Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKß independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

Thoraco-Omphalopagus Conjoined Twins: A Rare Presentation in the Dominican Republic.

The case involves a 23-year-old Dominican woman's admission to Hospital Docente Nuestra Señora De la Altagracia for an elective cesarean section at 38 weeks gestation with conjoined twins. Despite effective treatment for syphilis in the third trimester, her medical history complicated the situation. The twins, thoraco-omphalopagus conjoined, share vital organs and exhibit congenital anomalies, posing unique diagnostic and management challenges. This case contributes to the scarce literature on conjoined twins, especially in the Dominican Republic. It highlights the complexities of diagnosis, prognosis, and management strategies for such rare cases. This emphasizes the importance of ongoing research and medical intervention in addressing these challenges.

Effect of the Photoreduction Process on the Self-Cleaning and Antibacterial Activity of Au-Doped TiO2 Colloids on Cotton Fabric.

This study aims at understanding the effect of the photoreduction process during the synthesis of gold (Au)-doped TiO2 colloids on the conferred functionalities on cotton fabrics. TiO2/Au and TiO2/Au/SiO2 colloids were synthesized through the sol-gel method with and without undergoing the photoreduction step based on different molar ratios of Au:Ti (0.001 and 0.01) and TiO2/SiO2 (1:1 and 1:2.3). The colloids were applied to cotton fabrics, and the obtained photocatalytic self-cleaning, wet photocatalytic activity, UV protection, and antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) bacteria were investigated. The obtained results demonstrated that the photoreduction of Au weakened the self-cleaning effect and reduced the photocatalytic activity of coated fabrics. Also, an excess amount of Au deteriorated the photocatalytic activity under both UV and visible light. The most efficient self-cleaning effect was obtained on fabrics coated with a ternary TiO2/Au/SiO2 colloid containing ionic Au, where it decomposed coffee and red-wine stains after 3 h of illumination. Adding silica (SiO2) made the fabrics superhydrophilic and led to greater methylene blue (MB) dye adsorption, a faster dye degradation pace, and more efficient stain removal. Moreover, the photoreduction process affected the size of Au nanoparticles (NPs), weakened the antibacterial activity of fabrics against both types of tested bacteria, and modestly increased the UV protection. In general, the photoactivity of Au-doped colloids was influenced by the synthesis method, the ionic and metallic states of the Au dopant, the concentration of the Au dopant, and the presence and concentration of silica.

Puberty Blocker, Leuprolide, Reduces Sex Differences in Rough-and-Tumble Play and Anxiety-like Behavior in Juvenile Rats.

We examined the effect of the puberty blocker, leuprolide acetate, on sex differences in juvenile rough-and-tumble play behavior and anxiety-like behavior in adolescent male and female rats. We also evaluated leuprolide treatment on gonadal and pituitary hormone levels and activity-regulated cytoskeleton-protein messenger RNA levels within the adolescent amygdala, a region important both for rough-and-tumble play and anxiety-like behavior. Our findings suggest that leuprolide treatment lowered anxiety-like behavior during adolescent development, suggesting that the maturation of gonadotropin-releasing hormone systems may be linked to increased anxiety. These data provide a potential new model to understand the emergence of increased anxiety triggered around puberty. Leuprolide also reduced masculinized levels of rough-and-tumble play behavior, lowered follicle-stimulating hormone, and produced a consistent pattern of reducing or halting sex differences of hormone levels, including testosterone, growth hormone, thyrotropin, and corticosterone levels. Therefore, leuprolide treatment not only pauses sexual development of peripheral tissues, but also reduces sex differences in hormones, brain, and behavior, allowing for better harmonization of these systems following gender-affirming hormone treatment. These data contribute to the intended use of puberty blockers in stopping sex differences from developing further with the potential benefit of lowering anxiety-like behavior.

Target-locked: A mechanism for disaggregase binding to aggregated proteins.

ClpG is a novel autonomous disaggregase found in Pseudomonas aeruginosa that confers resistance to lethal heat stress. The mechanism by which ClpG specifically targets protein aggregates for disaggregation is unknown. In their recent work published in JBC, Katikaridis et al. (2023) identify an avidity-based mechanism by which four or more ClpG subunits, through specific N-terminal hydrophobic residues located on an exposed ß-sheet loop, interact with multiple hydrophobic patches on an aggregated protein substrate. This study establishes a model for substrate binding to a prokaryotic disaggregase that should inform further investigations into other autonomous disaggregases.

