Evaluation of the CLSI EP26-A protocol for detection of reagent lot-to-lot differences.
Verification of new reagent lots is a required laboratory task. The Clinical and Laboratory Standards Institute (CLSI) EP26-A guideline provides a lot-to-lot verification protocol to detect significant changes in test performance. The aim of this study was to compare the performance of EP26-A with our laboratory reagent lot verification protocol. Prospective evaluations for two reagent lots each for thyroid stimulating hormone (TSH), thyroglobulin (Tg), thyroxine (T4), triiodothyronine (T3), free triiodothyronine (fT3), and thyroid peroxidase antibody (TPOAb) were performed. The laboratory's lot verification process included evaluation of 20 patient samples with the current and new lots and acceptability based on a predefined criteria. For EP26-A, method imprecision data and critical differences based on previously defined lot-to-lot consistency goals were used to define sample size requirements and rejection limits. EP26-A required the following number of samples: 23 for TSH, 17 for Tg, 33 for T4, 31 for T3, 48 for fT3, and 1 for TPOAb. Our current protocol and EP26-A were in agreement in 9 of the 12 (75%) paired verifications. Of the 3 discrepant verifications, Tg and TSH reagent lots were rejected by EP26-A due to significant differences at medical decision points; whereas TPOAb was rejected by the current laboratory protocol. The EP26-A protocol arrived at the same conclusions as our protocol in 75% of the evaluations and required more samples for 4 of the 6 analytes tested. Challenges associated with determining rejection limits and the need for increased sample sizes may be critical factors that limit the utility of EP26-A.


Additive interaction of diabetes mellitus and chronic kidney disease in cancer patient mortality risk.
We investigated the additive interaction of diabetes mellitus (DM) and chronic kidney disease (CKD) on the risk of mortality in cancer patients and evaluated the impact of diabetic kidney disease (DKD) on mortality in cancer patients with DM. We retrospectively analyzed 101,684 cancer patients. A multivariable Cox regression model was used for assessing mortality risk. Relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI) were used to evaluate the additive interactive effect. The adjusted hazard ratio (aHR, 95%CI) for mortality was significant for those with CKD alone (1.53, 1.39-1.68), DM alone (1.25, 1.2-1.3), and both CKD and DM (1.99, 1.84-2.17) compared to non-CKD and non-DM cancer patients. The additive interaction between CKD and DM was significant (RERI 0.22[95%CI = 0.01-0.42], AP 0.11[0.01-0.21], SI 1.28[1.01-1.62]). Among cancer patients with DM, the presence of DKD raised the aHR for mortality (1.55, 95%CI = 1.33-1.81) compared to those without DKD. Coexistence of DM and CKD at the time of cancer diagnosis was significantly associated with an increased risk of mortality, and their interaction exerted an additive interactive effect on mortality. DKD was significantly associated with an increased risk of mortality in cancer patients with DM.


Excimer laser 6(th) generation: state of the art and refractive surgical outcomes.
After nearly three decades of innovation in excimer laser, today we are presented with a state of the art generation targeting minimally invasive refractive surgery with high speed laser, faster trackers, pupil monitoring systems and better customization profiles. These systems are capable of delivering better treatments with less induced postoperative high order aberrations. The results reported by many authors had confirmed the superiority in efficiency and safety profiles of this generation compared to previous generations. Still, current technology is facing major challenges in the correction of high hyperopic errors and in presbyopic treatments, with upgrades in ablation centration and thermal control needed, which will ensure better biomechanical results, as a step closer to perfection in refractive surgery.


AquaClimber: a limbed swimming and climbing robot based on reduced order models.
Many legged robots have taken insight from animals to run, jump, and climb. Very few, however, have extended the flexibility of limbs to the task of swimming. In this paper, we address the study of multi-modal limbed locomotion by extending our lateral plane reduced order dynamic model of climbing to swimming. Following this, we develop a robot, AquaClimber, which utilizes the model's locomotive style, similar to human freestyle swimming, to propel itself through fluid and to climb vertical walls, as well as transition between the two. A comparison of simulation and model results indicate that the simulation can predict how hand design, arm compliance, and driving frequency affect swimming speed and behavior. Using this reduced order model, we have successfully developed the first limbed aquatic-scansorial multi-modal robot.


Application of theory-based health behavior change techniques to the prevention of obesity in children.
Few studies that apply behavior change constructs such as goal setting, self-efficacy, and readiness for change to childhood obesity interventions exist. The purpose of this study was to adapt these constructs for use within a community-based obesity prevention program designed for fifth and sixth graders and their families. Games, worksheets, and a helpful acronym made the constructs developmentally appropriate and comprehensible to 11- and 12-year-olds. The age-adapted techniques have the potential to enhance obesity programs in a population for whom the obesity issue is critical.


Extending the duration of treatment with progesterone and equine chorionic gonadotropin improves fertility in suckled beef cows with low body condition score subjected to timed artificial insemination.
The objective of this study was to evaluate the effect of an extended progesterone treatment on follicular development and fertility in postpartum, suckled beef cows subjected to timed artificial insemination (TAI). In experiment 1, cows (n = 24) with body condition score (BCS) ≥4.5 received either a 2-g progesterone intravaginal device on Day -23 or a 0.558-g progesterone intravaginal device on Day -9. Then, all cows received 2 mg of estradiol benzoate on Day -9; removal of the device, 1-mg estradiol cypionate, and PGF2α on Day -2; and TAI on Day 0. Metabolic status was assessed between Days -9 and -2. Ovarian structures and plasma progesterone were determined weekly from Day -23 to -9, daily from Day -9 to 0, and weekly until Day 28. In experiment 2, cows (n = 302) with BCS ≥4.5 received identical treatment to cows in experiment 1, but on Day -2, cows received 400 IU of two different commercial preparations of equine chorionic gonadotropin (eCG). Ovarian structures were determined on Days -23 and -9 on a subset of cows (n = 40). Pregnancy was determined 39 days after TAI. In experiment 3, multiparous cows (n = 244) with BCS <5.0 received identical treatment as cows in experiment 1 initiated on Day -18, and on Day -2, cows received 400 IU of eCG or no treatment. Ovarian structures were determined in a subset of cows (n = 31) on Days -3, -2, -1, 0, 1, and on Day 10. Pregnancy was determined 39 days after TAI. The results indicated that in experiment 1, plasma progesterone was higher in treated than nontreated (control cows) during the first 14 days (P = 0.0001). The extended progesterone treatment increased the size of the largest follicle between Days -23 and Day -5 (Group by Day, P = 0.04) and tended to increase the size of the dominant follicle from Day -5 to Day -1 (Group by Day, P = 0.06). There was no effect of metabolic status or interaction between metabolic status and day on follicular growth. In experiment 2, extended progesterone treatment tended to increase the size of the largest follicle between Day -23 and -9 (P = 0.06). There was no effect of Group, eCG, BCS, and parity on pregnancy per AI. In experiment 3, extended progesterone treatment combined with eCG increased the size of the dominant follicle (P = 0.01). Both extended progesterone treatment (P = 0.02) and eCG (P = 0.03) increased pregnancy per AI. In conclusion, an extended progesterone treatment stimulated follicular growth postpartum and improved fertility only in cows with low BCS.


In situ blood-brain barrier permeability of a C-10 paclitaxel carbamate.
We report the synthesis and blood-brain barrier (BBB)-permeability of (14)C-CNDR-29, a paclitaxel C-10 carbamate derivative shown to be devoid of P-glycoprotein (Pgp)-interactions, in an in situ mouse brain perfusion model, in comparison with (14)C-paclitaxel. The results presented reveal a 3- to 4-fold higher BBB-permeability for the C-10 modified taxane compared to paclitaxel. These results support the notion that circumvention of Pgp-mediated efflux can lead to higher BBB-permeability. Further studies however are needed to evaluate the therapeutic potential of the C-10 carbamates paclitaxel derivatives for the treatment of CNS diseases.


Regulation of peroxisome proliferator-activated receptor gamma on milk fat synthesis in dairy cow mammary epithelial cells.
Peroxisome proliferator-activated receptor gamma (PPARγ) participates in lipogenesis in rats, goats, and humans. However, the exact mechanism of PPARγ regulation on milk fat synthesis in dairy cow mammary epithelial cells (DCMECs) remains largely unexplored. The aim of this study was to investigate the role of PPARγ regarding milk fat synthesis in DCMECs and to ascertain whether milk fat precursor acetic acid and palmitic acid could interact with PPARγ signaling to regulate milk fat synthesis. For this study, we examined the effects of PPARγ overexpression and gene silencing on cell growth, triacylglycerol synthesis, and the messenger RNA (mRNA) and protein expression levels of genes involved in milk fat synthesis in DCMECs. In addition, we investigated the influences of acetic acid and palmitic acid on the mRNA and protein levels of milk lipogenic genes and triacylglycerol synthesis in DCMECs transfected with PPARγ small interfering RNA (siRNA) and PPARγ expression vector. The results showed that when PPARγ was silenced, cell viability, proliferation, and triacylglycerol secretion were obviously reduced. Gene silencing of PPARγ significantly downregulated the expression levels of milk fat synthesis-related genes in DCMECs. PPARγ overexpression improved cell viability, proliferation, and triacylglycerol secretion. The expression levels of milk lipogenic genes were significantly increased when PPARγ was overexpressed. Acetic acid and palmitic acid could markedly improve triacylglycerol synthesis and upregulate the expression levels of PPARγ and other lipogenic genes in DCMECs. These results suggest that PPARγ is a positive regulator of milk fat synthesis in DCMECs and that acetic acid and palmitic acid could partly regulate milk fat synthesis in DCMECs via PPARγ signaling.


Step-Controlled Povarov-Type Reaction with 1,2-Dihydroquinolines as Precursors of Dienophiles: Direct Synthesis of Spirocyclic Bi-tetrahydroquinolines and Functionalized 1,2-Dihydroquinolines.
A novel Povarov-type reaction for straightforward synthesis of novel spiro bi-tetrahydroquinolines with readily available 1,2-DHQs (1,2-dihydroquinolines) and aromatic imines was developed. The reaction could be selectively stopped at the first stage under a Brønsted acid catalyst to afford the corresponding functionalized 1,2-DHQs conveniently.


