A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small-molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell-cycle, metabolic, and enzymatic assays were used to demonstrate their mechanism of action. A human patient-derived xenograft model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small-molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. Experimental design: We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. Results: We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. Conclusion: This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

Second Data Release from the European Pulsar Timing Array: Challenging the Ultralight Dark Matter Paradigm.

Pulsar Timing Array experiments probe the presence of possible scalar or pseudoscalar ultralight dark matter particles through decade-long timing of an ensemble of galactic millisecond radio pulsars. With the second data release of the European Pulsar Timing Array, we focus on the most robust scenario, in which dark matter interacts only gravitationally with ordinary baryonic matter. Our results show that ultralight particles with masses 10^{-24.0} eV≲m≲10^{-23.3} eV cannot constitute 100% of the measured local dark matter density, but can have at most local density ρ≲0.3 GeV/cm^{3}.

Contamination of microplastics in tropical coral reef ecosystems of Sri Lanka.

Microplastics (MPs) in different marine compartments are a global concern. This study investigated the abundance, distribution, and characteristics of microplastics from ten coral reef ecosystems in Sri Lanka, a non-quantified threat for some context. Microplastics were isolated and quantified in terms of abundance, shape, size, color, and polymer type with average abundances 546.7 ± 170.3 items kg-1, 9.8 ± 7.6 items m-3, and 46.3 ± 29.7 items kg-1 in corals, water, and sediments respectively. The most dominant microplastic type was blue, LDPE fibres. Acropora exhibited the highest amount. The significant differences in average microplastic abundances among corals suggest that they are capable of enriching microplastics depending on species-specific characteristics. Similar microplastic characteristics in corals and reef environment indicate that corals may have enriched microplastics from surface water and surface sediments. Microplastics being ubiquitous in selected reefs highlights the importance of coral reefs as a long-term microplastic sink in the ocean, contributing to the missing plastic phenomena.

Biolayer Interferometry Assay for Cyclin-Dependent Kinase-Cyclin Association Reveals Diverse Effects of Cdk2 Inhibitors on Cyclin Binding Kinetics.

Cyclin-dependent kinases (CDKs) are key mediators of cell proliferation and have been a subject of oncology drug discovery efforts for over two decades. Several CDK and activator cyclin family members have been implicated in regulating the cell division cycle. While it is thought that there are canonical CDK-cyclin pairing preferences, the extent of selectivity is unclear, and increasing evidence suggests that the cell-cycle CDKs can be activated by a pool of available cyclins. The molecular details of CDK-cyclin specificity are not completely understood despite their importance for understanding cancer cell cycles and for pharmacological inhibition of cancer proliferation. We report here a biolayer interferometry assay that allows for facile quantification of CDK binding interactions with their cyclin activators. We applied this assay to measure the impact of Cdk2 inhibitors on Cyclin A (CycA) association and dissociation kinetics. We found that Type I inhibitors increase the affinity between Cdk2 and CycA by virtue of a slowed cyclin dissociation rate. In contrast, Type II inhibitors and other small-molecule Cdk2 binders have distinct effects on the CycA association and dissociation processes to decrease affinity. We propose that the differential impact of small molecules on the cyclin binding kinetics arises from the plasticity of the Cdk2 active site as the kinase transitions between active, intermediate, and inactive states.

Prevalence of asthma and its symptoms in Sri Lankan adults.

BACKGROUND: Data on adult asthma is scarce in Sri Lanka. The objective of this study was to estimate the prevalence of asthma and its symptoms in adult Sri Lankans.  METHODS: A cross-sectional study using a translated version of the European Community Respiratory Health Survey screening questionnaire on subjects ≥ 18 years from 7 provinces in Sri Lanka was conducted. The asthma was defined as "wheezing in the past 12 months (current wheeze)", self-reported asthma attack in the past 12 months or on current asthma medication use. RESULTS: Among 1872 subjects (45.1% males, 48.8% between 18-44 years of age), the prevalence of current wheeze was 23.9% (95%CI: 22.0%-25.9%), self-reported asthma was 11.8% (95%CI: 10.3%-13.2%) and current asthma medication use was 11.1% (95% CI: 9.6%-12.5%). The prevalences were higher in adults > 44 years, 31.4% positively responded to any of the above questions (95%CI: 29.3%-33.4%) and 60.9% of current wheezers did not report having asthma whilst 38.2% used asthma medication. Among current wheezers, 80.1% had at least one other symptom, cough being the commonest. Those with no current wheeze, self-reported asthma and on current asthma medication use, 30%, 35.9% and 36.6%, respectively, reported at least one other symptom. Smokers comprises 22% current wheezers, 20.6% of self-reported asthmatics and 18.7% of current asthma medication users. CONCLUSIONS: The prevalence of asthma in Sri Lankan adults is higher than the other South Asian countries and higher in the older age group. A significant percentage of symptomatic individuals did not report having asthma or being on medication.

