Programmable promoter editing for precise control of transgene expression.

Subtle changes in gene expression direct cells to distinct cellular states. Identifying and controlling dose-dependent transgenes requires tools for precisely titrating expression. To this end, we developed a framework called DIAL for building editable promoters that allows for fine-scale, heritable changes in transgene expression. Using DIAL, we increase expression by recombinase-mediated excision of spacers between the binding sites of a synthetic zinc-finger transcription factor and the core promoter. By nesting varying numbers and lengths of spacers, DIAL generates a tunable range of unimodal setpoints from a single promoter construct. Through small-molecule control of transcription factors and recombinases, DIAL supports temporally defined, user-guided control of transgene expression. Integration of DIAL promoters into lentivirus allows for efficient delivery to primary cells. As promoter editing generates stable states, DIAL setpoints are heritable, facilitating mapping of transgene levels to phenotypes. The highly modular and extensible DIAL framework opens up new opportunities for screening and tailoring transgene expression to regulate gene and cell-based therapies.

Microwave-assisted synthesis, characterization and in vitro biomedical applications of Hibiscus rosa-sinensis Linn.-mediated carbon quantum dots.

In recent years, carbon quantum dots (CQDs) have garnered considerable attention as a promising material for biomedical applications because of their unique optical and biological properties. In this study, CQDs were derived from the leaves of Hibiscus rosa-sinensis Linn. via microwave-assisted technique and characterized using different techniques such as ultraviolet-visible, Fourier transform infrared, fluorescence spectrometry, X-ray diffraction, dynamic light scattering, transmission electron microscopy and energy-dispersive X-ray spectroscopy. Subsequently, their potential for biomedical applications was investigated through in vitro assays assessing scratch healing, anti-inflammatory, antibacterial, and cytotoxicity properties. It was found that the CQDs were fluorescent, polycrystalline, quasi-spherical, ~ 12 nm in size with presence of -OH and -COOH groups on their negatively charged surfaces, and demonstrated good anti-inflammatory by inhibiting protein denaturation, cyclooxygenase-2 and regulating inflammatory cytokines. The CQDs also exhibited antimicrobial activity against Klebsiella pneumoniae and Bacillus cereus, good biocompatibility, along with excellent promotion of cell proliferation in vitro, indicating their potential as a anti-inflammatory and wound healing material. The properties were more enhanced than their precursor, H. rosa-sinensis leaf extract. Hence, the CQDs synthesized from the leaves of H. rosa-sinensis can serve as a potential biomedical agent.

Nanomaterials Based Multifunctional Bioactivities of V2O5 and Mesoporous Carbon@V2O5 Composite: Preparation and Characterization.

Nanocarriers have attracted considerable interest due to their prospective applications in the delivery of anticancer medications and their distinct bioactivities. Biogenic nanostructures can be effective nanocarriers for delivering drugs as a consequence of sustainable and biodegradable biomass-derived nanostructures that perform specific functions. In this case, a vanadium oxide (V2O5) and mesoporous carbon@V2O5 (C@V) composite was developed as a possible drug delivery system, and its bioactivities, including antioxidant, antibacterial, and anticancer, were investigated. Doxorubicin (DOX), an anticancer drug, was introduced to the nanoparticles, and the loading and release investigation was conducted. Strong interfacial interactions between mesoporous carbon (MC) and V2O5 nanostructures have been found to improve performance in drug loading and release studies and bioactivities. After incubation, the potent anticancer effectiveness was seen based on C@V nanocomposite. This sample was also utilized to research potential biomedical uses as an antioxidant, antibacterial, and anticancer. The most effective antioxidant, the C@V sample (61.2%), exhibited a higher antioxidant activity than the V-2 sample (44.61%). The C@V sample ultimately attained a high DOX loading efficacy of 88%, in comparison to a pure V2O5 sample (V-2) loading efficacy of 80%. Due to the combination of mesoporous carbon and V2O5, which increases specific surface area and surface sites of action as well as the morphology, it proved that the mesoporous carbon@V2O5 composite (C@V) sample demonstrated greater efficacy.

Concurrent uterine surgery and uptake of hormone therapy in patients undergoing bilateral salpingo-oophorectomy for risk-reducing or therapeutic indications.

