Tob Regulates the Timing of Sleep Onset at Night in Drosophila.

Sleep is regulated by homeostatic sleep drive and the circadian clock. While tremendous progress has been made in elucidating the molecular components of the core circadian oscillator, the output mechanisms by which this robust oscillator generates rhythmic sleep behavior remain poorly understood. At the cellular level, growing evidence suggests that subcircuits in the master circadian pacemaker suprachiasmatic nucleus (SCN) in mammals and in the clock network in Drosophila regulate distinct aspects of sleep. Thus, to identify novel molecules regulating the circadian timing of sleep, we conducted a large-scale screen of mouse SCN-enriched genes in Drosophila Here, we show that Tob (Transducer of ERB-B2) regulates the timing of sleep onset at night in female fruit flies. Knockdown of Tob pan-neuronally, either constitutively or conditionally, advances sleep onset at night. We show that Tob is specifically required in "evening neurons" (the LNds and the fifth s-LNv) of the clock network for proper timing of sleep onset. Tob levels cycle in a clock-dependent manner in these neurons. Silencing of these "evening" clock neurons results in an advanced sleep onset at night, similar to that seen with Tob knockdown. Finally, sharp intracellular recordings demonstrate that the amplitude and kinetics of LNd postsynaptic potentials (PSPs) cycle between day and night, and this cycling is attenuated with Tob knockdown in these cells. Our data suggest that Tob acts as a clock output molecule in a subset of clock neurons to potentiate their activity in the evening and enable the proper timing of sleep onset at night.

Effects of a New Group of Antidiabetic Drugs in Metabolic Diseases.

The prevalence of type 2 diabetes mellitus (T2DM) is rising in the general population. This increase leads to higher cardiovascular risk, with cardiovascular diseases being the main cause of death in diabetic patients. New therapeutic weapons for diabetes mellitus are now available. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are novel drugs that are widely used due to their strong benefit in preventing hospitalization for decompensated heart failure and renal protection, limiting the deterioration of the glomerular filtration rate, independently of the presence of diabetes mellitus. These drugs have also shown benefit in the prevention of atherosclerotic cardiovascular events and cardiovascular mortality in diabetic patients with established cardiovascular disease. On the other hand, patients with T2DM usually present a high burden of associated comorbidities. Some of these entities are arterial hypertension, dyslipidemia, hyperuricemia, obesity, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), vascular aging, respiratory diseases, or osteoporosis and fractures. Healthcare professionals should treat these patients from an integral point of view, and not manage each pathology separately. Therefore, as potential mechanisms of SGLT2 inhibitors in metabolic diseases have not been fully reviewed, we conducted this review to know the current evidence of the use and effect of SGLT2 inhibitors on these metabolic diseases.

Effectiveness of a cardiac rehabilitation program on biomechanical, imaging, and physiological biomarkers in elderly patients with heart failure with preserved ejection fraction (HFpEF): FUNNEL + study protocol.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) have a low functional status, which in turn is a risk factor for hospital admission and an important predictor of survival in HFpEF. HFpFE is a heterogeneous syndrome and recent studies have suggested an important role for careful, pathophysiological-based phenotyping to improve patient characterization. Cardiac rehabilitation has proven to be a useful tool in the framework of secondary prevention in patients with HFpEF. Facilitating decision-making and implementing cardiac rehabilitation programs is a challenge in public health systems for HFpEF management. The FUNNEL + study proposes to evaluate the efficacy of an exercise and education-based cardiac rehabilitation program on biomechanical, physiological, and imaging biomarkers in patients with HFpEF. METHODS: A randomised crossover clinical trial is presented among people older than 70 years with a diagnosis of HFpEF. The experimental group will receive a cardiac rehabilitation intervention for 12 weeks. Participants in the control group will receive one educational session per week for 12 weeks on HFpEF complications, functional decline, and healthy lifestyle habits. VO2peak is the primary outcome. Biomechanical, imaging and physiological biomarkers will be assessed as secondary outcomes. Outcomes will be assessed at baseline, 12 weeks, and 24 weeks. DISCUSSION: Identifying objective functional parameters indicative of HFpEF and the subsequent development of functional level stratification based on functional impairment ("biomechanical phenotypes") may help clinicians identify cardiac rehabilitation responders and non-responders and make future clinical decisions. In this way, future pharmacological and non-pharmacological interventions, such as exercise, could be improved and tailored to improve quality of life and prognosis and reducing patients' hospital readmissions, thereby reducing healthcare costs. TRIAL REGISTRATION: NCT05393362 (Clinicaltrials.gov).

