Design and discovery of carboxamide-based pyrazole conjugates with multifaceted potential against Triple-Negative Breast cancer MDA-MB-231 cells.

We report the design, synthesis, and validation of carboxamide-based pyrazole and isoxazole conjugates with a multifaceted activity against Breast Cancer Cell Line MDA-MB-231. The study established that amongst the series, N-(3,5-bis(trifluoromethyl)benzyl)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazole-5-carboxamide (5g) exhibits the highest potency in inhibiting Breast Cancer Cell Line MDA-MB-231 with an IC50 value of 15.08 ± 0.04 µM. The MDA-MB-231 cells, upon treatment with compound 5g, exhibited characteristic apoptotic specific activities such as nuclear fragmentation, phosphatidylserine translocation to the outer plasma membrane, release of lactate dehydrogenase (LDH), and upregulation of caspase 3 and caspase 9 activities. Also, the modulation of pro and antiapoptotic proteins in 5g treated MDA-MB-231 cells was revealed by membrane array analysis. More importantly, the combination of paclitaxel and compound 5g has exhibited improved activity by several folds via their synergistic effects.

Semi-quantitative analysis of serum and cerebrospinal fluid transferrin glycoforms by top-down liquid chromatography mass spectrometry.

Detection of ß-2 transferrin in body fluid could help identify cerebrospinal fluid (CSF) leakage. The most common method, isoelectric focusing, was qualitative and could not provide detailed N-glycan structural information. We presented an alternative method using top-down liquid chromatography-time of flight mass spectrometry (LC-TOF MS). After immunoaffinity enrichment, fluid transferrin glycoforms were analyzed by a high-resolution LC-TOF MS, and the N-glycan structure predicted by accurate mass. The performance was validated with imprecision at 15%, with a cut-off of 0.04 for ß-2 transferrin to tetrasialotransferrin ratio to confirm the presence of CSF in fluid samples.

AB011. A propensity-score matched prospective study on the impact of tumour treating fields (TTF) on overall survival and quality of life in newly diagnosed WHO grade 4 astrocytoma patients.

BACKGROUND: World Health Organization (WHO) grade 4 astrocytoma is a high-grade brain tumour in adults. Tumour treating fields (TTF) has been shown to improve overall survival (OS). Few studies have explored quality-of-life (QoL) in these patients. This study aims to assess the QoL of TTF patients and OS. METHODS: This was a prospective multicenter study of adult patients diagnosed with WHO grade 4 astrocytoma from 2018 to 2023 receiving TTF for >1 month after completing standard therapy. A propensity-score matched comparison with a 1:2 ratio with historical control was performed for OS analysis. The patients completed European Organisation for Research and Treatment of Cancer (EORTC) QLQ-30/BN20 questionnaires before TTF and at 3-month interval. Primary outcomes included OS, and secondary outcomes included QoL and TTF-associated adverse effects at 3 months. RESULTS: A total of 141 patients were reviewed, with TTF patients (n=47, 33%) and propensity-score matched controls (n=94). The mean duration of TTF use was 10±8 months. The mean age of the TTF group was 54±13 years, and for the control group 52±13 years. Sixty percent (n=28) were male, similar to the control group with 71% (n=67) (P=0.16). Seventy-two percent of TTF patients had preoperative Karnofsky Performance Scale (KPS) score ≥80, while controls had 70% (P=0.79). Five (11%) TTF patients and 8 (9%) controls were IDH1 mutant (P=0.70). Twenty (43%) TTF patients and 42 (45%) controls were O6-methylguanine-DNA methyltransferase promoter (pMGMT) methylated (P=0.81). Twenty-one (45%) of TTF patients and 55 (59%) of controls had gross total resection (P=0.72). After adjusting for independent predictors for OS, the median OS of the TTF group was 22.4 months [interquartile range (IQR): 18.6-26.5 months], significantly longer than the control group (17.2 months; IQR: 12.1-22.3 months) (log-rank test: P=0.01). Forty-seven TTF patients and 40 control patients completed EORTC questionnaires. There was no difference for EORTC functional and symptom scores between the TTF and control group [P=0.45, analysis of variance (ANOVA)] at 3 months. Thirty-two (67%) of TTF patients reported associated RTOG grade I scalp dermatitis. CONCLUSIONS: TTF for WHO grade 4 astrocytoma patients is an independent predictor for OS. QoL between the groups was similar, and overall QoL over time for TTF patients was not affected. TTF is a novel and effective outpatient treatment with minimal adverse effects.

Adding brief content-related information to sensitive-content screens does not exacerbate screen- or image-related distress.