OBJECTIVE: This study aimed to analyze factors associated with concurrent uterine surgery in patients undergoing bilateral salpingo-oophorectomy (BSO) for risk reducing or therapeutic purposes. Additionally, trends in surgical choice and uptake of post-operative hormone therapy (HT) were examined. METHODS: A 10-year retrospective study was conducted on patients who underwent risk-reducing or therapeutic BSO at one institution. Multinomial regression analysis of patient and case characteristics was performed evaluating associations with surgery type (BSO, BSO and hysterectomy, or BSO and endometrial sampling). Trends in surgery type and uptake of HT post operatively are described. RESULTS: Among the study sample of 643 patients, 140 (22%) patients underwent therapeutic BSO for a history of hormone receptor (HR) positive breast cancer, while the remainder underwent risk-reducing BSO due to a pathogenic variant and/or family history. Pathogenic variants included BRCA1 (141, 40%) BRCA2 (173, 49%), and Lynch syndrome genes (15, 4%). Regression analysis revealed significant associations between concurrent hysterectomy and Black race (RR = 3.55, CI = 1.51-8.38, p = 0.004), history of HR positive breast cancer (RR = 1.88, CI = 1.03-3.42, p = 0.04), and surgeon (Surgeon 1, RR = 2.43, CI = 1.36-4.35, p = 0.003). Among eligible patients under age 51, 36% initiated HT. Over the study period, concurrent hysterectomy rates declined while endometrial sampling increased. CONCLUSIONS: Rates of hysterectomy declined over the study period and slightly more than one-third of eligible patients utilized post-operative HT. Further research on concurrent uterine surgery is needed to establish standardized treatment recommendations in the risk-reducing and therapeutic BSO population. Additionally, education regarding the benefits of postoperative HT in eligible patients is warranted.

The Use of Patient-Specific Implants for the Treatment of Upper Extremity Fractures.

In this article, we discuss the use of three-dimensional (3-D) printed patient-specific implants in the management of upper extremity fractures. Traditional fracture fixation methods involve the use of standard-sized implants, which may not adequately address the needs of every patient, particularly those who have complications related to fracture nonunion or malunion and those who have significant bone loss. The benefits and limitations of this technology are also discussed, along with considerations for implementation in clinical practice. Overall, the use of 3-D printed patient-specific implants holds promise for improving the accuracy and efficacy of upper extremity fracture management.

Impact of a Center of Excellence in Confirming or Excluding a Diagnosis of Hypertrophic Cardiomyopathy.

Tertiary hospitals with expertise in hypertrophic cardiomyopathy (HCM) are assuming a greater role in confirming and correcting HCM diagnoses at referring centers. The objectives were to establish the frequency of alternate diagnoses from referring centers and identify predictors of accuracy of an HCM diagnosis from the referring centers. Imaging findings from echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging (CMR) in 210 patients referred to an HCM Center of Excellence between September 2020 and October 2022 were reviewed. Clinical and imaging characteristics from pre-referral studies were used to construct a model for predictors of ruling out HCM or confirming the diagnosis using machine learning methods (least absolute shrinkage and selection operator logistic regression). Alternative diagnoses were found in 38 of the 210 patients (18.1%) (median age 60 years, 50% female). A total of 17 of the 38 patients (44.7%) underwent a new CMR after their initial visit, and 14 of 38 patients (36.8%) underwent review of a previous CMR. Increased left ventricular end-diastolic volume, indexed, greater septal thickness measurements, greater left atrial size, asymmetric hypertrophy on echocardiography, and the presence of an implantable cardioverter-defibrillator were associated with higher odds ratios for confirming a diagnosis of HCM, whereas increasing age and the presence of diabetes were more predictive of rejecting a diagnosis of HCM (area under the curve 0.902, p <0.0001). In conclusion, >1 in 6 patients with presumed HCM were found to have an alternate diagnosis after review at an HCM Center of Excellence, and both clinical findings and imaging parameters predicted an alternate diagnosis.

Rheumatoid Arthritis and Cognitive Impairment or Dementia: An Updated Review of Epidemiological Data.