Measuring mental well-being in Sri Lanka: validation of the Warwick Edinburgh Mental Well-being Scale (WEMWBS) in a Sinhala speaking community.

BACKGROUND: Well-being is an important aspect of people's lives and can be considered as an index of social progress. The Warwick Edinburgh Mental Well-being scale (WEMWBS) was developed to capture subjective mental well-being. It is a widely tested measure of mental well-being at the population level and has 14 items and a short-form with 7 items. This study was carried out to culturally validate and adapt the WEMWBS among a Sinhala speaking population in Sri Lanka. METHODS: A forward and backward translation of the scale into Sinhala was done followed by a cognitive interview. The translated and culturally adapted scale and other mental health scales were administered to a sample of 294 persons between the ages of 17-73 using a paper-based version (n = 210) and an online survey (n = 84). Internal consistency reliability and test-retest reliability were tested. Construct validity, and convergent and discriminant validity were assessed using the total sample. RESULTS: The translated questionnaire had good face and content validity. Internal consistency reliability was 0.91 and 0.84 for the 14-item and 7-item scales, respectively. Test-retest reliability over two weeks was satisfactory (Spearman r = 0.72 p < 0.001). Confirmatory factor analysis supported a one factor model. Convergent validity was assessed using WHO-5 well-being index (Spearman r = 0.67, p < 0.001), Patient Health Questionnaire (PHQ-9) (Spearman r = (-0.45), p < 0.001) and Kessler psychological distress scale (K10) (Spearman r = (-0.55), p < 0.001). CONCLUSIONS: The translated and culturally adapted Sinhala version of the WEMWBS has acceptable psychometric properties to assess mental well-being at the population level among the Sinhala speaking population in Sri Lanka.

Regional and demographic variations of Carotid artery Intima and Media Thickness (CIMT): A Systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Carotid artery intima media thickness (CIMT) is a strong predictor of Coronary Heart Disease (CHD) and independent phenotype of early atherosclerosis. The global variation of CIMT and its demographic association is yet unclear. We evaluated regional variations of CIMT based on WHO regions and assessed the differences by age and sex. METHODS: A systematic search was conducted on studies published between 1980 January up to December 2020. PubMed, Oxford Medicine Online, EBSCO, Taylor & Francis, Oxford University Press and Embase data bases were used for searching. Supplementary searches were conducted on the Web of Science and Google Scholar. Grey literature was searched in "Open Grey" website. The two major criteria used were "adults" and "carotid intima media". The search strategy for PubMed was created first and then adapted for the Oxford Medicine Online, EBSCO, Taylor & Francis, Oxford University Press and Embase databases. Covidence software (Veritas Health Innovation, Melbourne, Australia; http://www.covidence.org) was used to manage the study selection process. Meta-analyses were done using the random-effects model. An I2 ≥ 50% or p< 0:05 were considered to indicate significant heterogeneity. RESULTS: Of 2847 potential articles, 46 eligible articles were included in the review contributing data for 49 381 individuals (mean age: 55.6 years, male: 55.8%). The pooled mean CIMT for the non-CHD group was 0.65mm (95%CI: 0.62-0.69). There was a significant difference in the mean CIMT between regions (p = 0.04). Countries in the African (0.72mm), American (0.71mm) and European (0.71mm) regions had a higher pooled mean CIMT compared to those in the South East Asian (0.62mm), West Pacific (0.60mm) and Eastern Mediterranean (0.60mm) regions. Males had a higher pooled mean CIMT of 0.06mm than females in the non CHD group (p = 0.001); there were also regional differences. The CHD group had a significantly higher mean CIMT than the non-CHD group (difference = 0.23mm, p = 0.001) with regional variations. Carotid artery segment-specific-CIMT variations are present in this population. Older persons and those having CHD group had significantly thicker CIMTs. CONCLUSIONS: CIMT varies according to region, age, sex and whether a person having CHD. There are significant regional differences of mean CIMT between CHD and non-CHD groups. Segment specific CIMT variations exist among regions. There is an association between CHD and CIMT values.

Tackling increased risks in older adults with intellectual disability and epilepsy: Data from a national multicentre cohort study.