Stem cell aging: The upcoming era of proteins and metabolites.
So far, the investigation of stem cell aging has been primarily carried out at the genomic level to follow transcriptome changes, clonal dominance, epigenetic changes, and, more recently, population heterogeneity by single cell sequencing. Here, we review recent findings in the field of stem cell aging that include failure of proteostasis, the impact of age-related metabolic changes on stem cell differentiation and heterogeneity of stem cell niches. These emerging concepts highlight the need of a paradigm shift to move forward our understanding of stem cell aging to the next level, in particular, the need of investigating cell intrinsic changes in stem cells and their niche by looking in a quantitative manner to proteins and metabolites.


Efficient Inhibition of Bacterial Biofilm Through Interference of Protein-Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis.
Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein-protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR-SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein-protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens.


C-Arm for accurate reduction of zygomatic arch fracture--a case report.
Fracture of the zygomatic arch is usually treated using blind methods. As the fracture lines cannot be visualised directly in closed reduction, digital exploration and crepitus noise or conventional radiographic imaging are used clinically as a guide to reposition the fragments. Successful closed reductions are often difficult to evaluate clinically because of the great amount of swelling that often accompanies these fractures. Postoperative radiographs are often the only way to assess the adequacy of the reduction. This article describes a technique that uses the C-Arm to quickly and accurately evaluate the reduction intraoperatively so that appropriate corrections can be made. A case report of a patient who suffered a w-shaped depressed fracture of the left zygomatic arch and zygomatico-maxillary complex fracture is presented.


Intranasal recombinant human erythropoietin protects rats against focal cerebral ischemia.
Erythropoietin (EPO) is a hematopoietic growth factor with tissue-protective properties, and can protect animals from cerebral ischemic injury. However, the central nervous effects of EPO as a glycoprotein is limited by the potential complication resulted from its erythropoietic activity and the problem of the penetration through blood-brain barrier (BBB). To avoid these limitations, in this study we administered recombinant human EPO (rhEPO) intranasally (i.n.) to evaluate its neuroprotective effect in the rats with focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). We found that rhEPO i.n. at doses of 4.8, 12 and 24 U (administered 10 min after MCAO and 1h after reperfusion) reduced infarct volume, brain swelling and cell damage in the ischemic hemispheres, and improved behavioral dysfunction 24 h after cerebral ischemia. Intraperitoneal rhEPO (5000 U/kg) also showed the protective effect, but the heat-inactivated rhEPO did not show any effect. Thus, intranasal administration of relatively small doses of rhEPO protects rats from acute injury after focal cerebral ischemia, suggesting that intranasal rhEPO may be a more effective and safer administration route for treatments of ischemic or other brain diseases.


Identification of a new polymorphism on the wild-type canine distemper virus genome: could this contribute to vaccine failures?
The canine distemper virus (CDV) is responsible for a multisystem infectious disease with high prevalence in dogs and wild carnivores and has vaccination as the main control measure. However, recent studies show an increase in cases including vaccinated dogs in different parts of the world. There are several reasons for vaccine failures, including differences between vaccine strains and wild-type strains. In this study, a phylogenetic analysis of CDV strains from samples of naturally infected, vaccinated, and symptomatic dogs in Goiânia, Goiás, Brazil was performed with partial sequencing of the hemagglutinin (H) gene of CDV. Different sites of amino acid substitutions were found, and one strain had the Y549H mutation, typically present in samples from wild animals. Substitutions in epitopes (residues 367, 376, 379, 381, 386, and 388) that may interfere with the vaccine's ability to provide adequate protection against infection for CDV were observed. The identified strains were grouped in the South America 1/Europe lineage, with a significant difference from other lineages and vaccine strains. Twelve subgenotypes were characterized, considering a nucleotide identity of at least 98% among the strains. These findings highlight the relevance of canine distemper infection and support the need better monitoring of the circulating strains that contribute to elucidate if there is a need for vaccine update.


Base editing for reprogramming cyanobacterium Synechococcus elongatus.
Cyanobacteria can directly convert carbon dioxide (CO2) at the atmospheric level to biofuels, value-added chemicals and food products, making them ideal candidates to alleviate global climate change. Despite decades-long pioneering successes, the development of genome-editing tools, especially the CRISPR-Cas-based approaches, seems to lag behind other microbial chassis, slowing down the innovations of cyanobacteria. Here, we adapted and tailored base editing for cyanobacteria based on the CRISPR-Cas system and deamination. We achieved precise and efficient genome editing at a single-nucleotide resolution and demonstrated multiplex base editing in the model cyanobacterium Synechococcus elongatus. By using the base-editing tool, we successfully manipulated the glycogen metabolic pathway via the introduction of premature STOP codons in the relevant genes, building engineered strains with elevated potentials to produce chemicals and food from CO2. We present here the first report of base editing in the phylum of cyanobacteria, and a paradigm for applying CRISPR-Cas systems in bacteria. We believe that our work will accelerate the metabolic engineering and synthetic biology of cyanobacteria and drive more innovations to alleviate global climate change.


Management of non-melanoma skin cancer.
To review types of, and treatment for, non-melanoma skin cancer (NMSC): basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and less common NMSC. Standards of care, dermatology texts, peer-reviewed journals. BCC grows slowly and rarely metastasizes; some BCC subtypes can be aggressive and destructive. Early treatment of SCC is usually successful; untreated SCC will penetrate underlying tissue, invade lymph nodes, and metastasize. Treatment options for NMSC are based on patient and tumor characteristics, which determine whether a lesion is low or high risk for cancer recurrence after treatment. Nurses are integral for educating patients about measures to prevent new skin cancers and for monitoring for recurrence of NMSC.


In-vitro antiplatelet effect of melatonin in healthy individuals and patients with type 2 diabetes mellitus.
The incidence of acute myocardial infarctions (AMI) shows circadian variation typically peaking during morning hours with a decline at night. However, this variation does not occur in patients with diabetes mellitus (DM). The night's decline of AMI may be partially explained by melatonin-related platelet inhibition. Whether this effect is absent in diabetic patients is unknown. The aim was to study the effect of melatonin on in-vitro platelet aggregation in healthy individuals and patients with type 2 DM. Platelet aggregation was measured in blood samples from healthy individuals (n = 15) and type 2 DM patients (n = 15) using multiple electrode aggregometry. Adenosine diphosphate (ADP), arachidonic acid (ASPI) and thrombin (TRAP) were used as agonists. Aggregability for each subject was tested after adding melatonin in two concentrations. In healthy individuals, melatonin inhibited platelet aggregation in both higher (10-5 M) and lower concentrations (10-9 M) induced by ADP, ASPI, and TRAP (p < 0.001, p = 0.002, p = 0.029, respectively). In DM patients, melatonin did not affect platelet aggregation in both concentrations induced by ADP, ASPI, and TRAP. Melatonin decreased platelet aggregation induced by ADP, ASPI, and TRAP significantly more in healthy individuals compared to patients with DM. (p = 0.005, p = 0.045 and p = 0.048, respectively). Platelet aggregation was inhibited by melatonin in healthy individuals. In-vitro antiplatelet effect of melatonin in type 2 DM patients is significantly attenuated.


Helper T Cell 17 and Regulatory T Cell Levels in Peripheral Blood of Newly Diagnosed Patients with Autoimmune Thyroid Disease: A Meta-Analysis.
This article aims to explore associated immune indicators of autoimmune thyroid disease (AITD) through a meta-analysis of published case-control studies on newly diagnosed AITD patients, intending to provide some suggestions for research on the mechanisms of AITD. Six electronic databases were searched for case-control studies on newly diagnosed AITD patients from inception to August 15, 2022. A random-effects model was used to calculate the standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (95% CI). A total of 26 articles were included in this meta-analysis. Patients with newly diagnosed AITD had higher levels of helper T cell 17 (Th17) (Hashimoto's disease (HT): SMD=2.35, 95% CI: 1.98, 2.72; Graves' disease (GD): SMD=1.61, 95% CI: 1.23, 1.98), lower levels of regulatory T cell (Treg) (HT: SMD=-2.04, 95% CI: -2.67, -1.42; GD: SMD=-1.35, 95% CI: -2.11, -0.58), and lower levels of forkhead box P3 (FoxP3) mRNA (HT: SMD=-2.58, 95% CI: -3.12, -2.05; GD: SMD=-2.13, 95% CI: -2.56, -1.70), compared to the healthy population. In addition, the single nucleotide polymorphism rs3761548 and rs3761549 in the promoter region of FoxP3 showed a higher frequency in the comparison of genotype "CT" only in HT patients than in the healthy population (OR=1.66, 95%CI: 1.18, 2.34). In patients with newly diagnosed AITD, the Th17/Treg ratio imbalance may develop AITD. Monitoring Th17 and Treg levels may become an essential tool to assess the organism's immune homeostasis and hopefully guide clinical diagnosis and treatment.


Methylation of satellite DNA.
The lower amount of 5 methylcytosine in DNA from bull sperm relative to DNA of other bovine tissues is a result of the absence of this minor base from several of the satellite DNAs in sperm. This applies particularly to the 1.715, 1.711b and 1.709 satellites and less so to the 1.706 and 1.711a satellites. Mouse sperm DNA is also partially undermethylated.


Dominant-lethal study of technical-grade hexachlorocyclohexane in Swiss mice.
Male Swiss mice, 6-8 weeks old, were given a diet containing technical-grade hexachlorocyclohexane (BHC) at 500 ppm continuously for 4, 6 and 8 months. After the completion of the scheduled exposure period, the males were sequentially mated with 2-3 untreated virgin females at weekly intervals for 8 weeks. The females were autopsied at mid-term pregnancy for evaluation of dominant-lethal mutation. The number of dead implants, including deciduomas and dead embryos, showed a significant increase. Similarly, the percentage fertility and live embryos per female showed a decline when compared with the control


Effects of MHRA drug safety advice on time trends in prescribing volume and indices of clinical toxicity for quinine.
To ascertain the effects of the Medicines and Healthcare products Regulatory Agency's (MHRA) safety update in June 2010 on the volume of prescribing of quinine and on indices of quinine toxicity. We analysed quarterly primary care total and quinine prescribing data for England and quinine prescribing volume for individual Primary Care Trusts in the North East of England from 2007/8 to 2011/12 obtained from the ePACT.net database. We also analysed quinine toxicity enquiries to the National Poisons Information Service (NPIS) via Toxbase(®) and by telephone between 2004/5 and 2011/12. Joinpoint regression and Pearson's correlation tests were used to ascertain changes in trends in prescribing and indices of toxicity and associations between prescribing and indices of toxicity, respectively. Total prescribing continued to increase, but annual growth in quinine prescribing in England declined from 6.0 to -0.6% following the MHRA update [difference -0.04 (95% confidence interval -0.07 to -0.01) quinine prescriptions per 100 patients per quarter, P = 0.0111]. Much larger reductions were observed in Primary Care Trusts that introduced comprehensive prescribing reviews. The previously increasing trend in Toxbase(®) quinine searches was reversed [difference -19.76 (95% confidence interval -39.28 to -9.20) user sessions per quarter, P = 0.0575]. Telephone enquiries to NPIS for quinine have declined, with stabilization of the proportion of moderate to severe cases of quinine poisoning since the update. The MHRA advice was followed by limited reductions in the growth in quinine prescribing and in indicators of quinine overdose and toxicity. Quinine prescribing, however, remains common, and further efforts are needed to reduce availability and use.