Rheumatoid arthritis (RA) is hypothesized to be associated with cognitive impairment and dementia, including Alzheimer's disease, through shared biological processes related to inflammation. It is important to elucidate this potential relationship as both conditions confer increased morbidity and even mortality among older adults. This narrative review provides a survey of recent epidemiologic studies, examining the association between rheumatoid arthritis and either dementia or cognitive impairment. Sixteen studies were included after searching in PubMed and EMBASE. All were published between 2012 and 2022 and were characterized as epidemiologic studies (either cohort, cross-sectional, or case-control). Studies varied in location, design, measures of exposure and outcome, and covariates considered. Of the 16 studies included, only five found statistically significant positive associations between RA and dementia or cognitive impairment. One study found an inverse relationship, while five studies found no associations at all. The remaining five studies found variable statistically significant associations between demographic or RA disease characteristics and cognitive measures. Given these mixed findings, further studies at both the mechanistic and population level are needed to clarify the possible shared biological underpinnings of these two conditions.

Bioderived Mesoporous Carbon@Tungsten Oxide Nanocomposite as a Drug Carrier Vehicle of Doxorubicin for Potent Cancer Therapy.

Scientists have investigated the possibility of employing nanomaterials as drug carriers. These nanomaterials can preserve their content and transport it to the target region in the body. In this investigation, we proposed a simple method for developing distinctive, bioderived nanostructures with mesoporous carbon nanoparticles impregnated with tungsten oxide (WO3). Prior to characterizing and encapsulating WO3 with bioderived mesoporous carbon, the anticancer drug doxorubicin (DOX) was added to the nanoparticles and examined loading and release study. The approaches for both nanoparticle production and characterization are discussed in detail. Colloidal qualities of the nanomaterial can be effectively preserved while also allowing transdermal transportation of nanoparticles into the body by forming them into green, reusable, and porous nanostructures. Although the theories of nanoparticles and bioderived carbon each have been studied separately, the combination presents a new route to applications connected to nanomedicine. Furthermore, this sample was used to study exotic biomedical applications, such as antioxidant, antimicrobial, and anticancer activities. The W-3 sample had lower antioxidant activity (44.01%) than the C@W sample (56.34%), which was the most potent. A high DOX entrapment effectiveness of 97% was eventually achieved by the C@W sample, compared to a pure WO3 entrapment efficiency of 91%. It was observed that the Carbon/WO3 composite (C@W) sample showed more efficacy because the mesoporous carbon composition with WO3 increases the average surface area and surface-active locations.

Phytochemical Profiling, Antimicrobial, Antiproliferative and Apoptotic Effects of Stemodia viscosa Roxb. of Western Ghats Region, India.

The present study shows the chemical profile, antimicrobial, antiproliferative, and apoptotic effects of Stemodia viscosa extracts. Thirteen bioactive compounds were identified in the 80 % ethanolic extract by GC/MS analysis. The acetone extract exhibited a higher content of flavonoids and phenols of 805.10 µg QE/mg DW and 89.31 µg GAE/mg DW extracts, respectively. Furthermore, the acetone extract possessed the highest antioxidant activity (IC50 =9.96 µg/mL). The 80 % ethanolic extract exhibited significant antimicrobial activity; the highest activity was observed against Staphylococcus aureus with a zone of inhibition of 25±0.51 mm, MIC value of 4 mg/mL, and MBC value of 8 mg/mL. The antiproliferative results revealed the presence of anticancer activity with an IC50 =91.562 and 74.362 µg/mL against the B16F10 skin and COLO205 colon cancer cells, respectively. The flow cytometric analysis shows that the plant extracts cause cancer cell death through the induction of apoptosis. Our findings confirmed that Stemodia viscosa is a potential source of biologically active compounds.

Exploration of multifaceted molecular mechanism of angiotensin-converting enzyme 2 (ACE2) in pathogenesis of various diseases.

Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE (a transmembrane bound dipeptidyl peptidase enzyme). ACE2 converts angiotensinogen to the heptapeptide angiotensin-(1-7). ACE2 and its product, angiotensin-(1-7), have counteracting effects against the adverse actions of other members of renin-angiotensin system (RAS). ACE2 and its principal product, angiotensin-(1-7), were considered an under recognized arm of the RAS. The COVID-19 pandemic brought to light this arm of RAS with special focus on ACE2. Membrane bound ACE2 serves as a receptor for SARS-CoV-2 viral entry through spike proteins. Apart from that, ACE2 is also involved in the pathogenesis of various other diseases like cardiovascular disease, cancer, respiratory diseases, neurodegenerative diseases and infertility. The present review focuses on the molecular mechanism of ACE2 in neurodegenerative diseases, cancer, cardiovascular disease, infertility and respiratory diseases, including SARS-CoV-2. This review summarizes unveiled roles of ACE2 in the pathogenesis of various diseases which further provides intriguing possibilities for the use of ACE2 activators and RAS modulating agents for various diseases.

Construction of Waste Chalk Powder into mpg-C3N4-CaSO4 as an Efficient Photocatalyst for Dye Degradation under UV-Vis Light and Sunlight.

In this article, we present the synthesis of calcium sulfate nanoparticles (CaSO4 NPs) from waste chalk powder by the calcination method. These CaSO4 NPs were utilized for the construction of a mesoporous graphitic carbon nitride-calcium sulfate (mpg-C3N4-CaSO4) photocatalyst. Synthesized materials were confirmed by several characterization techniques. The photocatalytic performance of the synthesized samples was tested by the degradation of methylene blue (MB) in the presence of both UV-vis light and sunlight. The efficiency of photocatalytic degradation of MB dye using the optimized mpg-C3N4-CaSO4-2 composite reached 91% within 90 min in the presence of UV-vis light with superb photostability and recyclability after five runs compared to individual mpg-C3N4 and CaSO4 NPs and reached 95% within 120 min under sunlight. Histotoxicological studies on fish liver and ovary indicated that the dye containing the solution damaged the structure of the liver and ovary tissues, whereas the photodegraded solution of MB was found to be less toxic and caused negligible alterations in their typical structure similar to the control group.

Pseudogout of the lumbar spine.

Calcium pyrophosphate deposition involves deposition of calcium pyrophosphate dihydrate crystals in various joints throughout the body. The term "pseudogout" refers to an acute attack of calcium pyrophosphate crystal-induced arthritis. Though clinical presentation and joint involvement vary, involvement of the lumbar spine is rare. We present the case of a 61-year-old male who presented with 3 days of worsening lower back pain. He had elevated inflammatory markers, leukocytosis, and spinal tenderness on exam. Magnetic resonance imaging of the lumbar spine showed likely L4-L5 osteomyelitis; however, biopsy of the disk space revealed extensive calcium pyrophosphate crystal deposition. The patient was treated with prednisone taper with alleviation of symptoms. Though pseudogout of the spine is rare, our report supports literature urging clinicians to consider pseudogout when assessing elderly patients with back pain for prompt and appropriate treatment.

Tetraphenylethene-Based Fluorescent Chemosensor with Mechanochromic and Aggregation-Induced Emission (AIE) Properties for the Selective and Sensitive Detection of Hg2+ and Ag+ Ions in Aqueous Media: Application to Environmental Analysis.

It is critical to design a novel and simple bifunctional sensor for the selective and sensitive detection of ions in an aqueous media in environmental samples. As a result, in this study, tetraphenylethene hydrazinecarbothioamide (TPE-PVA), known as probe 1, was successfully synthesized and characterized as having impressive photophysical phenomena such as aggregation-induced emission (AIE) and mechanochromic properties by applying mechanical force to the solid of probe 1. The emission of the solid of probe 1 changed from turquoise blue to lemon yellow after grinding, from lemon yellow to parakeet green after annealing at 160 °C, and to arctic blue after fuming with DCM. Such characteristics could lead to a variety of applications in several fields. The probe was implemented and demonstrated remarkable selectivity and sensitivity toward mercury(II) and silver(I) ions by substantially switching off emission over other cations. Following an extensive photophysical analysis, it was discovered that detection limits (LOD) as low as 0.18344 and 0.2384 µg mL-1 for Hg2+ and Ag+, respectively, are possible with a quantum yield (Φ) of 2.26. Probe 1 was also explored as a Hg2+ and Ag+ paper strip-based sensor and kit for practical use. The binding mechanisms of probe 1 (TPE-PVA) with Hg2+ and Ag+ were confirmed by 1H NMR titration. These results could lead to the development of reliable onsite Hg2+ and Ag+ fluorescent probes in the future.