Content descriptions presented on sensitive-content screens reduce how often people view negative images. But does this reduction in exposure come at an emotional cost? Across two experiments, we investigated this possibility. In Experiment 1, we compared participants' change in state anxiety when exposed to sensitive-content screens with and without brief and detailed content descriptions. State anxiety was similar for participants who saw screens with and without brief content descriptions, but we found larger increases in state anxiety for detailed content descriptions. Therefore, detailed content descriptions negatively impact how people feel when they view sensitive-content screens. In Experiment 2, we presented participants with a single sensitive-content screen, either with or without a brief content description, and gave them the opportunity to uncover it. Participants who uncovered the screen viewed the negative image and then rated their distress. Most participants uncovered the screen and, irrespective of condition, reported similar image-related distress. Taken together, brief descriptions do not negatively impact how people feel when they view sensitive-content screens or the forewarned content. Therefore, brief content descriptions do not create an emotional cost. Social media platforms should move beyond merely warning about upcoming content and provide brief content descriptions indicating what the content depicts.

Buffer gas cooled ice chemistry. II. Ice generation and mm-wave detection of molecules desorbed from an ice.

This second paper in a series of two describes the chirped-pulse ice apparatus that permits the detection of buffer gas cooled molecules desorbed from an energetically processed ice using broadband mm-wave rotational spectroscopy. Here, we detail the lower ice stage developed to generate ices at 4 K, which can then undergo energetic processing via UV/VUV photons or high-energy electrons and which ultimately enter the gas phase via temperature-programmed desorption (TPD). Over the course of TPD, the lower ice stage is interfaced with a buffer gas cooling cell that allows for sensitive detection via chirped-pulse rotational spectroscopy in the 60-90 GHz regime. In addition to a detailed description of the ice component of this apparatus, we show proof-of-principle experiments demonstrating the detection of H2CO products formed through irradiation of neat methanol ices or 1:1 CO + CH4 mixed ices.

Role of Oral Veillonella Species in Predicting Surgical Site Infections After Maxillofacial Trauma: A Prospective Observational Study.

INTRODUCTION: There are comparatively fewer surgical site infections after craniofacial trauma than after trauma to the extremities, and the etiology is complex. Gram-negative facultative anaerobic bacteria Veillonella is a common commensal in the oral cavity and has been linked to osteomyelitis and surgical site infections in prosthetic joint infections. They serve as early biological indicators. AIMS/OBJECTIVES: This study aims to assess the presence of Veillonella in patients presenting with maxillofacial trauma, to document the difference in colony count in patients requiring surgical intervention at different time intervals as against patients with surgical site infections, and to provide better hospital care and management so as to improve the standard of care with an attempt to prevent the possibility of postoperative surgical site infections. METHODOLOGY: In this study, individuals with trauma/fractures of the maxillofacial region requiring surgical intervention at varied time spans, early, intermediate, and late, were included. After obtaining informed consent, the examination was done; the fracture type and site were noted, and a swab was taken on the day of admission, on the day of surgery, and on the day of discharge and given for microbiological evaluation. Findings were recorded. RESULTS: The primary and secondary objectives of the study were established. The mean colony count in colony-forming units/milliliter for patients undergoing early surgical intervention, on the day of admission, was 2.01E+0.6. On the day of discharge, the mean colony count was 1.51E+0.6. In contrast, for patients with surgical site infection, on the day of admission, the mean was 6.5E+0.7, and on the day of discharge, the mean colony count reduced to 4.01E+0.6. The time-colony-forming unit graph showed a difference in the colony count of Veillonella in patients operated at different time intervals as against patients with surgical site infection and modified relation with a number of other oral commensals. The colony count in patients with osteomyelitis was found and compared. CONCLUSION: There is a change in the colony count of Veillonella species and its relation to their commensals when intervened at different time intervals. Our study indicates that the estimation of Veillonella species and the colony count could aid in determining the possibility of a surgical site infection. This study also stresses on the appropriate reporting of maxillofacial trauma in cases of a poly-trauma for appropriate management.

Time Lens Photon Doppler Velocimetry (TL-PDV) for extreme measurements.

Capturing extreme surface velocities with  >50 km/s dynamic range, which arise in shock physics such as inertial confinement fusion (ICF), is beyond the reach of conventional photon Doppler velocimetry (PDV) systems due to the need for extremely large electrical bandwidth under such conditions. The recent ignition in ICF calls for new velocimetry that can measure velocities exceeding 100 km/s. Time lens PDV (TL-PDV) is a solution where the high frequency beat signal from a conventional PDV system is periodically temporally magnified in the optical domain using a time lens. Here we experimentally demonstrate TL-PDV for the first time, validate the performance over a 74 km/s velocity range with high accuracy using a temporal magnification factor of 7.6, and verify excellent agreement with conventional PDV for laser driven micro-flyer experiments. TL-PDV currently provides the largest velocity dynamic range among PDV systems and is scalable to even higher velocities, which makes it an ideal candidate for material characterization under the most extreme conditions such as optimizing fuel efficiency in ICF experiments.