Deficient Novelty Detection and Encoding in Early Alzheimer's Disease: An ERP Study.
Patients with early Alzheimer's disease (AD) have difficulty in learning new information and in detecting novel stimuli. The underlying physiological mechanisms are not well known. We investigated the electrophysiological correlates of the early (< 400 ms), automatic phase of novelty detection and encoding in AD. We used high-density EEG Queryin patients with early AD and healthy age-matched controls who performed a continuous recognition task (CRT) involving new stimuli (New), thought to provoke novelty detection and encoding, which were then repeated up to 4 consecutive times to produce over-familiarity with the stimuli. Stimuli then reappeared after 9-15 intervening items (N-back) to be re-encoded. AD patients had substantial difficulty in detecting novel stimuli and recognizing repeated ones. Main evoked potential differences between repeated and new stimuli emerged at 180-260 ms: neural source estimations in controls revealed more extended MTL activation for N-back stimuli and anterior temporal lobe activations for New stimuli compared to highly familiar repetitions. In contrast, AD patients exhibited no activation differences between the three stimulus types. In direct comparison, healthy subjects had significantly stronger MTL activation in response to New and N-back stimuli than AD patients. These results point to abnormally weak early MTL activity as a correlate of deficient novelty detection and encoding in early AD.


Determination of phenylalanine in river water by high-performance liquid chromatography.
The use of o-phthalaldehyde derivatisation of phenylalanine followed by high-performance liquid chromatography with fluorescence detection as used for amino acid analysis in clinical laboratories was examined to assess its suitability for the monitoring of river pollution by the dairy industry by measuring the phenylalanine levels in river water. The method is described together with its statistical evaluation.


Expediting knowledge acquisition by a web framework for Knowledge Graph Exploration and Visualization (KGEV): case studies on COVID-19 and Human Phenotype Ontology.
Knowledges graphs (KGs) serve as a convenient framework for structuring knowledge. A number of computational methods have been developed to generate KGs from biomedical literature and use them for downstream tasks such as link prediction and question answering. However, there is a lack of computational tools or web frameworks to support the exploration and visualization of the KG themselves, which would facilitate interactive knowledge discovery and formulation of novel biological hypotheses. We developed a web framework for Knowledge Graph Exploration and Visualization (KGEV), to construct and visualize KGs in five stages: triple extraction, triple filtration, metadata preparation, knowledge integration, and graph database preparation. The application has convenient user interface tools, such as node and edge search and filtering, data source filtering, neighborhood retrieval, and shortest path calculation, that work by querying a backend graph database. Unlike other KGs, our framework allows fast retrieval of relevant texts supporting the relationships in the KG, thus allowing human reviewers to judge the reliability of the knowledge extracted. We demonstrated a case study of using the KGEV framework to perform research on COVID-19. The COVID-19 pandemic resulted in an explosion of relevant literature, making it challenging to make full use of the vast and heterogenous sources of information. We generated a COVID-19 KG with heterogenous information, including literature information from the CORD-19 dataset, as well as other existing knowledge from eight data sources. We showed the utility of KGEV in three intuitive case studies to explore and query knowledge on COVID-19. A demo of this web application can be accessed at http://covid19nlp.wglab.org . Finally, we also demonstrated a turn-key adaption of the KGEV framework to study clinical phenotypic presentation of human diseases by Human Phenotype Ontology (HPO), illustrating the versatility of the framework. In an era of literature explosion, the KGEV framework can be applied to many emerging diseases to support structured navigation of the vast amount of newly published biomedical literature and other existing biological knowledge in various databases. It can be also used as a general-purpose tool to explore and query gene-phenotype-disease-drug relationships interactively.


Sargassum blooms in the East China Sea and Yellow Sea: Formation and management.
Large-scale Sargassum blooms, known as golden tides, have been occurring along the coast of the Yellow Sea in recent years, resulting in an enormous loss of Pyropia yezoensis production. To locate the source of the blooms, we performed large-scale spatio-temporal sampling in the South Yellow Sea, East China Sea, and Jeju Island, South Korea. Based on morphology and molecular traits, the attached and floating Sargassum samples collected from the three regions were all identified as Sargassum horneri, although slight differences were observed in morphology among samples. Genetic distance and automatic barcode gap discovery analysis revealed very low genetic diversity among the three regions. The 33 samples from 12 sites were divided into six haplotypes, and the samples from the ECS shared more haplotypes than samples from other two regions. Our results suggested that S. horneri in the ECS was responsible for the formation of blooms in the Yellow Sea.


Special Issue: "Computational Mechanics of Structures and Materials".
Computational methods have always affected many engineering fields due to their enormous potential and ability to facilitate various tasks [...].


Frontal 'oculomotor' area in alert cat. II. Unit discharges associated with eye movements and neck muscle activity.
(1) Unit activity in front 'oculomotor' cortex was recorded extracellularly from sites where subsequent electrical stimulation, using threshold current (50 microamperes), could elicit both eye movements and simultaneous neck EMG acitivity. (2) Of 103 cells, 19% were related to either eye movements or neck EMG activity. Cells could be grouped into three categories: (a) Directional (D) cells (31%) discharged before and during saccadic eye movements, whenever the eyes followed a target in one specific direction. Spontaneous saccades, or vestibularly driven nystagmus, in either the light or dark, elicited no responses. (b) Conditionally directional (CD) cells (43%) discharged following (i) tracking saccades; (ii) spontaneous saccades and (iii) the quick phase of nystagmus, in all directions. There usually was a slight discharge preference for one given direction, and this preference was enhanced whenever visual tracking was restricted to the preferred direction. One-third of CD cells responded to stimulation of the contralateralal biventer cervicis neck muscle (min lat. 20 msec). (c) Neck EMG (N) cells (26%) discharged in association with, and preceding, changes in neck muscle activity. These cells also responded to stimulation of the contralateral biventer cervicis muscle (min lat. 10 msec). (3) For points in the lateral 'oculomotor' region (as defined by stimulation: see ref. 17), the directions of evoked saccades, and the directions of spontaneous saccades associated with unit discharges, were sililar. In the medial region 17, the directions of evoked saccades were roughly opposite to the directions of spontaneous eye movements favoured by unit discharges.


Influence of blue light on effective removal of arsenic by photosynthetic bacterium Rhodobacter sp. BT18.
Arsenic (As) contamination in an ecosystem has been a serious threat for the ecosystem as well as human health. Thus, the present study was established an eco-friendly remediation of As by using As resistant Rhodobacter sp. Accordingly, the growth of Rhodobacter sp. in As stress environment was assessed. Expectedly, enhanced growth order of the Rhodobacter sp., under As stress was found to be control >50 > 100 > 200 > 300 > 400 > 500 mg/L of As. In addition, the present study explored the influence of various light sources (Yellow, light blue, red, green and white) on growth and As removal mechanisms of Rhodobacter sp. The growth profile of the bacteria indicated that the light blue source showed an enhanced growth at 72 h of incubation. Based on optimization experiments, an increased As removal percentage rate was found to be at 87.5% at pH 7.0, 3% of glucose, 1% of citrate supplemented in the medium. The As resistant genetic pattern for arsenic transformation, the genes arsenate reductase (arsC), arsenite oxidase (aio) was investigated. To study the transcript level expression of arsC and aio genes were performed after exposure to different concentrations of As (50, 100, 150, and 200 mg/L) at different time intervals (24, 48, 72 and 96 h). The results showed that both arsC and aio were up regulated from 24 to 72 h and the down regulation was observed at 96 h. The obtained results indicated that the Rhodobacter sp., possess significant AS tolerance and removal potential would make it is a noteworthy candidate for future As remediation practices.


Pharmacokinetic effects of vigabatrin on cerebrospinal fluid amino acids in humans.
A study was conducted to assess the impact of single dosing and different dosing intervals of vigabatrin [gamma vinyl GABA (GVG)] in 11 patients with drug-resistant complex partial seizures. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), GVG, and 5-hydroxyindolacetic acid were measured up to seven days after a single dose. GVG levels were maximal within 24 h, suggesting that GVG acts to inhibit GABA-transaminase, and may also increase biogenic amines.


Critical assessment of methods of protein structure prediction (CASP)--round 6.
This article is an introduction to the special issue of the journal Proteins, dedicated to the sixth CASP experiment to assess the state of the art in protein structure prediction. The article describes the conduct of the experiment and the categories of prediction included, and outlines the evaluation and assessment procedures. A brief summary of progress over the decade of CASP experiments is also provided.


Validation of the functional fitness age (FFA) index in older Japanese women.
Functional fitness age (FFA), which we previously described, is a measure of functional age that reflects a person's overall physical ability to complete daily tasks such as preparing meals and performing various household chores. The purpose of this study was to validate FFA in two elderly populations: 1) older subjects from different communities, and 2) older subjects participating in an exercise intervention program. FFA was calculated from 4 performance tests: performing arm curls; moving beans with chopsticks; demonstrating functional reach; and sitting and walking around two cones. The first study group was selected from 4 different communities (N=127), and was subdivided into a less active group (N=87) and an active group (N=40). The results of the 4 tests for the less active group were not significantly different from those for the original validation group used in developing the FFA equation. The FFA of the less active group (71.1+/-7.7 yrs) was not different from their chronological age (70.4+/-6.6 yrs). In the active group, except for the arm curls, test scores were significantly higher than those of the original validation group. The FFA of the active group (66.2+/-5.1 yrs) was significantly younger than their chronological age (70.9+/-4.2 yrs). Another group of 14 older women (79.5+/-3.9 yrs) was recruited for pre- and post-training testing. After the 3-month exercise program, they showed significant improvements in sitting and walking around two cones and functional reach; their FFA decreased significantly from 81.5+/-5.0 yrs to 78.3+/-4.5 yrs. The control group selected from the same community (N=16, 79.8+/-5.3 yrs) showed no significant changes in the 4 performance tests, and their FFA remained unchanged. These results indicate that our FFA is highly cross-validated for different Japanese communities, and is sensitive to changes associated with participation in an exercise intervention program.