Effects of different crash data variables on EMS response time for a rural county in alabama.

Response time of Emergency Medical Services (EMS) is an important factor related to preventable deaths in road crash incidents. This study focuses on analyzing the effects of different independent variables on the EMS Response Time (ERT). Independent variables considered for this investigation are travel time, day of the week, crash severity, weather, time of the day, and lighting condition. Understanding outcomes resulting from variations of the considered parameters on ERT is crucial to minimize the possibility of adverse outcomes which are tied to different types of injuries, and vital to limit the prospect of fatalities. Crash data used for this study is from a rural county in Alabama where only one EMS control location is available. Results from the analysis indicate that ERT becomes larger as travel time increases. ERT is also larger on weekends than on weekdays. ERT is larger in the evening and night when compared with morning. When the weather is clear or cloudy, the ERT parameter is shorter. But when the weather is extreme, with mist, fog, or rain, the parameter is longer. When roads are dark, ERT is long. When daylight is present, the ERT is shorter. If the crash is fatal, the parameter is longer compared with situations when crash injuries are non-severe.

Correlation of Clinical Features in Oral Submucous Fibrosis: A 9-Year Retrospective Study.

BACKGROUND: Oral Submucous Fibrosis is a chronic debilitating disease and potentially malignant disorder of the oral cavity known in medical literature for a long time. The study aims to correlate the clinical staging of Oral Submucous Fibrosis with various clinical findings of the oral mucosa like hyperpigmentation, erosions, ulcerations, VAS score, tongue protrusion, and cheek flexibility. METHODS: A retrospective observational study was undertaken and records of 1267 clinically diagnosed cases of OSMF were included in the study. Clinical grading was done as per criteria by Lai DR et al. The observations were tabulated and subjected to statistical analysis using SPSS software. RESULTS: In our study, the incidence of hyperpigmentation, erosions, and ulcerations was higher in Group C OSMF. Visual analog scores in the range of 5-6 was noted in 40.9% of the total subjects, out of which 36.2% belonged to Group C OSMF. Tongue protrusion of less than 25 mm was seen in 10.65% of the subjects. Cheek flexibility of less than 0.6 cm was seen in 19.62% of the subjects, most of which belonged to Group D. CONCLUSION: In our study, we found an increase in the occurrence and severity of symptoms with an increase in grades of OSMF, but this increase was not observed to be consistent. Hence classification based on a single clinical entity cannot be sufficient and correlations to other clinical findings should be studied over a large population and a multi-tier classification could be proposed in the future.

Analysis of Neurological Adverse Events Reported in VigiBase From COVID-19 Vaccines.

BACKGROUND: Fifteen COVID-19 vaccines have been granted emergency approval before the completion of conventional phases of clinical trials. The present study aimed to analyze the neurological adverse events (AEs) post-COVID-19 vaccination and focuses on determining the association of AEs with the vaccine. METHODOLOGY: The neurological AEs reported for COVID-19 vaccines in the WHO pharmacovigilance database (VigiBase) were extracted from the System Organ Classes - neurological disorders and investigations. Descriptive statistics are reported as percentage and frequency and the disproportionality analysis was also conducted. RESULTS:  For the neurological system, 19,529 AEs were reported. Of these, 15,638 events were reported from BNT162b2 vaccine, 2,751 from AZD1222 vaccine, 1,075 from mRNA-1273 vaccine, eight from Vero vaccine, two from Covaxin, and for 55 AEs, vaccine name was not mentioned. The reason for more AEs reported with BNT162b2 can be maximum vaccination with BNT162b2 vaccine in the study period. According to the disproportionality analysis based on IC025 value, ageusia, anosmia, burning sensation, dizziness, facial paralysis, headache, hypoaesthesia, lethargy, migraine, neuralgia, paresis, parosmia, poor sleep quality, seizure, transient ischemic attack, and tremor are some of the AEs that can be associated with the administration of the vaccine. CONCLUSION: The vaccines should be monitored for these AEs till the causality of these AEs with COVID-19 vaccines is established through further long-term follow-up studies. These neurological AEs reported in VigiBase should not be taken as conclusive and mass vaccination should be carried out to control the pandemic until a definite link of these adverse effects is established.