Factors associated with anxiety and depression among patients with chronic obstructive pulmonary disease.

OBJECTIVES: This study investigated factors associated with anxiety and depression in COPD outpatients. METHODS: A cross-sectional study of 702 COPD outpatients from two major Jordanian hospitals using the Hospital Anxiety and Depression Scale (HADS) was conducted. RESULTS: Significant associations were found with gender (Anxiety OR: 5.29, 95%CI: 2.38-11.74; Depression OR: 0.20, 95%CI: 0.08-0.51), disease severity (Anxiety OR: 2.97, 95%CI: 1.80-4.91; Depression OR: 15.95, 95%CI: 5.32-52.63), LABA use (Anxiety OR: 16.12, 95%CI: 8.26-32.26; Depression OR: 16.95, 95%CI: 8.33-34.48), medication count (Anxiety OR: 0.73, 95%CI: 0.59-0.90; Depression OR: 0.51, 95%CI: 0.40-0.64), mMRC score (Anxiety OR: 2.41, 95%CI: 1.81-3.22; Depression OR: 2.31, 95%CI: 1.76-3.03), and inhalation technique (Anxiety OR: 0.95, 95%CI: 0.93-0.97; Depression OR: 0.92, 95%CI: 0.90-0.95). Other factors associated with anxiety included high income, urban living, diabetes, hypertension, LAMA use, and fewer COPD medications. Depression was also linked with heart disease, increased age, and longer disease duration. CONCLUSION: The prevalence of anxiety and depression among COPD patients necessitates targeted interventions. Future research that recruits a more diverse sample in multiple sites and establishes the cause-effect relationship between the study predictors and outcome could provide a more robust conclusion on factors associated with anxiety and depression among COPD patients.

AI-Enabled Soft Sensing Array for Simultaneous Detection of Muscle Deformation and Mechanomyography for Metaverse Somatosensory Interaction.

Motion recognition (MR)-based somatosensory interaction technology, which interprets user movements as input instructions, presents a natural approach for promoting human-computer interaction, a critical element for advancing metaverse applications. Herein, this work introduces a non-intrusive muscle-sensing wearable device, that in conjunction with machine learning, enables motion-control-based somatosensory interaction with metaverse avatars. To facilitate MR, the proposed device simultaneously detects muscle mechanical activities, including dynamic muscle shape changes and vibrational mechanomyogram signals, utilizing a flexible 16-channel pressure sensor array (weighing ≈0.38 g). Leveraging the rich information from multiple channels, a recognition accuracy of ≈96.06% is achieved by classifying ten lower-limb motions executed by ten human subjects. In addition, this work demonstrates the practical application of muscle-sensing-based somatosensory interaction, using the proposed wearable device, for enabling the real-time control of avatars in a virtual space. This study provides an alternative approach to traditional rigid inertial measurement units and electromyography-based methods for achieving accurate human motion capture, which can further broaden the applications of motion-interactive wearable devices for the coming metaverse age.

Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

DPCD is a regulator of R2TP in ciliogenesis initiation through Akt signaling.

R2TP is a chaperone complex consisting of the AAA+ ATPases RUVBL1 and RUVBL2, as well as RPAP3 and PIH1D1 proteins. R2TP is responsible for the assembly of macromolecular complexes mainly acting through different adaptors. Using proximity-labeling mass spectrometry, we identified deleted in primary ciliary dyskinesia (DPCD) as an adaptor of R2TP. Here, we demonstrate that R2TP-DPCD influences ciliogenesis initiation through a unique mechanism by interaction with Akt kinase to regulate its phosphorylation levels rather than its stability. We further show that DPCD is a heart-shaped monomeric protein with two domains. A highly conserved region in the cysteine- and histidine-rich domains-containing proteins and SGT1 (CS) domain of DPCD interacts with the RUVBL2 DII domain with high affinity to form a stable R2TP-DPCD complex both in cellulo and in vitro. Considering that DPCD is one among several CS-domain-containing proteins found to associate with RUVBL1/2, we propose that RUVBL1/2 are CS-domain-binding proteins that regulate complex assembly and downstream signaling.