Regulation of Energy and Glucose Homeostasis by the Nucleus of the Solitary Tract and the Area Postrema.

The central nervous system regulates feeding, weight and glucose homeostasis in rodents and humans, but the site-specific mechanisms remain unclear. The dorsal vagal complex in the brainstem that contains the nucleus of the solitary tract (NTS) and area postrema (AP) emerges as a regulatory center that impacts energy and glucose balance by monitoring hormonal and nutrient changes. However, the specific mechanistic metabolic roles of the NTS and AP remain elusive. This mini-review highlights methods to study their distinct roles and recent findings on their metabolic differences and similarities of growth differentiation factor 15 (GDF15) action and glucose sensing in the NTS and AP. In summary, future research aims to characterize hormonal and glucose sensing mechanisms in the AP and/or NTS carries potential to unveil novel targets that lower weight and glucose levels in obesity and diabetes.

Assessing the impact of stricter drink driving policy on alcohol consumption in a population of Hanoi, Vietnam using wastewater analysis.

INTRODUCTION: On 1 January 2020, Vietnam introduced a new law with harsher fines and penalties for driving under the influence of alcohol. Reports of empty beer restaurants following this implementation suggested the new law has the potential to reduce population-level alcohol consumption. This pilot study aims to quantify short-term changes in alcohol consumption levels after the implementation of the new law and assess whether it could lead to a reduction in total alcohol consumption in the population. METHODS: Wastewater samples were collected from two sites along a sewage canal in Hanoi during two periods: Period 1 (15 December 2018 to 14 January 2019) and Period 2 (15 December 2019 to 14 January 2020). Ethyl sulfate, a specific metabolite of alcohol, was quantified to monitor the trend of alcohol consumption. Both interrupted time series and controlled interrupted time series approaches were utilised, with Period 1 and Period 2 serving as the control and intervention periods, respectively. RESULTS: Our analysis indicated that the implementation of the new law did not result in an immediate and significant reduction in alcohol consumption at the population level. Meanwhile, there was no significant difference in alcohol consumption between weekdays and weekends both before and after the implementation of the new law. DISCUSSION AND CONCLUSIONS: Long-term monitoring is needed to assess the impact of stricter DUI policy on alcohol consumption in the urban areas of Vietnam.

Synthesis and In vitro evaluation of bichalcones as novel anti-toxoplasma agents.

Toxoplasmosis is a zoonotic disease caused by Toxoplasma gondii, an apicomplexan parasite that infects approximately a third of the world's human population. This disease can cause serious complications during pregnancy and can be fatal in immunocompromised hosts. The current treatment options for toxoplasmosis face several limitations. Thus, to address the urgent medical need for the discovery of novel anti-toxoplasma potential drug candidates, our research focused on exploring a series of monomeric and dimeric chalcones, polyphenolic molecules belonging to the class of flavonoids. Chalcones 1aa-1bg and axially chiral A-A'-connected bichalcones 2aa-2bg were evaluated in vitro against the proliferation of the parasite in a cell-based assay. A comparison of the efficacy demonstrated that, in several cases, bichalcones exhibited increased bioactivity compared to their corresponding monomeric counterparts. Among these compounds, a bichalcone with a phenyl substituent and a methyl moiety 2ab showed the most potent and selective inhibitory activity in the nanomolar range. Both enantiomers of this bichalcone were synthesized using an axially chiral biphenol building block. The biaryl bond was forged using Suzuki cross-coupling in water under micellar catalysis conditions. Separation of the atropisomers of this biphenol building block was conducted by chiral HPLC on a preparative scale. The biological evaluation of the enantiomers revealed that the (R a)-enantiomer (R a)-2ab is the eutomer. These studies suggest that bichalcones may be important drug candidates for further in vivo evaluations for the discovery of anti-toxoplasma drugs.

Anomalous h/2e Periodicity and Majorana Zero Modes in Chiral Josephson Junctions.