Current management of gestational trophoblastic neoplasia.
Gestational trophoblastic neoplasms are malignant lesions that arise from placental villous and extravillous trophoblast. Four clinicopathologic conditions make up this entity: invasive mole (IM), choriocarcinoma (CCA), placental-site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). IM and CCA, which make up the majority of these tumors, are highly responsive to chemotherapy with an overall cure rate exceeding 90%, making it usually possible to achieve cure while preserving reproductive function. PSTT and ETT, which rarely occur, are relatively resistant to chemotherapy, making surgery the primary treatment modality, chemotherapy being used only when the disease has metastasized.


A Pilot Study on the FEST program - Friendship and Emotional Skills Training for Children on the Autism Spectrum.
Social skills difficulties among children on the autism spectrum can impede social, emotional, and academic development, especially with increasing age and social demands. This pilot study examined the efficacy of a 5-week skill-building program for children on the autism spectrum. Although effective social skills programs are available for adolescents with autism spectrum disorder (ASD), very few programs are explicitly intended for 10-12-year-old children. This pilot study examined the efficacy of the 9-session Friendship and Emotional Skills Training (FEST Program) for children with ASD without intellectual disability. Participants were 22 children randomly assigned to the FEST Program or a delayed intervention control group. Eleven children (boys = 8; girls = 3) received the FEST Program in two separate groups, and 11 were wait-listed for a delayed intervention. Parents, teachers, and the children answered questionnaires at baseline, post-intervention, and a 3-month follow-up. Upon completing the FEST Program (post-intervention), parents reported an increase in overall social skills (on the Social Skills Rating System - SSRS) and a reduction on the Autistic Mannerisms factor (on the Social Responsiveness Scale - SRS) compared to the control group. These changes were also maintained at the 3-month follow-up. The children's assessment also showed a significant increase in assertion (on the SSRS) post-intervention. Teachers also reported a significant reduction on the Autistic Mannerisms factor at the 3-month follow-up. The findings suggest that the FEST Program shows some promising results as one possibility for supporting children with ASD and their families in everyday life.


[3H]N-methyl-carbamylcholine, a new radioligand specific for nicotinic acetylcholine receptors in brain.
The present study characterized the binding of [3H]N-methyl-carbamylcholine ([3H]methyl-carbachol), a new radioligand, to rat cerebral cortex membranes and demonstrated the autoradiographic distribution of these sites in rat brain. With atropine used to block muscarinic acetylcholine sites and nicotine to define non-specific binding, [3H]methyl-carbachol bound specifically, saturably and with high affinity (Kd = 11.0 nM, Bmax = 118.4 fmol/mg protein and Hill coefficient = 0.92) to a population of presumably nicotinic sites in cerebral cortex membranes. When nicotine was used to block nicotinic acetylcholine sites and atropine to define non-specific binding there was no specific binding of [3H]methyl-carbachol (concentrations up to 45 nM) to possible muscarinic sites in cerebral cortex membranes. The binding parameters under non-selective conditions (without blockade of either muscarinic or nicotinic acetylcholine sites) had very similar values to those obtained under nicotinic conditions (Kd = 8.0 nM, Bmax = 125.0 fmol/mg protein and Hill coefficient = 0.98). [3H]Methyl-carbachol binding was potently inhibited by nicotinic agonists and antagonists but only poorly displaced by muscarinic agents. Autoradiographic studies evidenced high densities of [3H]methyl-carbachol binding sites in the interpeduncular nucleus, various thalamic nuclei, superior colliculus and layers III/IV of the cortex. Such a distribution was very similar to those previously reported for nicotinic acetylcholine sites and other radioligands. These results suggest that [3H]methyl-carbachol is a specific radioligand of the neuronal nicotinic receptor. Its stability and high selectivity constitute distinct advantages over previously used nicotinic radioligands such as acetylcholine and nicotine.


Spatiotemporal variability in salinity and hydraulic relationship with salt intrusion in the tidal reaches of the Minjiang River, Fujian Province, China.
Salinity is one of the most important factors for tidal-affected water bodies including estuaries and tidal river reaches. However, due to the limitations of simultaneous manual monitoring in long-distance areas, studies of estuaries are preferred to tidal reaches. Hence, in this study, we investigated the tidal reach of the Minjiang River and five sets of field observations were used to determine the influence of saltwater intrusion in different seasons. During the dry and wet season with low discharge, the longitudinal salinity profiles showed that a station located about 45 km from the river mouth still suffered from saltwater intrusion especially when the upstream discharge was under 754 m3 s-1, where the periodical fluctuation in the salinity remained the same with the water level, but there was a time lag of approximately 4 h compared with the discharge process. However, during the wet season in April and May 2016, the monitored salinity was approximately at the detectable limit of 0.02-0.04 ppt at the station close to the river mouth, which indicated that there was no saltwater exchange into the river, although dual flow directions were observed in the survey periods. The major differences among five survey periods were mainly related to upstream discharge rather than the seasons, the tidal range, and tidal excursion. The conclusions of this study have strategic importance for protecting water sources by guiding the government to assess the optimal freshwater release time and discharge rate to prevent saltwater entering the important tidal-affected river reaches.


[Laparocentesis in emergency abdominal surgery].
The results of 180 diagnostic punctures of the abdomen after the A. N. Berkutov technic are reported (120--for abdominal trauma and 60-- for acute diseases). Indications to laparocentesis in urgent surgery of the abdomen are presented.


Plasmin generation plays different roles in the formation and removal of arterial and venous thrombus in mice.
The role of plasminogen (Plg) and alpha2-antiplasmin (alpha2-AP) in vascular thrombolysis in vivo was investigated in mice deficient in plasminogen (Plg-/-) or a2-AP (alpha2-AP-/-) or their wild type (PAI-1+/+, alpha2-AP+/+). A thrombus was induced in the murine carotid artery or the internal jugular vein by endothelial injury. Blood flow was continuously monitored for 90 min and for 6 h 30 min after the initiation of endothelial injury. The times to occlusion by the developing thrombus in the carotid artery and the jugular vein of wild type mice were 12+/-1.8 and 7.2+/-1.9 min, respectively. The arterial thrombus formation in alpha2-AP-/- mice was indistinguishable from the one in wild type mice, whereas the time to occlusion in Plg-/- was significantly shortened to 5.9+/-1.7 min. Vascular patency after spontaneous reperfusion was markedly improved in alpha2-AP-/- mice. On the contrary, arteriarpatency in Plg-/- mice was aggravated. In venous thrombus formation, the time to occlusion in alpha2-AP-/- mice was significantly prolonged (27.1+/-5.2 min), whereas in Plg-/- it was slightly shortened to 6.5+/-2.5 min. Vascular patency after spontaneous reperfusion was also improved in alpha2-AP-/- mice, but not in Plg-/- mice. Histological observations using SEM indicated that fibrin nets were firmly fixed on the injured area in Plg-/- mice, but not in alpha2-AP-/- mice. The tail bleeding time was not different in any type of mice. However, re-bleeding time using a template bleeding device was significantly prolonged in alpha2-AP-/- as compared with that of wild type mice. In conclusion, lack of plasminogen markedly reduces the antithrombotic activities in vivo, whereas alpha2-AP plays a more important role in the formation and removal of venous thrombus in mice. Consequently, the inhibition of alpha2-AP could be a useful tool for the therapy of venous thrombosis and the prevention of re-thrombus formation.


Perception of exertion in the elderly, effects of aging, mode of exercise and physical training.
Ratings of perceived exertion by the Borg psychophysical scale have been made on 26 men and 30 women aged 60 to 70 yr. All were volercise lines relating the ratings of exertion to heart rate were closely similar in men and women, scores at all heart rates being 2 or 3 units higher than in young adults. A brief progressive exercise protocol on the treadmill yielded somewhat lower ratings than bicycle ergometer work, the discrepancy being marked in women. At any given oxygen intake, ratings were higher for females than malesy nd higher for old than young subjects. However, when oxygen intake was expressed as a percentage of the directly measured maximum oxygen intake, scores became independent of sex and age. A 35-wk. period of conditioning substantially reduced heart rates but had little effect on the perception of effort at a given work load. This unexpected result may reflect a closer approximation of core and skin temperatures with reduction of sub-cutaneous fat.


CRISPR-Cas9 Mediated Telomere Removal Leads to Mitochondrial Stress and Protein Aggregation.
Aging is considered the major risk factor for neurodegenerative diseases including Parkinson's disease (PD). Telomere shortening is associated with cellular senescence. In this regard, pharmacological or genetic inhibition of telomerase activity has been used to model cellular aging. Here, we employed CRISPR-Cas9 technology to instantly remove the telomere to induce aging in a neuroblastoma cell line. Expression of both Cas9 and guide RNA targeting telomere repeats ablated the telomere, leading to retardation of cell proliferation. Instant deletion of telomere in SH-SY5Y cells impaired mitochondrial function with diminished mitochondrial respiration and cell viability. Supporting the pathological relevance of cell aging by CRISPR-Cas9 mediated telomere removal, alterations were observed in the levels of PD-associated proteins including PTEN-induced putative kinase 1, peroxisome proliferator-activated receptor γ coactivator 1-α, nuclear respiratory factor 1, parkin, and aminoacyl tRNA synthetase complex interacting multifunctional protein 2. Significantly, α-synuclein expression in the background of telomere removal led to the enhancement of protein aggregation, suggesting positive feed-forward interaction between aging and PD pathogenesis. Collectively, our results demonstrate that CRISPR-Cas9 can be used to efficiently model cellular aging and PD.