Clean Synthetic Strategies to Biologically Active Molecules from Lignin: A Green Path to Drug Discovery.

Deriving active pharmaceutical agents from renewable resources is crucial to increasing the economic feasibility of modern biorefineries and promises to alleviate critical supply-chain dependencies in pharma manufacturing. Our multidisciplinary approach combines research in lignin-first biorefining, sustainable catalysis, and alternative solvents with bioactivity screening, an in vivo efficacy study, and a structural-similarity search. The resulting sustainable path to novel anti-infective, anti-inflammatory, and anticancer molecules enabled the rapid identification of frontrunners for key therapeutic indications, including an anti-infective against the priority pathogen Streptococcus pneumoniae with efficacy in vivo and promising plasma and metabolic stability. Our catalytic methods provided straightforward access, inspired by the innate structural features of lignin, to synthetically challenging biologically active molecules with the core structure of dopamine, namely, tetrahydroisoquinolines, quinazolinones, 3-arylindoles and the natural product tetrahydropapaveroline. Our diverse array of atom-economic transformations produces only harmless side products and uses benign reaction media, such as tunable deep eutectic solvents for modulating reactivity in challenging cyclization steps.

Prevalence of Alpha, Beta, and Gamma Human Papillomaviruses in Patients With Head and Neck Cancer and Noncancer Controls and Relation to Behavioral Factors.

BACKGROUND: Human papillomaviruses (HPVs) cause head and neck cancer (HNC), which is increasing in incidence in developed countries. We investigated the prevalence of alpha (α), beta (ß), and gamma (γ) HPVs among HNC cases and controls, and their relationship with sociodemographic, behavioral, and oral health factors. METHODS: We obtained oral rinse and brush samples from incident HNC cases (n = 369) and hospital-based controls (n = 439) and tumor samples for a subsample of cases (n = 121). We genotyped samples using polymerase chain reaction with PGMY09-PGMY11 primers and linear array for α-HPV and type-specific multiplex genotyping assay for ß-HPV and γ-HPV. Sociodemographic and behavioral data were obtained from interviews. RESULTS: The prevalence of α-, ß-, and γ-HPV among controls was 14%, 56%, and 24%, respectively, whereas prevalence among cases was 42%, 50%, and 33%, respectively. Prevalence of α- and γ-HPV, but not ß-HPV, increased with increase in sexual activity, smoking, and drinking habits. No HPV genus was associated with oral health. Tumor samples included HPV genotypes exclusively from the α-genus, mostly HPV-16, in 80% of cases. CONCLUSIONS: The distribution of α- and γ-HPV, but not ß-HPV, seems to vary based on sociodemographic and behavioral characteristics. We did not observe the presence of cutaneous HPV in tumor tissues.

Decoupling Activation and Transport by Electron-Regulated Atomic-Bi Harnessed Surface-to-Pore Interface for Vanadium Redox Flow Battery.

Vanadium redox flow battery (VRFB) promises a route to low-cost and grid-scale electricity storage using renewable energy resources. However, the interplay of mass transport and activation processes of high-loading catalysts makes it challenging to drive high-performance density VRFB. Herein, a surface-to-pore interface design that unlocks the potential of atomic-Bi-exposed catalytic surface via decoupling activation and transport is reported. The functional interface accommodates electron-regulated atomic-Bi catalyst in an asymmetric Bi─O─Mn structure that expedites the V3+ /V2+ conversion, and a mesoporous Mn3 O4 sub-scaffold for rapid shuttling of redox-active species, whereby the site accessibility is maximized, contrary to conventional transport-limited catalysts. By in situ grafting this interface onto micron-porous carbon felt (Bi1 -sMn3 O4 -CF), a high-performance flow battery is achieved, yielding a record high energy efficiency of 76.72% even at a high current density of 400 mA cm-2 and a peak power density of 1.503 W cm-2 , outdoing the battery with sMn3 O4 -CF (62.60%, 0.978 W cm-2 ) without Bi catalyst. Moreover, this battery renders extraordinary durability of over 1500 cycles, bespeaking a crucial breakthrough toward sustainable redox flow batteries (RFBs).

Broad spectrum post-entry inhibitors of coronavirus replication: Cardiotonic steroids and monensin.