Recent experiments reported that quantum Hall chiral edge state-mediated Josephson junctions (chiral Josephson junctions) could exhibit Fraunhofer oscillations with a periodicity of either h/e [Vignaud et al., Nature (London) 624, 545 (2023)NATUAS0028-083610.1038/s41586-023-06764-4] or h/2e [Amet et al., Science 352, 966 (2016)SCIEAS0036-807510.1126/science.aad6203]. While the h/e-periodic component of the supercurrent had been anticipated theoretically before, the emergence of the h/2e periodicity is still not fully understood. In this Letter, we systematically study the Fraunhofer oscillations of chiral Josephson junctions. In chiral Josephson junctions, the chiral edge states coupled to the superconductors become chiral Andreev edge states. We find that in short junctions, the coupling of the chiral Andreev edge states can trigger the h/2e-magnetic flux periodicity. Our theory resolves the important puzzle concerning the appearance of the h/2e periodicity in chiral Josephson junctions. Furthermore, we explain that when the chiral Andreev edge states couple, a pair of localized Majorana zero modes appear at the ends of the Josephson junction, which are robust and independent of the phase difference between the two superconductors. As the h/2e periodicity and the Majorana zero modes have the same physical origin in the wide junction limit, the Fraunhofer oscillation period could be useful in identifying the regime with Majorana zero modes.

Pediatric mandibular malignancies: a comprehensive analysis of SEER data.

Mandibular malignancies are rare in the pediatric population and subsequently not well characterized. SEER 18 registry data was collected, applying age 0-18 years and ICD-O-3 code C41.1 ('mandible'). Univariate Cox regression analysis was conducted, and hazard ratios (HR) were calculated for overall survival (OS) and disease-specific survival (DSS) according to patient demographics, tumor characteristics, and treatment. Kaplan-Meier survival curves were generated for OS and DSS. Sixty-four patients met the inclusion criteria. The median age at diagnosis was 13.0 years, and median survival was 8.7 years. Osteosarcoma was the most common histological diagnosis (n = 22). Sex, race, age (<13 vs ≥13 years), histological type, odontogenic origin, and treatment modality were found not to be associated with OS or DSS. The SEER stage 'distant' was significantly associated with an elevated HR of 6.28 for DSS (P = 0.027) and 5.29 for OS (P = 0.025). Kaplan-Meier survival curves demonstrated significantly lower 5-year DSS (P<0.001) and OS (P<0.001) for SEER 'distant' stage. This study includes the analysis of a large number of pediatric mandibular malignancies when compared to previous studies. 'Distant' stage was associated with decreased survival. Early clinical suspicion and diagnosis are paramount for improved survival.

Telemedicine Awareness Among Chennai-Based Dentists: A Web-Based Questionnaire Survey.

OBJECTIVES: Teledentistry has emerged as a crucial tool to address oral health needs amidst social distancing measures and lockdowns. Teledentistry during COVID-19 underscores its potential as an adaptive solution, transforming the delivery of dental care and providing a platform for maintaining oral health while prioritizing public safety. The purpose of this study is to investigate the views of Chennai dental professionals on teledentistry, which may serve as a foundation for advancements in patient care and virtual dentistry in the future, and to evaluate awareness, usefulness, and data security regarding telemedicine among Chennai dental professionals using a pretested questionnaire. METHODS: By distributing a pretested web-based questionnaire to licensed dental professionals in Chennai, a descriptive cross-sectional study was conducted. The results were statistically analyzed and evaluated. RESULTS: A total of 90 dentists in Chennai responded to the questionnaire, out of which 65 (72.2%) were aware of teledentistry and 32 (35.6%) practiced teledentistry. Around 25 to 29 (30%-37%) dentists were very much concerned about obtaining patients' consent, digital forgery, confidentiality, and hardware reliability in teledentistry. CONCLUSION: This is the first kind of study ever done among dentists in Chennai, which shows enormous work is required to create awareness and knowledge among dental professionals. To inform dentists and the general public about teledentistry, targeted advertisements pertaining to the same are required.

Epileptic seizures revealing tuberous sclerosis in a tropical environment: A study of 12 case series.

Background: Epilepsy remains a significant public health concern in Sub-Saharan Africa (SSA) where diverse etiological factors contribute to its prevalence. Among these factors are conditions originating from the neuroectoderm, such as tuberous sclerosis. Insufficient medical attention and a lack of comprehensive multidisciplinary care contribute to its under-recognition. Materials and methods: We conducted a retrospective descriptive study, involving 12 patients admitted to the neurology and pediatric departments of the University Hospital Ignace Deen between 2010 and 2022 due to recurring epileptic seizures. Subsequently, these patients were diagnosed with Tuberous sclerosis using the Schwartz 2007 criteria. The aim of this study is to reassess this condition from a clinical and paraclinical point of view in a tropical environment. Results: Tuberous sclerosis, also known as Bourneville disease, was diagnosed in 12 patients exhibiting focal motor seizures and complex focal seizures likely associated with cortical and subcortical tubers detectable by EEG and neuroimaging, including CT and MRI. Delayed treatment resulted in varying degrees of mental decline. Additionally, some patients displayed cardiac hamartomas and intracranial posterior and anterior aneurysms as minor diagnostic indicators. Conclusion: The study reveals a consistent clinical presentation accompanied by deteriorating neurological and psychological symptoms attributed to delayed multidisciplinary management. These findings are utilized to assess therapeutic strategies and prognostic outcomes.