De-escalating axillary surgery in early-stage breast cancer.
The role of axillary surgery has evolved over the last three decades from routine axillary lymph node dissection (ALND) to sentinel lymph node biopsy to omission of axillary surgery altogether in select patients. This evolution has been achieved through the design and conduct of multiple clinical trials demonstrating that ALND does not impact survival and is not necessary for local control in patients with early-stage breast cancer and limited nodal involvement. Importantly, this practice-changing shift mirrored the trend towards earlier stage at diagnosis and the recognition of the interplay between local and systemic therapies in maintaining local control. There are numerous clinical scenarios today in which axillary staging can be safely avoided, including (1) DCIS treated with lumpectomy, (2) at the time of contralateral prophylactic mastectomy, and (3) in elderly patients with early-stage, HR+/HER2-clinically node-negative (cN0) disease. Ongoing clinical trials seek to expand the cohorts in which surgical nodal staging can be omitted. These populations include a broader range of early-stage, cN0 patients undergoing upfront surgery, as seen in the SOUND, INSEMA, BOOG 2013-08, SOAPET and NAUTILUS trials. Omission of axillary surgery in cN0 patients with HER2+ or triple-negative disease treated with neoadjuvant chemotherapy is also being tested in the ASICS and EUBREAST-01 trials. Continued advances in imaging and the growing role of genomic assays in selecting patients for systemic therapy are likely to further minimize the need for axillary surgery; thereby further reducing the morbidity of local therapy for women with breast cancer.


Effectiveness and mechanism of cyanide remediation from contaminated soils using thermally activated persulfate.
Persulfate (PS)-based advanced oxidation processes have been frequently employed for contaminant remediation, but the effectiveness of PS oxidation for the elimination of cyanide-bearing contaminants from soil, and the underlying mechanisms, have rarely been explored. This study investigated the degradation of two iron-cyanide (Fe-CN) complexes (ferricyanide and ferrocyanide) with thermally activated PS via two remediation strategies, namely one-step oxidation (direct PS oxidation) and two-step oxidation (alkaline extraction followed by PS oxidation). The two-step oxidation process was more effective for the elimination of cyanide pollutants from soil, reaching >94% remediation efficiency for both Fe-CN complexes studied. The presence of dissolved soil components, especially soil organic matter, increased consumption of PS during the remediation process. A combined analysis based on electron paramagnetic resonance (EPR), free radical scavenging, and degradation product identification revealed that SO4- and HO were the principal reactive radicals responsible for Fe-CN degradation. Based on the determination of radical species and identification of decomposition products, a transformation pathway for Fe-CN complexes during thermally activated PS oxidation is proposed. Overall, this study demonstrates the effectiveness of the thermally activated PS oxidation technique for cyanide elimination from polluted soil. Further study is required to verify the feasibility of this method for field applications.


A further assessment of bladder transection in the management of adult enuresis and allied conditions.
The use of bladder transection for the management of adult enuresis and allied conditions is reported. The beneficial effects of the operation, assessed by an improvement of symptoms and measured objectively by urodynamic investigation, have been found to be maintained during 4 years' experience of the procedure.


Giardia intestinalis: electrophoretic evidence for a species complex.
The technique of allozyme electrophoresis was applied to 29 Australasian stocks and 48 clones of Giardia intestinalis from humans as a means of increasing the number of genetic markers currently available for identification and classification. Fifty different enzymes were examined and of these 26 loci were found to be suitable for use as genetic markers. The data indicate the presence of four discrete genetic groups within the sample of G. intestinalis examined. The groups had fixed genetic differences at 23-69% of loci established. The evidence suggests that G. intestinalis is a species complex. The results have important implications for the systematics of human isolates of Giardia, as well as for studies on the epidemiology and demography of giardiasis in Australia and elsewhere.


Studies of RNA isolated from Piptoporus betulinus as interferon inducer.
Crude RNA isolated from Piptoporus betulinus and two fractions of it obtained after the chromatography contain single-stranded RNA. The crude RNA, but not its chromatographic fractions, are resistant to the pancreatic RNA-ase. The crude preparation of RNA from P. betulinus contains beside ribose, considerable amounts of glucose, galactose and mannose. The crude RNA from P. betulinus induces in the human fibroblasts interferon with specific activity of 400 units per mg of protein.


Effects of oral administration of Stephania tetrandra S. Moore on neovascularization of retinal and choroidal capillaries of diabetes in rats.
In rats, an injection of streptozotocin (STZ) elevated blood levels of glucose 4 weeks later (STZ-induced diabetes) and an over-production of microvessels of retinal and choroidal capillaries of eyes developed. A previous study has shown that administration of Stephania tetrandra S. Moore (STSM) in culture prevented the over-production of microvessels of those capillaries of STZ-induced diabetes in vitro. Therefore, the study investigated whether or not orally administered STSM could inhibit over-production of microvessels of those capillaries of STZ injected rats in vivo. When STSM was given at the same time as the STZ injection and continued daily for 7 weeks, STSM prevented the elevation of blood glucose level and over-production of microvessels of those capillaries. When STSM was given after elevation of blood glucose level of glucose (4 weeks after STZ injection) and continued daily for 4 weeks, STSM lowered the elevated blood glucose level but had no effect on the over-production of microvessels of those capillaries. It was inferred that deposition of N(epsilon)(carboxymethyl) lysine in retinal and choroidal tissues, which is induced by STZ-induced diabetes may deteriorate the blood-retinal barrier and the blood-choroidal barrier. One might, therefore, speculate that advanced STZ-induced diabetes may deteriorate the blood-retinal barrier and blood-choroidal barrier. Therefore, STSM may not reach the retinal and choroidal tissues in the posterior ocular region in vivo.


Synthesis and anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid against B16F10 cells via induction of endoplasmic reticulum stress-mediated autophagy through ERK/AKT signaling pathway.
Melanoma is an aggressive form of cancer with poor prognosis and survival rates and limited therapeutic options. Here, we report the anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid (NPC-402), a derivative of glycyrrhtinic acid, from a reputed medicinal plant Glycyrrhiza glabra against B16F10 cells. We studied the cytotoxic effect of NPC-402 on melanoma cells and investigated the role of mitogen-activated protein (MAP) kinase, AKT axis, and endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated autophagy as the involved signaling cascade by studying specific marker proteins. In this study, 4-phenylbutyric acid (4PBA, a chemical chaperone) and small interference RNA (siRNA) knockdown of C/EBP Homologous Protein (CHOP)/growth arrest- and DNA damage-inducible gene 153(GAD153) blocked NPC-402-mediated autophagy induction, thus confirming the role of ER stress and autophagy in melanoma cell death. NPC-402 induced oxidative stress and apoptosis in melanoma cells, which were effectively mitigated by treatment with N-acetylcysteine (NAC). In vivo studies showed that intraperitoneal (i.p.) injection of NPC-402 at 10 mg/kg (5 days in 1 week) significantly retarded angiogenesis in the Matrigel plug assay and reduced the tumor size and tumor weight without causing any significant toxic manifestation in C57BL/6J mice. We conclude that NPC-402 has a high potential to be developed as a chemotherapeutic drug against melanoma.


Bioinformatics approach to analyse COVID-19 biomarkers accountable for generation of intracranial aneurysm in COVID-19 patients.
COVID-19 became a health emergency on January 30, 2020. SARS-CoV-2 is the causative agent of the coronavirus disease known as COVID-19 and can develop cardiometabolic and neurological disorders. Intracranial aneurysm (IA) is considered the most significant reason for hemorrhagic stroke,and it accounts for approximately 85% of all subarachnoid hemorrhages (SAH). Retinoid signaling abnormalities may explain COVID-19's pathogenesis with inhibition of AEH2, from which COVID-19 infection may enhance aneurysm formation and rupture due to abrupt blood pressure changes, endothelial cell injury, and systemic inflammation. The objective of this study was to investigate the potential biomarkers, differentially expressed genes (DEGs), and metabolic pathways associated with both COVID-19 and intracranial aneurysm (IA) using simulation databases like DIsGeNET. The purpose was to confirm prior findings and gain a comprehensive understanding of the underlying mechanisms that contribute to the development of these conditions. We combined the regulated genes to describe intracranial aneurysm formation in COVID-19. To determine DEGs in COVID-19 and IA patient tissues, we compared gene expression transcriptomic datasets from healthy and diseased individuals. There were 41 differentially expressed genes (DEGs) shared by both the COVID-19 and IA datasets (27 up-regulated genes and 14 down-regulated genes). Using protein-protein interaction analysis, we were able to identify hub proteins (C3, NCR1, IL10RA, OXTR, RSAD2, CD38, IL10RB, MX1, IL10, GFAP, IFIT3, XAF1, USP18, OASL, IFI6, EPSTI1, CMPK2, and ISG15), which were not described as key proteins for both COVID-19 and IA before. We also used Gene Ontology analysis (6 significant ontologies were validated), Pathway analysis (the top 20 were validated), TF-Gene interaction analysis, Gene miRNA analysis, and Drug-Protein interaction analysis methods to comprehend the extensive connection between COVID-19 and IA. In Drug-Protein interaction analysis, we have gotten the following three drugs: LLL-3348, CRx139, and AV41 against IL10 which was both common for COVID-19 and IA disease. Our study with different cabalistic methods has showed the interaction between the proteins and pathways with drug analysis which may direct further treatment development for certain diseases.


Optogenetics enlightens neuroscience drug discovery.
Optogenetics - the use of light and genetics to manipulate and monitor the activities of defined cell populations - has already had a transformative impact on basic neuroscience research. Now, the conceptual and methodological advances associated with optogenetic approaches are providing fresh momentum to neuroscience drug discovery, particularly in areas that are stalled on the concept of 'fixing the brain chemistry'. Optogenetics is beginning to translate and transit into drug discovery in several key domains, including target discovery, high-throughput screening and novel therapeutic approaches to disease states. Here, we discuss the exciting potential of optogenetic technologies to transform neuroscience drug discovery.


[The lethal alcohol intoxications and deaths due to severe drunkenness in North Slovakia regions (1994-1996, 2003-2005): a medicolegal comparative study].
The authors performed the complex analysis of the mortuary files (since 1994 to 1996 and 2003 to 2005) with particular focusing on the cases of deaths caused by alcohol intoxication, and the cases of deaths where an alcohol played the dominating role, in the northern regions of Slovak republic. Based on the analysis mentioned, authors point out the continuous rise of alcohol abuse, followed by the fatal consequences for human beings. The authors are to express the urgent need of public discussion concerning the alcohol consumption in Slovakia; the phenomenon being widely tolerated by the society, thus leading to the number of social tragedies even in 21st century.