A small molecule screen identified several cardiotonic steroids (digitoxin and ouabain) and the ionophore monensin as potent inhibitors of HCoV-229E, HCoV-OC43, and SARS-CoV-2 replication with EC50s in the low nM range. Subsequent tests confirmed antiviral activity in primary cell models including human nasal epithelial cells and lung organoids. Addition of digitoxin, ouabain, or monensin strongly reduced viral gene expression as measured by both viral protein and RNA accumulation. Furthermore, the compounds acted post virus entry. While the antiviral activity of digitoxin was dependent upon activation of the MEK and JNK signaling pathways but not signaling through GPCRs, the antiviral effect of monensin was reversed upon inhibition of several signaling pathways. Together, the data demonstrates the potent anti-coronavirus properties of two classes of FDA approved drugs that function by altering the properties of the infected cell, rendering it unable to support virus replication.

Current state of inclusion and diversity in pediatric urology fellowship programs.

BACKGROUND: Increased racial/ethnic diversity of the physician workforce can improve health outcomes for marginalized populations. Currently, the pediatric urology workforce is less racially/ethnically diverse than the pediatric population it serves. OBJECTIVE: We aimed to assess current recruitment efforts and barriers to recruitment of underrepresented in medicine (URM) fellows in pediatric urology fellowship programs. METHODS: A 20-question REDCap survey was created and distributed to 27 pediatric urology fellowship program directors (PDs). The survey consisted of 4 sections of questions focused on PD demographics, program characteristics, recruitment efforts, and perceptions of barriers to recruitment. RESULTS: A total of 20 PDs responded to the survey (74 %), including 3 incomplete responses. A majority of participants identified as Caucasian/white (79 %), male (68 %), over 40 years of age (89 %), and had served as PD for 5 years or more (68 %). Most PDs (70 %) identified their program having 5-10 full-time pediatric urologists. Many PDs (75 %, 15/20) identified their program as less diverse than the patient population served, and 53 % (9/17) reported having no methods in place for diversity recruitment. Of those who reported a recruitment method, mentorship was the most common (35 %, 6/17). When asked about recruitment barriers, 59 % (10/17) reported that no barriers existed, while those who identified a barrier most commonly cited an overall limited applicant pool (18 %, 3/17). DISCUSSION: Pediatric urology fellowship programs are less diverse than the patient populations served; while PDs value program diversity, most PDs report that there are no mechanisms in place to recruit racially/ethnically diverse trainees. To address this, we recommend active and intentional efforts to increase URM recruitment in pediatric urology. By taking an active role in existing recruitment efforts, pediatric urologists can increase their visibility, broadcast their commitment to diversity, form relationships with trainees earlier in training and increase opportunities for mentorship and early exposure to the field. CONCLUSION: Intentional recruitment efforts are needed to recruit URM trainees to pediatric urology fellowship programs and ensure the diversity of the pediatric urology workforce can better reflect patients served.

A novel approach for power ramps classification in wind generation.

Ramp events are characterized by large power changes in a short period and increase with increasing renewable generation. Even with hourly forecasts, their predictions are still unreliable. Thus, grid operators should classify these power ramps to understand their expected occurrence periods and range to balance them. Previous research was based on a binary classification of ramp events, which assumed that ramp events were similar to one another, which is not true. Some other studies used randomization and non-causative classification methods. Hence, a more accurate method is still needed. The paper presents two new methods for ramp event classification. The first method depends on the standard deviation score, and the second method assigns a score to each ramp, which depends on the maximum value of the historical power ramps that occurred within the studied time period. The new classification methods are applied to the output power of Belgium's aggregated wind farms from 2015 to 2019, and the relative frequency of each ramp category is determined. The results revealed that, even though the capacity of wind installations has doubled, ramping behaviour is nearly the same in all years.

Knowledge, Attitude, and Practice Regarding the Use of Isotretinoin in Saudi Arabia.

