Transformer 4 (GPT-4) and the Crystal Graph Convolutional Neural Network (CGCNN) to the problem of discovering rare-earth-doped phosphors for solid-state lighting. We used GPT-4 to datamine the chemical formulas and emission wavelengths of 264 Eu 2+ -doped phosphors from 274 articles. A CGCNN model was trained on the acquired data set, achieving a test R 2 of 0.77. Using this model, we predicted the emission wavelengths of over 40 000 inorganic materials. We also used transfer learning to fine-tune a bandgap-predicting CGCNN model for emission wavelength prediction. The workflow requires minimal human supervision and is generalizable to other fields.

The flexible thermoelectric technique, which can convert heat from the human body to electricity via the Seebeck effect, is expected to provide a peerless solution for the power supply of wearables. The recent discovery of ductile semiconductors has opened a new avenue for flexible thermoelectric technology, but their power factor and figure-of-merit values are still much lower than those of classic thermoelectric materials. Herein, we demonstrate the presence of morphotropic phase boundary in Ag 2 Se-Ag 2 S pseudobinary compounds. The morphotropic phase boundary can be freely tuned by adjusting the material thermal treatment processes. High-performance ductile thermoelectric materials with excellent power factor (22 μWcm -1  K -2 ) and figure-of-merit (0.61) values are realized near the morphotropic phase boundary at 300 K. These materials perform better than all existing ductile inorganic semiconductors and organic materials. Furthermore, the in-plane flexible thermoelectric device based on these high-performance thermoelectric materials demonstrates a normalized maximum power density reaching 0.26 Wm -1 under a temperature gradient of 20 K, which is at least two orders of magnitude higher than those of flexible organic thermoelectric devices. This work can greatly accelerate the development of flexible thermoelectric technology., (© 2023. The Author(s).)

Introduction: Bifidobacterium longum subspecies infantis ( B. infantis ) may play a key role in infant gut development. This trial evaluated safety, tolerability, and efficacy of B. infantis LMG11588 supplementation., Methods: This randomized, placebo-controlled, double-blind study conducted in the Philippines included healthy breastfed and/or formula-fed infants (14-21 days old) randomized for 8 weeks to a control group (CG; n  = 77), or any of two B. infantis experimental groups (EGs): low (Lo-EG; 1*10 8 CFU/day; n  = 75) or high dose (Hi-EG; 1.8*10 10 CFU/day; n  = 76). Primary endpoint was weight gain; secondary endpoints included stooling patterns, gastrointestinal symptoms, adverse events, fecal microbiome, biomarkers, pH, and organic acids., Results: Non-inferiority in weight gain was demonstrated for Hi-EG and Lo-EG vs. CG. Overall, probiotic supplementation promoted mushy-soft stools, fewer regurgitation episodes, and increased fecal acetate production, which was more pronounced in the exclusively breastfed infants (EBF) and positively correlated with B. infantis abundance. In EBF, fecal pro-inflammatory cytokines (IL-1 beta, IL-8) were reduced. Strain-level metagenomic analysis allowed attributing the increased abundance of B. infantis in EGs versus CG, to LMG11588 probiotic colonization. Colonization by autochthonous B. infantis strains was similar between groups., Discussion: B. infantis LMG11588 supplementation was associated with normal infant growth, was safe and well-tolerated and promoted a Bifidobacterium -rich microbiota driven by B. infantis LMG11588 colonization without disturbing the natural dispersal of autochthonous B. infantis strains. In EBF, supplementation stimulated microbial metabolic activity and beneficially modulated enteric inflammation., Competing Interests: Authors employed by Nestlé Nutrition and Nestlé Research, Société des Produits Nestlé SA, Switzerland were involved in the study design (CIC), data analysis (CM, MN, KV, GLC, AF, BB, CB, CIC), as well as preparation and decision to submit the manuscript (TS, MN, KV, GLC, AF, BB, CIC). In addition, JMM, JKV, PM, and HBN, employees of Clinical Microbiomics, were involved in data analysis and preparation of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Capeding, Phee, Ming, Noti, Vidal, Le Carrou, Frézal, Moll, Vogt, Myers, Nielsen, Boulangé, Samuel, Berger and Cercamondi.)