Oral submucous fibrosis and its impact on psychological stress: a case-control study.

Our aim was to evaluate the impact of OSF on psychological stress. Ninety OSF cases and age and sex-matched controls, enrolled from relatives or accompanying person were included in the study. Psychological stress was evaluated by the Psychological General Well Being Index short version (PGWBI-S). Sets of the psychological component were generated by principal component analysis (PCA). Association between components was accommodated for confounder and interaction was evaluated by conditional stepwise logistic regression analysis. Psychological component generated was component 1 (depressed mood, lack of positive well being, low vitality, anxiety, low vitality, and low self-control). The odds ratio (OR) of low score of component 1 for OSF was 3.66. Depressed mood, lack of positive well being, low vitality, anxiety, low vitality, and low self-control were associated with OSF. Psychological intervention should, therefore, be included in the management of OSF.

Insights into the structural requirements of triazole derivatives as promising DPP IV inhibitors: computational investigations.

Diabetes is one of the leading causes of death globally as per World Health Organization 2019. To cope up with side effects of current diabetes therapy, researchers have found several novel targets for the treatment of diabetes. Currently, dipeptidyl peptidase IV (DPP IV) has emerged as a target in modulating the diabetes physiology. In the present work, various 3D-Quantitative structure activity relationship (QSAR) techniques namely comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis, topomer CoMFA and molecular hologram QSAR are used to explore the structural requirements of triazole derivatives as DPP IV inhibitors. Different models generated by 3D QSAR studies had acceptable statistical values for further prediction of molecules. From the contour maps of QSAR results, important structural features are deduced. Substitutions on N1 and N2 of triazole ring with H-bond donor group enhances the biological activity. Aliphatic side chain, less bulky group, H-bond donor group and -COOH group on N3 of triazole ring are vital for the DPP IV inhibition. Moreover, electron withdrawing side chain on the triazole ring improves the biological activity. Further, novel triazole derivatives were designed and docking results of these compounds proved the efficiency of the developed 3D QSAR model. In future, results of this study may provide promising DPP IV inhibitors for the treatment of diabetes. Communicated by Ramaswamy H. Sarma.

Extent of tumor fibrosis/hyalinization and infarction following neoadjuvant radiation therapy is associated with improved survival in patients with soft-tissue sarcoma.

INTRODUCTION: Current standard of care for most intermediate and high-grade soft-tissue sarcomas (STS) includes limb-preserving surgical resection with either neoadjuvant radiation therapy (NRT) or adjuvant radiation therapy. To date, there have been a few studies that attempt to correlate histopathologic response to NRT with oncologic outcomes in patients with STS. METHODS: Using our institutional database, we identified 58 patients who received NRT followed by surgical resection for primary intermediate or high-grade STS and 34 patients who received surgical resection without NRT but did receive adjuvant radiation therapy or did not receive any radiation therapy. We analyzed four histologic parameters of response to therapy: residual viable tumor, fibrosis/hyalinization, necrosis, and infarction (each ratiometrically determined). Data were stratified into two binary groups. Unadjusted, 5- and 10-year overall survival, and relapsed-free survival (RFS) were calculated using the Kaplan-Meier method. RESULTS: Analysis of pathologic characteristics showed that patients treated with NRT demonstrate significantly higher tumor infarction, higher tumor fibrosis/hyalinization, and a lower percent viable tumor compared with patients not treated with NRT (p < 0.0001). Based on Kaplan-Meier curve analysis and multivariate cox proportional hazard model for OS and RFS, patients treated with NRT and showing >12.5% tumor fibrosis/hyalinization have significantly higher overall survival and recurrence-free survival at 5 and 10 years. DISCUSSION AND CONCLUSION: We have identified three histopathologic characteristics-fibrosis, hyalinization, and infarction-that may serve as predictive biomarkers of response to NRT for STS patients. Future prospective studies will be needed to confirm this association.