Background Acne vulgaris is a widespread chronic inflammatory dermatological disease with a worldwide prevalence of 9.4%, affecting a large percentage of the young population in the Kingdom of Saudi Arabia. This study aimed to measure the knowledge, attitude, and practice toward the use of isotretinoin among the Saudi population. Methodology This cross-sectional study was conducted among the general population in Saudi Arabia between April 2023 and July 2023. A self-administered questionnaire was distributed across five regions of Saudi Arabia (central, eastern, western, southern, and northern) using Google Survey. The questionnaire included sociodemographic data, the pattern of isotretinoin used, and a 24-item questionnaire to assess the knowledge about isotretinoin. Results Of the 3,001 participants, 77.1% were females, and 55.4% were aged between 16 and 25 years. The prevalence of participants who previously used isotretinoin was 30.6%. The total mean knowledge score was 10.4 (SD = 5.99) out of 24 points, with more than half (52.9%) considered to have poor knowledge, 39.1% moderate knowledge, and only 7.9% good knowledge. Younger participants, female gender, Saudi nationality, never been married, and previous use of isotretinoin were associated with increased knowledge. Conclusions The knowledge of the general population regarding isotretinoin use was lacking. However, younger Saudi females who had previous isotretinoin usage tended to be more knowledgeable about isotretinoin compared to the rest of the participants. Increasing the general public's knowledge regarding isotretinoin and its safe use is necessary.

Improved production of Bacillus subtilis cholesterol oxidase by optimization of process parameters using response surface methodology.

BACKGROUND: Cholesterol oxidase has numerous biomedical and industrial applications. In the current study, a new bacterial strain was isolated from sewage and was selected for its high potency for cholesterol degradation (%) and production of high cholesterol oxidase activity (U/OD600). RESULTS: Based on the sequence of 16S rRNA gene, the bacterium was identified as Bacillus subtilis. The fermentation conditions affecting cholesterol degradation (%) and the activity of cholesterol oxidase (U/OD600) of B. subtilis were optimized through fractional factorial design (FFD) and response surface methodology (RSM). According to this sequential optimization approach, 80.152% cholesterol degradation was achieved by setting the concentrations of cholesterol, inoculum size, and magnesium sulphate at 0.05 g/l, 6%, and 0.05 g/l, respectively. Moreover, 85.461 U of cholesterol oxidase/OD600 were attained by adjusting the fermentation conditions at initial pH, 6; volume of the fermentation medium, 15 ml/flask; and concentration of cholesterol, 0.05 g/l. The optimization process improved cholesterol degradation (%) and the activity of cholesterol oxidase (U/OD600) by 139% and 154%, respectively. No cholesterol was detected in the spectroscopic analysis of the optimized fermented medium via gas chromatography-mass spectroscopy (GC-MS). CONCLUSION: The current study provides principal information for the development of efficient production of cholesterol oxidase by B. subtilis that could be used in various applications.

Prognostic Factors Influencing Survival in Stage II and Stage III Colorectal Cancer Patients.

Background Colorectal cancer (CRC) is a global health concern with rising incidence. This study analyzed demographic and clinicopathological factors influencing overall survival (OS) and disease-free survival (DFS) in Jordanian CRC patients. Methodology This retrospective, single-center study collected data from CRC patients at the Royal Medical Services, Jordan, from January 2018 to June 2020. Patient variables included disease stage, stage risk, tumor location, history of chemotherapy, and metastasis status. OS and DFS were defined as the time from surgery to death, last follow-up, or metastasis confirmation. Kaplan-Meier curves and Cox models were used for survival analysis. Results Of 127 CRC patients, 33.3% died during the follow-up period. Most patients were males (55.1%), diagnosed with stage III (55.9%), and classified as high risk (59.2%). Metastasis occurred in 24.4%, and 65.4% received chemotherapy. OS at one, two, and end of the follow-up years was 85.2%, 75.6%, and 66.9%, respectively. Metastasis-free rates were 85%, 78.5%, and 71%, respectively. Multivariate analysis showed that stage III (hazard ratio (HR) = 2.968) and high-risk stage (HR = 2.966) were associated with shorter OS and increased metastasis risk. Right-sided tumors (HR = 2.183) had shorter OS, while chemotherapy recipients (HR = 0.430) had longer OS. Stage III and high-risk stages were strong predictors of mortality, while only stage III and high-risk stages were robust predictors of metastasis. Demographic variables (sex and age) showed no significant associations with survival outcomes. Conclusions Our findings highlight the prognostic significance of disease stage, stage risk, tumor location, and chemotherapy in CRC survival among Jordanian patients. Understanding these factors can guide tailored treatment and improve outcomes.