This paper summarizes key features of the dose-finding strategies used in the development of 11 approved new molecular entities that are first-in-class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose-finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in in vitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose-finding in early phase clinical studies in a well-defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial. Two important considerations for successful dose selection include (1) identifying appropriate disease-specific endpoints, including pharmacodynamic (PD) end points and intermediate clinical end points or clinical end points, and (2) designing a study with adequate treatment durations for evaluating these end points. Appropriately selected PD biomarkers is useful for dose selection, and early development of these biomarkers can facilitate the overall clinical development program. Optimization of ERT doses, as well as evaluations of patient intrinsic factors and/or immune tolerance strategies may be necessary to overcome antibody responses or increase efficacy in IEM., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Alzheimer's disease (AD), particularly late-onset Alzheimer's disease (LOAD), is a prevalent form of dementia that significantly affects patients' cognitive and behavioral capacities and longevity. Although approximately 70 genetic risk factors linked with AD have been identified, their influence on patient longevity remains unclear. Further, recent studies have associated copy number variations (CNVs) with the longevity of healthy individuals and immune-related pathways in AD patients. This study aims to investigate the role of CNVs on the longevity of AD patients by integrating the Whole Genome Sequencing (WGS) and transcriptomics data from the Religious Orders Study/Memory and Aging Project (ROSMAP) cohort through causality network inference. Our comprehensive analysis led to the construction of a CNV-Gene-Age of Death (AOD) causality network. We successfully identified three key CNVs (DEL5006, mCNV14192, and DUP42180) and seven AD-longevity causal genes ( PLGRKT , TLR1 , PLAU , CALB2 , SYTL2 , OTOF , and NT5DC1 ) impacting AD patient longevity, independent of disease severity. This outcome emphasizes the potential role of plasminogen activation and chemotaxis in longevity. We propose several hypotheses regarding the role of identified CNVs and the plasminogen system on patient longevity. However, experimental validation is required to further corroborate these findings and uncover precise mechanisms. Despite these limitations, our study offers promising insights into the genetic influence on AD patient longevity and contributes to paving the way for potential therapeutic interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hao, Li, Wang and Ming.)

Disuse osteoporosis is characterized by decreased bone mass caused by abnormal mechanical stimulation of bone. Piezo1 is a major mechanosensitive ion channel in bone homeostasis. However, whether intervening in the action of Piezo1 can rescue disuse osteoporosis remains unresolved. In this study, a commonly-used hindlimb-unloading model is employed to simulate microgravity. By single-cell RNA sequencing, bone marrow-derived mesenchymal stem cells (BMSCs) are the most downregulated cell cluster, and coincidentally, Piezo1 expression is mostly enriched in those cells, and is substantially downregulated by unloading. Importantly, activation of Piezo1 by systemically-introducing yoda1 mimics the effects of mechanical stimulation and thus ameliorates bone loss under simulated microgravity. Mechanistically, Piezo1 activation promotes the proliferation and osteogenic differentiation of Gli1 + BMSCs by activating the β-catenin and its target gene activating transcription factor 4 (ATF4). Inhibiting β-catenin expression substantially attenuates the effect of yoda1 on bone loss, possibly due to inhibited proliferation and osteogenic differentiation capability of Gli1 + BMSCs mediated by ATF4. Lastly, Piezo1 activation also slightly alleviates the osteoporosis of OVX and aged mice. In conclusion, impaired function of Piezo1 in BMSCs leads to insufficient bone formation especially caused by abnormal mechanical stimuli, and is thus a potential therapeutic target for osteoporosis., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Importance: Respiratory syncytial virus (RSV) matrix (M) protein is indispensable for virion assembly and release. It is localized to the nucleus during early infection to perturb host transcription. However, the function of RSV M protein in other cellular activities remains poorly understood. In this study, several interferon response-associated host factors, including RACK1, were identified by proteomic analysis as RSV M interactors. Knockdown of RACK1 attenuates RSV-restricted IFN signaling leading to enhanced host defense against RSV infection, unraveling a role of M protein in antagonizing IFN response via association with RACK1. Our study uncovers a previously unrecognized mechanism of immune evasion by RSV M protein and identifies RACK1 as a novel host factor recruited by RSV, highlighting RACK1 as a potential new target for RSV therapeutics development., Competing Interests: The authors declare no conflict of interest.

Importance: Human papillomavirus 16 (HPV16) is a causative agent in around 3%-4% of all human cancers, and currently, there are no anti-viral therapeutics available for combating this disease burden. In order to identify new therapeutic targets, we must increase our understanding of the HPV16 life cycle. Previously, we demonstrated that an interaction between E2 and the cellular protein TopBP1 mediates the plasmid segregation function of E2, allowing distribution of viral genomes into daughter nuclei following cell division. Here, we demonstrate that E2 interaction with an additional host protein, BRD4, is also essential for E2 segregation function, and that BRD4 exists in a complex with TopBP1. Overall, these results enhance our understanding of a critical part of the HPV16 life cycle and presents several therapeutic targets for disruption of the viral life cycle., Competing Interests: The authors declare no conflict of interest.