The Latin American Spanish version of the Face-Name Associative Memory Exam is sensitive to cognitive and pathological changes in preclinical autosomal dominant Alzheimer's disease.
To determine whether performance on the Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) can differentiate between cognitively intact carriers of an autosomal dominant Alzheimer's disease mutation (E280A) in Presenilin-1, who are genetically determined to develop early-onset dementia, from matched non-carriers. We also sought to examine whether LAS-FNAME performance is associated with amyloid-β and regional tau burden in mutation carriers. A total of 35 cognitively intact mutation carriers (age range 26-41), 19 symptomatic carriers, and 48 matched non-carriers (age range 27-44) completed a neuropsychological assessment including the LAS-FNAME. A subset of participants (31 carriers [12 symptomatic] and 35 non-carriers) traveled from Colombia to Boston to undergo positron emission tomography (PET) using Pittsburgh compound B to measure mean cortical amyloid-β and flortaucipir for regional tau. ANOVA analyses and Spearman correlations were used to examine group differences and relationships among LAS-FNAME performance and amyloid-β and tau accumulation. Compared to non-carriers, cognitively intact mutation carriers had lower scores on the LAS-FNAME Total Scores (p = .040). Across all carriers (including symptomatic carriers), higher levels of amyloid-β (r = - .436, p = .018) and regional tau in the entorhinal (r = - .394, p = .031) and inferior temporal cortex (r = - .563, p = .001) were associated with lower LAS-FNAME Total Scores. Performance on the LAS-FNAME differentiated between cognitively intact mutation carriers from non-carriers and was associated with greater amyloid and tau burden when examining all carriers. Findings suggest that the LAS-FNAME is sensitive to early clinical and pathological changes and can potentially help track disease progression in Spanish-speaking individuals.


Long-term follow-up of photochemotherapy in pityriasis lichenoides.
Five patients with a histopathologically confirmed diagnosis of pityriasis lichenoides were treated with PUVA or irradiated with a light source emitting UVB and UVA, without prior intake of psoralens. All patients showed a good response to treatment. Long-term follow up showed that patients remained free of lesions during a period of 20 to 36 months; 3 patients had a recurrence of the disease, though less extensive than before, after 25, 23, and 23 months, respectively.


Effects of continuous lighting or continuous darkness on large granulated vesicles in sympathetic nerve fibers of the mouse pineal--quantitative electron microscopic observations.
The influence of continuous light or darkness on the large granulated vesicles in sympathetic nerve fibers of the mouse pineal was investigated by means of quantitative electron microscopic techniques. Continuous illumination at about 20 lux caused the disappearance of the diurnal rhythm in the number of the large granulated vesicles, followed by an accumulation of these vesicles. The diurnal rhythm of the large granulated vesicles was abolished in mice kept in continuous darkness for 7 days. These results suggest that the diurnal variation of the large granulated vesicles may be controlled directly by environmental light. Based on these findings, the relationships between small and large granulated vesicles were discussed.


Plasma amyloid-beta oligomer is related to subjective cognitive decline and brain amyloid status.
Subjective cognitive decline (SCD) is a target for Alzheimer's disease prediction. Plasma amyloid-beta oligomer (AβO), the pathogenic form of Aβ in blood, has recently been proposed as a novel blood-based biomarker of AD prediction by representing brain Aβ deposition. The relationship between plasma AβO, brain Aβ deposition, and SCD in individuals with normal objective cognition has not been investigated. In this cross-sectional study, we analyzed 126 participants with normal objective cognition. More SCD symptoms were expressed as higher scores of the Subjective Cognitive Decline Questionnaire (SCDQ) and Memory Age-associated Complaint Questionnaire (MACQ). The plasma AβO level of each participant was measured twice for validation and expressed as a concentration (ng/mL) and a ratio relative to the mean value of two internal standards. Brain Aβ deposition was assessed by [18F] flutemetamol positron emission tomography (PET) and expressed as standard uptake value ratio (SUVR). Associations of SCDQ and MACQ with plasma AβO levels or SUVR were analyzed in multiple linear regression models. The association between plasma AβO level and flutemetamol PET positivity was assessed in logistic regression and receiver operative characteristic analyses. Overall, participants were 73.3 years old with female predominance (69.0%). After adjustment for confounders, high SCDQ and MACQ scores were associated with the high plasma AβO levels as both concentrations and ratios (ratios: standardized coefficient = 0.246 and p = 0.023 for SCDQ, standardized coefficient = 0.209 and p = 0.029 for MACQ; concentrations: standardized coefficient = 0.257 and p = 0.015 for SCDQ, standardized coefficient = 0.217 and p = 0.021 for MACQ). In contrast, SCDQ and MACQ were not significantly associated with SUVRs (p = 0.134 for SCDQ, p = 0.079 for MACQ). High plasma AβO levels were associated with flutemetamol PET (+) with an area under the curve of 0.694 (ratio) or 0.662 (concentration). Combined with APOE e4, plasma AβO presented area under the curves of 0.789 (ratio) and 0.783 (concentration). Our findings indicate that the high plasma AβO level could serve as a potential surrogate biomarker of severe SCD and the presence of brain Aβ deposition in individuals with normal objective cognition.


The effect of ischemia/reperfusion on rabbit bladder--role of Rho-kinase and smooth muscle regulatory proteins.
To detect the effect of ischemia/reperfusion (I/R) injury on rabbit bladder, using physiological study and immunoblotting techniques. Twelve male New Zealand White rabbits were separated into three groups of 4 rabbits each. Group 1 served as control. Group 2 rabbits (ischemia-alone group) underwent in vitro bilateral ischemia surgery for 2 hours. In group 3 (I/R group), bilateral ischemia was similarly induced, and the rabbits were allowed to recover for 2 weeks. The contractile responses to electrical field stimulation, adenosine triphosphate, carbachol, and KCl were recorded. Expression levels of the signaling targets, Rho-kinase (ROK), protein kinase C potentiated inhibitor (CPI-17), caldesmon (CaD), and calponin (CaP) were analyzed by Western blotting. Ischemia alone resulted in significant reductions in the contractile responses, whereas I/R resulted in further decreases after all forms of stimulation. In muscle layer, ROK expression increased immediately after ischemia and recovered to the control level after 2 weeks' recovery. However, in mucosa layer, ROK expression showed no significant change after ischemia but significantly increased after reperfusion. After ischemic damage, CPI-17, the functional protein involved in smooth-muscle Ca(2+) sensitization, was significantly increased and then decreased after 2 weeks of reperfusion. The expression of CaP significantly increased after ischemia and decreased after reperfusion. Levels of high-molecular-weight CaD significantly decreased after ischemia and remained very low after reperfusion. This study provides further understanding of the role of regulatory proteins in detrusor muscle after ischemia and I/R-induced contractile dysfunction.


Parental periconceptional smoking and male: female ratio of newborn infants.
We assessed whether the smoking habits of parents around the time of conception affects the likelihood of the offspring being male or female. We found that the offspring sex ratio (male to female) was lower when either one or both of the parents smoked more than 20 cigarettes per day compared with couples in which neither of the parents smoked. We found the lowest sex ratio among children whose mothers and fathers both smoked more than 20 cigarettes per day (p<0.0001). Parental periconceptional smoking might be a contributing factor to a lower male to female sex ratio of offspring.


Crohn's disease in the Jewish population of Tel-Aviv-Yafo. Epidemiologic and clinical aspects.
A survey of the incidence and prevalence of Crohn's disease in the Jewish population of Tel-Aviv-Yafo was carried out from 1970 to 1976. The annual incidence rate was 1.28, and the prevalence was 12.31 per 10(5) population. The prevalence of 16.69 per 10(5) population among Ashkenazi jews was significantly higher than that found in "non-Ashkenazi" Jews, 4.19 per 10(5) population. Even so, Crohn's disease is significantly less common in Tel-Aviv than outside Israel, according to most recently published surveys. Similarly, the complication, surgery, and mortality rate are less marked than those reported from other studies. These figures confirm the authors' impression that inflammatory bowel disease in general is less common and possible less severe in Tel-Aviv than in the United State and Western Europe. The strikingly higher prevalence in the Ashkenazi community, especially in the Israeli-born population, suggests a hereditary predisposition. The apparent differences among Askhenazi Jews in various parts of the world may relate to environmental factors.


Alternative splicing: new insights from global analyses.
Recent analyses of sequence and microarray data have suggested that alternative splicing plays a major role in the generation of proteomic and functional diversity in metazoan organisms. Efforts are now being directed at establishing the full repertoire of functionally relevant transcript variants generated by alternative splicing, the specific roles of such variants in normal and disease physiology, and how alternative splicing is coordinated on a global level to achieve cell- and tissue-specific functions. Recent progress in these areas is summarized in this review.


Effects of an Atractylodes lancea rhizome extract and a volatile component β-eudesmol on gastrointestinal motility in mice.
The rhizomes of Atractylodes lancea DC (Compositae) are used clinically to treat gastrointestinal symptoms, including functional dyspepsia and gastroparesis, in China and Japan, but their influence and mechanism on gastrointestinal motility are not yet proven in detail. This study examined the effects of an Atractylodes lancea extract, and isolated β-eudesmol, on gastric emptying and small intestinal motility in atropine-, dopamine-, and 5-hydroxytryptamine (5-HT)-treated mice. The extract (500 or 1000mg/kg) and β-eudesmol (50 or 100mg/kg), as well as itopride hydrochloride (a dopamine D(2) receptor antagonist, 10 or 50mg/kg), stimulated small intestinal motility in normal mice. They inhibited reductions in gastric emptying and gastrointestinal motility induced by dopamine (1mg/kg, intraperitoneal injection, ip). The extract (1000mg/kg) and β-eudesmol (100mg/kg) inhibited the atropine-induced decrease in small intestinal motility, but not gastric emptying. Furthermore, the extract (500 or 1000mg/kg) and β-eudesmol (25, 50, or 100mg/kg) inhibited reductions in gastric emptying and small intestinal motility caused by 5-HT (4mg/kg, ip) or the 5-HT(3) receptor agonist 1-(3-chlorophenyl) biguanide (0.5mg/kg, ip), but not a 5-HT(2C) receptor agonist. These findings suggest that the extract of Atractylodes lancea and β-eudesmol may stimulate gastric emptying or small intestinal motility by inhibiting the dopamine D(2) receptor and 5-HT(3) receptor.