PURPOSE: People with intellectual disabilities (ID) suffer multimorbidity, polypharmacy and excess mortality at a younger age than general population. Those with ID and epilepsy are at higher risk of worse clinical outcomes than their peers without epilepsy. In the ID population the health profile of those aged ≥40 years can be compared to those aged over 65 in the general population. To date there is limited data available to identify clinical characteristics and risk factors in older adults (≥40 years) with ID and epilepsy. METHODS: The Epilepsy in ID National Audit (Epi-IDNA) identified 904 patients with ID and epilepsy from 10 sites in England and Wales. This subsequent analysis of the Epi-IDNA cohort compared the 405 adults over 40 years with 499 adults ≥18 years aged under 40 years. Comparison was made between clinical characteristics and established risk factors using the Sudden Unexpected Death in Epilepsy (SUDEP) and Seizure Safety Checklist. RESULTS: The older adults' cohort had significantly higher levels of co-morbid physical health conditions, mental health conditions, anti-seizure medications (median 5), and antipsychotics compared to the younger cohort. The older group were significantly less likely to be diagnosed with a co-morbid neurodevelopmental disorder, and to have an epilepsy care plan. CONCLUSION: This is the largest study to date focused on adults with ID and epilepsy over 40 years. The ≥40 years cohort compared to the younger group has higher levels of clinical risk factors associated with multi-morbidity, potential iatrogenic harm and premature mortality with worse clinical oversight mechanisms.

An Innovative Telemedicine Initiative From Sri Lanka: The Value of Volunteerism in a Resource-Constrained Scenario During the COVID-19 Pandemic.

The unprecedented rise in COVID-19 cases in Sri Lanka since July 2021 led to a situation where the health system was getting overwhelmed. The priority shifted toward triaging patients and identifying those who need immediate medical intervention and managing the rest in home settings. An integrated patient management system where patients could access a medical professional through a short messages service (SMS) and calling system was established. This service provided telephone triage, patient advice, and coordinated with the national ambulance system to evacuate ill patients. This integrated helpline system had a major impact on the management of the recent surge of COVID-19 pandemic in Sri Lanka by patients needing urgent care were directed for hospitalization and the rest managed at home with support, reassurance, and guidance. The numbers of oxygen-dependent patients and deaths declined rapidly and the number of available beds increased. The system played a major role in bringing the crisis under control. Despite many challenges, this innovative integrated system is a unique example of medical volunteerism. The pandemic catalyzed the utilization of information and communication technologies effectively by providing healthcare with a reduction of the burden on healthcare institutions and professionals.

ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.

The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that the RNase of IRE1α can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1α RNase (PAIRs), that partially antagonize the IRE1α RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix αC in the IRE1α kinase domain. In insulin-producing ß-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1α, captures a desirable conformation for drugging this master UPR sensor/effector.

STANDING SEDATION WITH XYLAZINE AND REVERSAL WITH YOHIMBINE IN JUVENILE ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

Evaluation and improvement of immobilization methods are important for wildlife welfare and biodiversity conservation. The sedative and physiological effects of xylazine (50-110 mg per elephant; 0.09-0.15 mg/kg IM) were evaluated in 15 juvenile Asian elephants (Elephas maximus) in Sri Lanka. The time from xylazine injection until first sign of sedation, handling, and reversal with yohimbine (0.009-0.03 mg/kg IV) were recorded. Behavioral signs, level of sedation (no effect, light, moderate, or deep) and response to handling were assessed. Rectal temperature, pulse, and respiratory rates were recorded and arterial blood samples were analyzed 30 and 45 min after xylazine injection. The first sign of sedation occurred within 5-18 min. Standing sedation was induced in all elephants, but the level of sedation varied differently over time for each elephant. Twelve elephants remained standing throughout the sedation period, while 3 elephants became laterally recumbent. Sedative effects included lowered head and trunk, droopy ears, snoring, and penis protrusion. Pulse rate, respiratory rate, and rectal temperature ranged between 30-45 beats/min, 4-12 breaths/min, and 35.6-37.2°C, respectively, at 30 min after xylazine injection, and there were no changes over time. Pulmonary function and acid-base balance were adequate (range partial pressures of arterial oxygen 73-123 mmHg and carbon dioxide 33-52 mmHg, arterial hemoglobin oxygen saturation 96-99%, pH 7.34-7.54, lactate 0.9-2.5 mmol/L). Yohimbine was administered 46-110 min after the injection of xylazine, and the first sign of recovery occurred within 1-4 min. Resedation after reversal with yohimbine was observed in two elephants. In conclusion, xylazine at the doses used induced light to deep sedation with stable physiology and most elephants remained standing.

Assessing mental well-being in a Sinhala speaking Sri Lankan population: validation of the WHO-5 well-being index.