Consequences of diverse evolutionary processes on american genetic gradients of modern humans.

European genetic gradients of modern humans were initially interpreted as a consequence of the demic diffusion of expanding Neolithic farmers. However, recent studies showed that these gradients may also be influenced by other evolutionary processes such as population admixture or range contractions. Genetic gradients were observed in the Americas, although their specific evolutionary causes were not investigated. Here we extended the approach used to study genetic gradients in Europe to analyze the influence of diverse evolutionary scenarios on American genetic gradients. Using extensive computer simulations, we evaluated the impact of (i) admixture between expansion waves of modern humans, (ii) the presence of ice-sheets during the last glacial maximum (LGM) and (iii) long-distance dispersal (LDD) events, on the genetic gradients (detected by principal component analysis) of the entire continent, North America and South America. The specific simulation of North and South America showed that genetic gradients are usually orthogonal to the direction of range expansions-either expansions from Bering or posterior re-expansions to recolonize northern regions after ice sheets melting-and we suggest that they result from allele surfing processes. Conversely, our results on the entire continent show a northwest-southeast gradient obtained with any scenario, which we interpreted as a consequence of isolation by distance along the long length of the continent. These findings suggest that distinct genetic gradients can be detected at different regions of the Americas and that subcontinent regions present gradients more sensible to evolutionary and environmental factors (such as LDD and the LGM) than the whole continent.

Evaluation of cervical posture improvement of children with cerebral palsy after physical therapy based on head movements and serious games.

BACKGROUND: This paper presents the preliminary results of a novel rehabilitation therapy for cervical and trunk control of children with cerebral palsy (CP) based on serious videogames and physical exercise. MATERIALS: The therapy is based on the use of the ENLAZA Interface, a head mouse based on inertial technology that will be used to control a set of serious videogames with movements of the head. METHODS: Ten users with CP participated in the study. Whereas the control group (n = 5) followed traditional therapies, the experimental group (n = 5) complemented these therapies with a series of ten sessions of gaming with ENLAZA to exercise cervical flexion-extensions, rotations and inclinations in a controlled, engaging environment. RESULTS: The ten work sessions yielded improvements in head and trunk control that were higher in the experimental group for Visual Analogue Scale, Goal Attainment Scaling and Trunk Control Measurement Scale (TCMS). Significant differences (27% vs. 2% of percentage improvement) were found between the experimental and control groups for TCMS (p < 0.05). The kinematic assessment shows that there were some improvements in the active and the passive range of motion. However, no significant differences were found pre- and post-intervention. CONCLUSIONS: Physical therapy that combines serious games with traditional rehabilitation could allow children with CP to achieve larger function improvements in the trunk and cervical regions. However, given the limited scope of this trial (n = 10) additional studies are needed to corroborate this hypothesis.

The Role of Heparin in Postural Orthostatic Tachycardia Syndrome and Other Post-Acute Sequelae of COVID-19.

The therapeutic management and short-term consequences of the coronavirus disease 2019 (COVID-19) are well known. However, COVID-19 post-acute sequelae are less known and represent a public health problem worldwide. Patients with COVID-19 who present post-acute sequelae may display immune dysregulation, a procoagulant state, and persistent microvascular endotheliopathy that could trigger microvascular thrombosis. These elements have also been implicated in the physiopathology of postural orthostatic tachycardia syndrome, a frequent sequela in post-COVID-19 patients. These mechanisms, directly associated with post-acute sequelae, might determine the thrombotic consequences of COVID-19 and the need for early anticoagulation therapy. In this context, heparin has several potential benefits, including immunomodulatory, anticoagulant, antiviral, pro-endothelial, and vascular effects, that could be helpful in the treatment of COVID-19 post-acute sequelae. In this article, we review the evidence surrounding the post-acute sequelae of COVID-19 and the potential benefits of the use of heparin, with a special focus on the treatment of postural orthostatic tachycardia syndrome.

Effects of Genetic Origin of Honeybees and Climate on Prevalence and Infestation Levels of Varroa.