Accelerated Premalignant Polyposis and Second Colon Cancers: Incriminating Immunosuppression, Radiotherapy, and Systemic Chemotherapy Agents.
Cancer survivors are known to be at increased risk for second primary cancers. In addition, immunosuppression and previous cancer treatments such as radiotherapy and systemic chemotherapy are linked with increased risk of both colonic adenomas and adenocarcinomas. We performed a systematic review searching for manuscripts discussing second colon cancers, accelerated polyposis, immunosuppression, radiation, and chemotherapy. We sought to identify a link between immunosuppression and increased risks specific to premalignant polyposis and second colon cancers. We identified multiple studies demonstrating associations between radiotherapy, systemic chemotherapy, and immunosuppression with a higher propensity for second colon adenomas and adenocarcinomas. When compared to the general population, these risks were more profound and the rate at which these second malignancies developed was significantly increased. We believe that timing for colonoscopic surveillance in these patients should be different from the general population in order to identify promptly these rapidly progressive neoplasms. Screening for second malignancies should be considered early after remission of the primary cancer is documented, especially when a prolonged survival or a cure is anticipated. We also recommend consideration be given to increasing the frequency of colonoscopy in these cohorts. Future studies are required in order to establish the optimal time interval for surveillance colonoscopy in these high-risk individuals.


Pain intensity influences the relationship between anger management style and depression.
There is an abundance of studies concerning depression and pain, while the mechanisms and the relationships of anger expression and pain are less well known. The validity of commonly used depression questionnaires as measures of depression in pain patients has been questioned, as they include items which can be related to the pain problem as well as to signs of depression. The aim of this study was to investigate the relationships between pain severity, various signs of depression, and anger management style. Subjects were 100 consecutive patients referred to the Helsinki University Pain Clinic. Demographic data and pain intensity (VAS) were collected by a questionnaire. Two subscales (negative view and physical function) from the Beck Depression Inventory, and the Anger Expression Scales (Anger-in and Anger-out) from the Spielberg State Trait Anger Expression Inventory 2 were used to assess depression and anger expression, respectively. The results showed that pain severity modulates the relationship between anger expression and physical signs of depression. In patients with more severe pain, the relationships between anger management style, specifically, inhibition of anger and depression were strong, while no such relationships were found in the group of patients with less severe pain. No correlations were found between pain intensity and depression as measured by the sum score of the BDI. However, analysing separately the two subscales of the BDI, negative view and physical function, significant positive relationships between pain intensity and both subscales appeared.


Presence of the cofactor speeds up folding of Desulfovibrio desulfuricans flavodoxin.
Flavodoxin is an alpha/beta protein with a noncovalently bound flavin-mononucleotide (FMN) cofactor. The apo-protein adopts a structure identical to that of the holo-form, although there is more dynamics in the FMN-binding loops. The equilibrium unfolding processes of Azotobacter vinelandii apo-flavodoxin, and Desulfovibrio desulfuricans ATCC strain 27774 apo- and holo-flavodoxins involve rather stable intermediates. In contrast, we here show that both holo- and apo-forms of flavodoxin from D. desulfuricans ATCC strain 29577 (75% sequence similarity with the strain 27774 protein) unfold in two-state equilibrium processes. Moreover, the FMN cofactor remains bound to the unfolded holo-protein. The folding and unfolding kinetics for holo-flavodoxin exhibit two-state behavior, albeit an additional slower phase is present at very low denaturant concentrations. The extrapolated folding time in water for holo-flavodoxin, approximately 280 microsec, is in excellent agreement with that predicted from the protein's native-state topology. Unlike the holo-protein behavior, the folding and unfolding reactions for apo-flavodoxin are best described by two kinetic phases, with rates differing approximately 15-fold, suggesting the presence of a kinetic intermediate. Both folding phases for apo-flavodoxin are orders of magnitude slower (40- and 530-fold, respectively) than that for the holo-protein. We conclude that polypeptide-cofactor interactions in the unfolded state of D. desulfuricans strain 29577 flavodoxin alter the kinetic-folding path towards two-state and speed up the folding reaction.


A case of esomeprazole-induced transient diabetes and hepatitis: the role of liver inflammation in the pathogenesis of insulin resistance.
We describe a case report of a patient who developed transient type 2 diabetes after a drug-induced (esomeprazole) sub-acute hepatitis. This case evidences the pathophysiological relevance, also in humans, of liver inflammation in the pathogenesis of type 2 diabetes.


[Gains associated with caring for people with dementia: an Spanish adaptation of the GAIN scale].
The aim of this research is to translate and validate the GAIN scale into Spanish, and test its relationship with a set of variables related to caregivers and the caregiving situation. Responses to a sociodemographic questionnaire and to the GAIN scale were obtained from a sample made up of 140 caregivers of people with dementia. In order to analyze the psychometric properties of the scale, its reliability and factorial structure were tested, and the contribution of every single item to its internal consistency was estimated, as well as their standard deviation and their discrimination index. Descriptive procedures were performed to examine the responses of the caregivers to the different items of the scale, and their overall score on this. The relationship between this variable and their age, sex, marital status, educational level, religiosity and health status was also determined, along with the length of the care provided and the number of hours per day and days per week devoted to it, as well as the type of relationship existing between caregiver and care receiver. The GAIN scale proved to be unidimensional, and showed a high reliability (Cronbach's Alpha=.872). This value did not improve by eliminating any of its items. Almost all the items reached high discrimination indexes (>.50) and a high standard deviation (>1). The mean score on the scale was 28.10 (range from 0 to 40), and 96.4% of the caregivers ascribed at least one gain to their role. Scores on the scale were not significantly associated with any of the studied variables, except caregivers' religiosity, suggesting that those caregivers with more intense religious feelings might find more gains in their role. Gains appear to be a common experience among most caregivers, and the psychometric properties of the validated version of the GAIN scale suggest that it constitutes a suitable instrument for their evaluation.


Ralstonia solanacearum lipopeptide induces chlamydospore development in fungi and facilitates bacterial entry into fungal tissues.
Ralstonia solanacearum is a globally distributed soil-borne plant pathogenic bacterium, which shares a broad ecological range with many plant- and soil-associated fungi. We sought to determine if R. solanacearum chemical communication directs symbiotic development of polymicrobial consortia. R. solanacearum produced a diffusible metabolite that induced conserved morphological differentiation in 34 species of fungi across three diverse taxa (Ascomycetes, Basidiomycetes and Zygomycetes). Fungi exposed to this metabolite formed chlamydospores, survival structures with thickened cell walls. Some chlamydospores internally harbored R. solanacearum, indicating a newly described endofungal lifestyle for this important plant pathogen. Using imaging mass spectrometry and peptidogenomics, we identified an undescribed lipopeptide, ralsolamycin, produced by an R. solanacearum non-ribosomal peptide synthetase-polyketide synthase hybrid. Inactivation of the hybrid non-ribosomal peptide synthetase-polyketide synthase gene, rmyA, abolished ralsolamycin synthesis. R. solanacearum mutants lacking ralsolamycin no longer induced chlamydospore development in fungal coculture and invaded fungal hyphae less well than wild-type. We propose that ralsolamycin contributes to the invasion of fungal hyphae and that the formation of chlamydospores may provide not only a specific niche for bacterial colonization but also enhanced survival for the partnering fungus.


RACK1 Mediates NLRP3 Inflammasome Activation by Promoting NLRP3 Active Conformation and Inflammasome Assembly.
The NLRP3 inflammasome, a critical component of the innate immune system, induces caspase-1 activation and interleukin (IL)-1β maturation in response to microbial infection and cellular damage. However, aberrant activation of the NLRP3 inflammasome contributes to the pathogenesis of several inflammatory disorders, including cryopyrin-associated periodic syndromes, Alzheimer's disease, type 2 diabetes, and atherosclerosis. Here, we identify the receptor for activated protein C kinase 1 (RACK1) as a component of the NLRP3 complexes in macrophages. RACK1 interacts with NLRP3 and NEK7 but not ASC. Suppression of RACK1 expression abrogates caspase-1 activation and IL-1β release in response to NLRP3- but not NLRC4- or AIM2-activating stimuli. This RACK1 function is independent of its ribosomal binding activity. Mechanistically, RACK1 promotes the active conformation of NLRP3 induced by activating stimuli and subsequent inflammasome assembly. These results demonstrate that RACK1 is a critical mediator for NLRP3 inflammasome activation.


Rod and cone a-waves in central retinal vein occlusion.
To evaluate rod and cone a-waves in cases with unilateral central retinal vein occlusion (CRVO). Scotopic and photopic flash electroretinograms (ERGs) were recorded in seven patients aged 54-84 with unilateral hemorrhagic CRVO. Rod and cone a-waves were analyzed using photoreceptor models, and Rm(p3) (maximum a-wave amplitude) and S (sensitivity) were calculated. Decreased rod log S was found in all seven cases, and decreased cone log S was found in five cases. In only one case, rod log S in the fellow eye was decreased. The alterations in rod and cone log Rm(p3) were smaller than those in rod and cone log S. Of three cases in which ERGs could be recorded again after a certain follow-up period, rod log S and cone logS became larger in two cases and smaller in one case. The change in the phototransduction cascade was confirmed not only in rods but also in cones in five of our seven cases of CRVO. The ERG findings might reflect the functional change in the photoreceptor layer after the onset of CRVO.


Repolarization features as detectable from electrograms and electrocardiograms.
This contribution discusses the feasibility of extracting the major features of repolarization: its spatio-temporal behaviour, and how much of its global or local behaviour might be deduced from signals that can be observed experimentally. The analysis presented is based on source-volume-conductor configurations ranging from the classic cable theory, with sources derived from reaction diffusion computations, to a realistic thorax model comprising a whole heart model with electric sources represented by the equivalent electric double layer. The analysis focuses on the fact that the local activation recovery interval (ARI) at regions activated by expanding wave fronts is significantly longer than those activated by contracting ones. The consequences of this effect on observed magnitude and wave form of recorded signals are illustrated.