PURPOSE: The WHO-5 well-being index is a widely used, short rating scale that measures subjective well-being. We translated the WHO-5 index into Sinhala and tested its psychometric properties including measurement invariance among diverse groups in a community sample in Sri Lanka. METHODS: The sample of 267 persons aged between 16 and 75 years was recruited from a semi-urban area. 219 completed a paper-based questionnaire and 48 responded to an online survey. Construct validity was tested for factorial validity (Confirmatory Factor Analysis -CFA), convergent validity and known group validity. Composite reliability for congeneric measures and test-retest reliability were also tested. Multi-group CFA (MG-CFA) was used to test measurement invariance. RESULTS: The translated Sinhala version demonstrated good content and face validity. Internal consistency reliability of the five items had a Cronbach's alpha of 0.85 and test-retest reliability over 2 weeks was satisfactory (Pearson r = 0.72, p < 0.001, ICC = 0.82). Confirmatory factor analysis supported factorial validity with a [Formula: see text] =4.99 (p = 0.28), a RMSEA of 0.03 (90% C.I. =0.00-0.10), a SRMR of 0.02, a TLI of 0.99 and a CFI of 0.99; factor loadings were between 0.55 and 0.89. Measurement invariance was acceptable for configural, metric and scalar invariance for gender. WHO-5 scores were significantly negatively correlated with the Patient Health Questionnaire (PHQ-9) (Pearson's r = - 0.45, p < 0.001) scores and the Kessler Psychological Distress Scale (K10) scores (Pearson's r = - 0.56, p < 0.001). CONCLUSION: The Sinhala translation of WHO-5 well-being index has shown acceptable psychometric properties and can be used for assessing mental well-being in the community in Sri Lanka. Further testing of the measure with larger and diverse (including different ethnic/cultural) groups are indicated to test measurement invariance of the measure.

Corrigendum to "Adsorptive removal of Co(II) in aqueous solutions using clearing nut seed powder" [Heliyon 6 (4) (2020) Article e03684].

[This corrects the article DOI: 10.1016/j.heliyon.2020.e03684.].

Asymmetric mass ratios for bright double neutron-star mergers.

The discovery of a radioactively powered kilonova associated with the binary neutron-star merger GW170817 remains the only confirmed electromagnetic counterpart to a gravitational-wave event1,2. Observations of the late-time electromagnetic emission, however, do not agree with the expectations from standard neutron-star merger models. Although the large measured ejecta mass3,4 could be explained by a progenitor system that is asymmetric in terms of the stellar component masses (that is, with a mass ratio q of 0.7 to 0.8)5, the known Galactic population of merging double neutron-star systems (that is, those that will coalesce within billions of years or less) has until now consisted only of nearly equal-mass (q > 0.9) binaries6. The pulsar PSR J1913+1102 is a double system in a five-hour, low-eccentricity (0.09) orbit, with an orbital separation of 1.8 solar radii7, and the two neutron stars are predicted to coalesce in [Formula: see text] million years owing to gravitational-wave emission. Here we report that the masses of the pulsar and the companion neutron star, as measured by a dedicated pulsar timing campaign, are 1.62 ± 0.03 and 1.27 ± 0.03 solar masses, respectively. With a measured mass ratio of q = 0.78 ± 0.03, this is the most asymmetric merging system reported so far. On the basis of this detection, our population synthesis analysis implies that such asymmetric binaries represent between 2 and 30 per cent (90 per cent confidence) of the total population of merging binaries. The coalescence of a member of this population offers a possible explanation for the anomalous properties of GW170817, including the observed kilonova emission from that event.

COVID-19 and people with intellectual disability: impacts of a pandemic.

The impacts of the COVID-19 pandemic affect all groups in society. People with intellectual disability (ID) are especially vulnerable to the physical, mental and social effects of the pandemic. Cognitive impairments can limit understanding of information to protect them relying on carers to be vigilant on their behalf during quarantine. Restrictions on usual activities are likely to induce mental stress especially among those who are autistic leading to an escalation in challenging behaviours, risk of placement breakdown and increased the use of psychotropic medication. People with ID are vulnerable to exploitation by others where the usual community supports no longer function to protect them. In future pandemics, it is important that lessons are learned from the impacts COVID-19 have on people with ID. Collecting the evidence through a rigorous approach should help to empower people with ID and their carers to face future outbreaks of infectious diseases.

Adsorptive removal of Co(II) in aqueous solutions using clearing nut seed powder.

The present study assessed the potential use of clearing nut seed powder (Strychnos potatorum) as an adsorbent for the removal of Co(II) ions from aqueous solutions. Based on FTIR analysis, the adsorbent possesses hydroxyl, C-N, and C-O functional groups and SEM analysis indicated the presence of uneven porous surface structure, which is important for adsorption. Batch adsorption studies were performed to investigate the effect of contact time, initial pH, initial Co(II) concentration, adsorbent dosage, and temperature on adsorption. The Langmuir isotherm model provided the best explanation to experimental data with the highest correlation coefficient and the maximum monolayer adsorption capacity obtained was 4.245 mg/g. The pseudo-second-order kinetic model fitted well with the adsorption kinetic data. Sorption thermodynamic data showed that the adsorption process is spontaneous and exothermic in nature. The clearing nut seed powder obtained after surface modification by acid treatment showed a higher adsorption capacity.