The objective of this study was to evaluate the effect of honeybee genetic origin, climate type and the interactions between these variables on the prevalence and infestation levels of Varroa in a large population of honeybee colonies (n = 1134). For each colony, the morphotype, haplotype and climate type were determined. No differences between the Africanized, European and Hybrid morphotypes were found for the prevalence and infestation levels of Varroa (p > 0.05). Differences between honeybee haplotypes were found for the prevalence of Varroa (p < 0.05), and the prevalence was higher in the African haplotype than in the European haplotype. No differences between honeybee haplotypes were found for the infestation levels of Varroa (p > 0.05). Differences were found between climate type for the prevalence and infestation levels of Varroa (p < 0.05): the temperate sub-humid climate had a higher prevalence and higher infestation levels than the semi-warm climate and the warm sub-humid climate. Correlations between the infestation levels of Varroa and mean annual temperature, mean annual precipitation, winter precipitation and Lang index were found.

Mitochondrial RNA methyltransferase TRMT61B is a new, potential biomarker and therapeutic target for highly aneuploid cancers.

Despite being frequently observed in cancer cells, chromosomal instability (CIN) and its immediate consequence, aneuploidy, trigger adverse effects on cellular homeostasis that need to be overcome by anti-stress mechanisms. As such, these safeguard responses represent a tumor-specific Achilles heel, since CIN and aneuploidy are rarely observed in normal cells. Recent data have revealed that epitranscriptomic marks catalyzed by RNA-modifying enzymes change under various stress insults. However, whether aneuploidy is associated with such RNA modifying pathways remains to be determined. Through an in silico search for aneuploidy biomarkers in cancer cells, we found TRMT61B, a mitochondrial RNA methyltransferase enzyme, to be associated with high levels of aneuploidy. Accordingly, TRMT61B protein levels are increased in tumor cell lines with an imbalanced karyotype as well as in different tumor types when compared to control tissues. Interestingly, while TRMT61B depletion induces senescence in melanoma cell lines with low levels of aneuploidy, it leads to apoptosis in cells with high levels. The therapeutic potential of these results was further validated by targeting TRMT61B in transwell and xenografts assays. We show that TRM61B depletion reduces the expression of several mitochondrial encoded proteins and limits mitochondrial function. Taken together, these results identify a new biomarker of aneuploidy in cancer cells that could potentially be used to selectively target highly aneuploid tumors.

A genetic analysis of the stinging and guarding behaviors of the honey bee.

In order to identify genes that are influencing defensive behaviors, we have taken a new approach by dissecting colony-level defensive behavior into individual behavioral measurements using two families containing backcross workers from matings involving European and Africanized bees. We removed the social context from stinging behavior by using a laboratory assay to measure the stinging response of individual bees. A mild shock was given to bees using a constant-current stimulator. The time it took bees to sting in response to this stimulus was recorded. In addition, bees that were seen performing guard behaviors at the hive entrance were collected. We performed QTL mapping in two backcross families with SNP probes within genes and identified two new QTL regions for stinging behavior and another QTL region for guarding behavior. We also identified several candidate genes involved in neural signaling, neural development and muscle development that may be influencing stinging and guarding behaviors. The lack of overlap between these regions and previous defensive behavior QTL underscores the complexity of this behavior and increases our understanding of its genetic architecture.

Efficacy and Safety of Semaglutide for the Management of Obese Patients With Type 2 Diabetes and Chronic Heart Failure in Real-World Clinical Practice.

Background: The impact of glucagon-like peptide-1 receptor agonists on patients with heart failure has not been fully described. Our main objective was to evaluate the safety and clinical and glycemic efficacy of once-weekly semaglutide in obese patients with type 2 diabetes and heart failure. Methods: In this observational, retrospective, real-world study, we enrolled outpatients with type 2 diabetes, obesity, and heart failure who started semaglutide and were followed-up on at 3, 6, and 12 months. Results: A total of 136 patients were included. From baseline to 12 months, there was a significant improvement on the Kansas City Cardiomyopathy Questionnaire total symptom score (59.0 ± 24.1 vs 79.9 ± 28.4 points, p<0.01), a reduction in the proportion of patients with New York Heart Association functional class III (40.4% to 16.2%, p<0.01), and a reduction in N-terminal pro-brain natriuretic peptide levels (969.5 ± 653.5 vs 577.4 ± 322.1 pg/mL, p<0.01). Emergency department visits due to heart failure, hospitalizations due to heart failure, and all-cause hospitalizations also declined. Additionally, significant reductions in glycated hemoglobin (-1.4%) and body weight (-12.7 kilograms) were observed as well as a de-intensification of antidiabetic therapy. Moreover, semaglutide was safe and well-tolerated. Conclusion: In obese patients with type 2 diabetes and heart failure, the use of once-weekly semaglutide was safe and clinically efficacious, improving health and functional status. Nevertheless, more strong evidence on glucagon-like peptide-1 receptor agonists in heart failure is required.