Senescent cell accumulation mechanisms inferred from parabiosis.
Senescent cells are growth-arrested cells that cause inflammation and play a causal role in aging. They accumulate with age, and preventing this accumulation delays age-related diseases. However, the mechanism for senescent cell accumulation is not fully understood. Accumulation can result from increasing production or decreasing removal of senescent cells with age, or both. To distinguish between these possibilities, we analyze data from parabiosis, the surgical conjoining of two mice so that they share circulation. Parabiosis between a young and old mouse, called heterochronic parabiosis, reduces senescent cell levels in the old mouse, while raising senescent cell levels in the young mouse. We show that parabiosis data can reject mechanisms for senescent cell accumulation in which only production rises with age or only removal decreases with age; both must vary with age. Since removal drops with age, senescent cell half-life rises with age. This matches a recent model for senescent cell accumulation developed from independent data on senescent cell dynamics, called the SR model, in which production rises linearly with age and senescent cells inhibit their own removal. The SR model further explains the timescales and mechanism of rejuvenation in parabiosis, based on transfer of spare removal capacity from the young mouse to the old. The present quantitative understanding can help design optimal treatments that remove senescent cells, by matching the time between treatments to the time it takes senescent cells to re-accumulate.


The Paediatric AirWay Suction (PAWS) appropriateness guide for endotracheal suction interventions.
Endotracheal suction is an invasive and potentially harmful technique used for airway clearance in mechanically ventilated children. Choice of suction intervention remains a complex and variable process. We sought to develop appropriate use criteria for endotracheal suction interventions used in paediatric populations. The RAND Corporation and University of California, Los Angeles Appropriateness Method was used to develop the Paediatric AirWay Suction appropriateness guide. This included defining key terms, synthesising current evidence, engaging an expert multidisciplinary panel, case scenario development, and two rounds of appropriateness ratings (weighing harm with benefit). Indications (clinical scenarios) were developed from common applications or anticipated use, current practice guidelines, clinical trial results, and expert consultation. Overall, 148 (19%) scenarios were rated as appropriate (benefit outweighs harm), 542 (67%) as uncertain, and 94 (11%) as inappropriate (harm outweighs benefit). Disagreement occurred in 24 (3%) clinical scenarios, namely presuction and postsuction bagging across populations and age groups. In general, the use of closed suction was rated as appropriate, particularly in the subspecialty population 'patients with highly infectious respiratory disease'. Routine application of 0.9% saline for nonrespiratory indications was more likely to be inappropriate/uncertain than appropriate. Panellists preferred clinically indicated suction versus routine suction in most circumstances. Appropriate use criteria for endotracheal suction in the paediatric intensive care have the potential to impact clinical decision-making, reduce practice variability, and improve patient outcomes. Furthermore, recognition of uncertain clinical scenarios facilitates identification of areas that would benefit from future research.


Effects of salinity stress on antioxidant status and inflammatory responses in females of a "Near Threatened" economically important fish species Notopterus chitala: a mechanistic approach.
In the present study, acute stress responses of adult female Notopterus chitala were scrutinized by antioxidant status and inflammation reaction in the gill and liver at five different salinity exposures (0, 3, 6, 9, 12 ppt). Oxidative defense was assessed by determining superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase, and glutathione reductase activities, while malondialdehyde (MDA), glutathione, and xanthine oxidase levels were determined as indicators of oxidative load. Pro-inflammatory cytokines (IL-1β, IL-6, IL-10, and TNFα) and caspase 1 levels were also analyzed. Expression levels of transcription factors (NRF2 and NF-κB) and molecular chaperons (HSF, HSP70, and HSP90) were estimated to evaluate their relative contribution to overcome salinity stress. MDA showed a significant (P < 0.05) increase (gill, + 25.35-90.14%; liver, + 23.88-80.59%) with salinity; SOD (+ 13.72-45.09%) and CAT (+ 12.73-33.96%) exhibited a sharp increase until 9 ppt, followed by a decrease at the highest salinity (12 ppt) (gill, - 3.92%; liver, - 2.18%). Levels of cytokines were observed to increase (+ 52.8-127.42%) in a parallel pattern with increased salinity. HSP70 and HSP90 expressions were higher in gill tissues than those in liver tissues. NRF2 played pivotal role in reducing salinity-induced oxidative load in both the liver and gills. Serum cortisol and carbonic anhydrase were measured and noted to be significantly (P < 0.05) upregulated in salinity stressed groups. Gill Na+-K+-ATPase activity decreased significantly (P < 0.05) in fish exposed to 6, 9, and 12 ppt compared to control. Present study suggests that a hyperosmotic environment induces acute oxidative stress and inflammation, which in turn causes cellular death and impairs tissue functions in freshwater fish species such as Notopterus chitala.


Association Between Peer Victimization, Gender Diversity, Mental Health, and Recurrent Headaches in Adolescents: A Canadian Population-Based Study.
It is unknown whether bullying and gender diversity are associated with increased headache frequency in adolescents. Our study aimed to assess the association between peer victimization, gender diversity, and frequent recurrent headaches in adolescents, while controlling for age, sex, socioeconomic status, and potential confounders (mood and anxiety disorders, suicidality). This was a cross-sectional observational study of adolescents aged 12-17 years using data from a Canadian population-based health survey. Headache frequency was dichotomized into "≤once/wk" or ">once/wk" (i.e., frequent recurrent headaches). Logistic regression was used to quantify the association between frequent peer victimization (overt or relational), gender diversity (female sex at birth + male gender, male sex at birth + female gender, or gender diverse), mood/anxiety disorder, suicidality, and the odds of frequent recurrent headaches. The fully adjusted multivariable logistic regression model included all exposures and was controlled for age, sex, and socioeconomic status. Bootstrap replicate weighting was used to account for survey design effects. There were an estimated 2,268,840 eligible participants (weighted sample size) (mean age = 14.4 years, 48.8% female, 0.5% gender diverse), and 11.2% reported frequent recurrent headaches. Frequent recurrent headaches were associated with older age (odds ratio [OR] = 1.26 per year of age, 95% CI 1.20-1.31), female sex (OR = 2.89, 95% CI 2.47-3.37), and being gender diverse (OR = 3.30, 95% CI 1.64-6.63, adjusted for age/sex). Youth with frequent headaches had higher odds of experiencing both overt and relational bullying compared with peers (OR = 2.69, 95% CI 2.31-3.14, and OR = 3.03, 95% CI 2.58-3.54, adjusted for age/sex). In the fully adjusted model, frequent headaches were no longer associated with gender diversity (OR = 1.53, 95% CI 0.63-3.69) but were still associated with frequent overt and relational peer victimization (OR = 1.82, 95% CI 1.41-2.34, and OR = 1.54, 95% CI 1.17-2.03, respectively), suicidality (OR = 1.83, 95% CI 1.44-2.32), and having a mood or anxiety disorder (OR = 1.50, 95% CI 1.01-2.21, and OR = 1.74, 95% CI 1.24-2.45, respectively). In a model adjusted for age, sex, and mood/anxiety disorders, the risk of suicidality increased incrementally with headache frequency. Peer victimization and suicidality may be associated with higher headache frequency in adolescents with headaches, independently of mood and anxiety symptoms. Gender-diverse adolescents may have a higher risk of experiencing frequent headaches when compared with cisgender peers, and this may be explained by associated psychosocial factors (anxiety, depression, suicidality, and peer victimization).


Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice.
The farnesoid X receptor (FXR) is a bile acid-activated transcription factor that regulates the expression of genes critical for bile acid and lipid homeostasis. This study was undertaken to investigate the pathological consequences of the loss of FXR function on the risk and severity of atherosclerosis. For this purpose, FXR-deficient (FXR-/-) mice were crossed with apolipoprotein E-deficient (ApoE-/-) mice to generate FXR-/- ApoE-/- mice. Challenging these mice with a high-fat, high-cholesterol (HF/HC) diet resulted in reduced weight gain and decreased survival compared with wild-type, FXR-/-, and ApoE-/- mice. FXR-/- ApoE-/- mice also had the highest total plasma lipids and the most atherogenic lipoprotein profile. Livers from FXR-/- and FXR-/- ApoE-/- mice exhibited marked lipid accumulation, focal necrosis (accompanied by increased levels of plasma aspartate aminotransferase), and increased inflammatory gene expression. Measurement of en face lesion area of HF/HC-challenged mice revealed that although FXR-/- mice did not develop atherosclerosis, FXR-/- ApoE-/- mice had approximately double the lesion area compared with ApoE-/- mice. In conclusion, loss of FXR function is associated with decreased survival, increased severity of defects in lipid metabolism, and more extensive aortic plaque formation in a mouse model of atherosclerotic disease.


Myocyte-specific enhancer binding factor 2C (MEF2C) expression in the dentate gyrus during development and after pilocarpine-induced status epilepticus: a preliminary report.
As axon outgrowth and dentate granule cell neurogenesis are hallmarks of hippocampal development and are also the two morphologic changes in the structure of the dentate gyrus after status epilepticus (SE), we hypothesized that molecules involved in normal development may also play a role during epileptogenesis. Using in situ hybridization, we have characterized mRNA expression of myocyte-specific enhancer binding factor 2C (MEF2C) in the dentate gyrus during development (P0, P3, P7, P14 and P28) and at multiple time points following pilocarpine-induced SE (3, 7, 14, 28 days after SE). It was demonstrated that MEF2C is up-regulated during development (P0, P3, P7, P14 and P28) and in the adult rat dentate gyrus following SE (3, 7, 14, 28 days after SE). The molecules controlling cell-fate decisions in the developing dentate gyrus are also operative during epileptogenesis.


Bayesian inference of mixed models in quantitative genetics of crop species.
The objectives of this study were to implement a Bayesian framework for mixed models analysis in crop species breeding and to exploit alternatives for informative prior elicitation. Bayesian inference for genetic evaluation in annual crop breeding was illustrated with the first two half-sib selection cycles in a popcorn population. The Bayesian framework was based on the Just Another Gibbs Sampler software and the R2jags package. For the first cycle, a non-informative prior for the inverse of the variance components and an informative prior based on meta-analysis were used. For the second cycle, a non-informative prior and an informative prior defined as the posterior from the non-informative and informative analyses of the first cycle were used. Regarding the first cycle, the use of an informative prior from the meta-analysis provided clearly distinct results relative to the analysis with a non-informative prior only for the grain yield. Regarding the second cycle, the results for the expansion volume and grain yield showed differences among the three analyses. The differences between the non-informative and informative prior analyses were restricted to variance components and heritability. The correlations between the predicted breeding values from these analyses were almost perfect.