Glycaemic control and microvascular complications among paediatric type 2 diabetes mellitus patients in Hong Kong at 2 years after diagnosis.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is becoming increasingly common among children and adolescents worldwide, including those in Hong Kong. This study analysed the characteristics and prevalence of microvascular complications among paediatric T2DM patients in Hong Kong at diagnosis and 2 years after diagnosis. METHODS: All patients aged <18 years who had been diagnosed with DM at public hospitals in Hong Kong were recruited into the Hong Kong Childhood Diabetes Registry. Data collected at diagnosis and 2 years after diagnosis were retrospectively retrieved from the Registry for patients diagnosed from 2014 to 2018. RESULTS: Median haemoglobin A1c (HbA1c) levels were 7.5% (n=203) at diagnosis and 6.5% (n=135) 2 years after diagnosis; 59.3% of patients achieved optimal glycaemic control (HbA1c level <7%) at 2 years. A higher HbA1c level at diagnosis was associated with worse glycaemic control at 2 years (correlation coefficient=0.39; P<0.001). The presence of dyslipidaemia (adjusted odds ratio [aOR]=3.19; P=0.033) and fatty liver (aOR=2.50; P=0.021) at 2 years were associated with suboptimal glycaemic control. Diabetic neuropathy and retinopathy were rare in our cohort, but 18.6% of patients developed microalbuminuria (MA) within 2 years after diagnosis. Patients with MA had a higher HbA1c level at 2 years (median: 7.2% vs 6.4%; P=0.037). Hypertension was a risk factor for MA at 2 years, independent of glycaemic control (aOR=4.61; P=0.008). CONCLUSION: These results highlight the importance of early diagnosis and holistic management (including co-morbidity management) for paediatric T2DM patients.

Fate and transport of fragmented and spherical microplastics in saturated gravel and quartz sand.

Microplastics in urban runoff undergo rapid fragmentation and accumulate in the soil, potentially endangering shallow groundwater. To improve the understanding of microplastic transport in groundwater, column experiments were performed to compare the transport behavior of fragmented microplastics (FMPs ∼1-µm diameter) and spherical microplastics (SMPs ∼1-, 10-, and 20-µm diameter) in natural gravel (medium and fine) and quartz sand (coarse and medium). Polystyrene microspheres were physically abraded with glass beads to mimic the rapid fragmentation process. The experiments were conducted at a constant flow rate of 1.50 m day-1 by injecting two pore volumes of SMPs and FMPs. Key findings indicate that SMPs showed higher breakthrough, compared to FMPs in natural gravel, possibly due to size exclusion of the larger SMPs. Interestingly, FMPs exhibited higher breakthrough in quartz sand, likely due to tumbling and their tendency to align with flow paths, while both sizes (larger and smaller relative to FMPs) of SMPs exhibited higher removal in quartz sand. Therefore, an effect due to shape and size was observed.

Multikingdom and functional gut microbiota markers for autism spectrum disorder.

Associations between the gut microbiome and autism spectrum disorder (ASD) have been investigated although most studies have focused on the bacterial component of the microbiome. Whether gut archaea, fungi and viruses, or function of the gut microbiome, is altered in ASD is unclear. Here we performed metagenomic sequencing on faecal samples from 1,627 children (aged 1-13 years, 24.4% female) with or without ASD, with extensive phenotype data. Integrated analyses revealed that 14 archaea, 51 bacteria, 7 fungi, 18 viruses, 27 microbial genes and 12 metabolic pathways were altered in children with ASD. Machine learning using single-kingdom panels showed area under the curve (AUC) of 0.68 to 0.87 in differentiating children with ASD from those that are neurotypical. A panel of 31 multikingdom and functional markers showed a superior diagnostic accuracy with an AUC of 0.91, with comparable performance for males and females. Accuracy of the model was predominantly driven by the biosynthesis pathways of ubiquinol-7 or thiamine diphosphate, which were less abundant in children with ASD. Collectively, our findings highlight the potential application of multikingdom and functional gut microbiota markers as non-invasive diagnostic tools in ASD.