Effects of hydroxytyrosol-enriched sunflower oil consumption on CVD risk factors.

Inclusion of biophenols in traditional foods transforms them into functional foods that may help to decrease CVD risk. The aim of the present study was to determine whether the consumption of hydroxytyrosol-enriched sunflower oil (HSO) improves certain CVD biomarker values. A total of twenty-two healthy volunteers participated in a cross-over study involving two 3-week periods, separated by a 2-week washout period, in which volunteers consumed 800-1275 µg/d [corrected] of either HSO (45-50 mg/d of hydroxytyrosol) or non-enriched (control) sunflower oil. Total cholesterol, LDL-cholesterol, HDL-cholesterol, arylesterase activity, oxidised LDL and soluble vascular cell adhesion molecule (sVCAM-1) levels were measured in the plasma obtained at the beginning and at the end of each treatment period. The HSO group displayed a significantly higher level (P < 0·01) of arylesterase activity and significantly lower levels of oxidised LDL and sVCAM-1 (both P < 0·05) than the control group. These results suggest that HSO may help prevent CVD.

Effects of Nori- and Wakame-enriched meats with or without supplementary cholesterol on arylesterase activity, lipaemia and lipoproteinaemia in growing Wistar rats.

Some seaweeds exert antioxidant and hypocholesterolaemic properties. The effects of diets including restructured meats (RM) containing Wakame (W) or Nori (N) algae on arylesterase (AE) activity and lipoprotein concentration and composition were tested. In the present study, six groups of ten male growing Wistar rats each were fed a mix of 85 % AIN-93M diet and 15 % freeze-dried RM for 35 d. The control group (C) consumed control RM, the W and N groups consumed RM with 5 % W and 5 % N, respectively. The cholesterol-enriched C (CC), W (CW) and N (CN) groups consumed their corresponding basal diets with supplementary cholesterol (2·43 %) and cholic acid (0·49 %). Cholesterol in the diet induced lower (P < 0·001) growth ratios. Both W and N diets significantly increased AE activity. VLDL-cholesterol values were lower in N rats than in W rats. AE activity increased (P < 0·001) in CC and CW rats but not in CN rats compared with their corresponding counterparts. AE was lower (P < 0·05) in the CN group than in the CC and CW groups. The CN diet partially blocked (P < 0·001) the hypercholesterolaemic induction observed in CC and CW diets and reduced TAG levels (at least P < 0·05) with respect to those of CC rats. Although dietary cholesterol supplementation increased total cholesterol, VLDL-cholesterol and (intermediate-density lipoprotein+LDL)-cholesterol (all P < 0·001) in all rats, the CN diet moderately improved the lipoprotein profile of hypercholesterolaemic rats. Changes in AE activity and plasma cholesterol in CN rats but not in CW rats suggest a possible relationship between the two parameters. It is concluded that inclusion of RM enriched with N may be used in hypercholesterolaemic diets to improve lipoprotein metabolism.

Effects of APOA5 S19W polymorphism on growth, insulin sensitivity and lipoproteins in normoweight neonates.

Apolipoprotein (Apo) A5 is a protein involved in the activation of lipoprotein lipase (LPL) and the metabolism of triglyceride (TG)-rich lipoproteins. LPL plays a major role in the metabolism of TG-rich lipoproteins, and placental LPL activity is known to correlate positively with foetal fat deposition and size. We examine the association between the common APOA5 S19W polymorphism and neonatal anthropometrical measurements, lipoprotein and hormone concentrations, and insulin sensitivity in 58 normal weight Caucasian newborns from the Mérida cohort. Neonates with the W allele displayed lower BMI (P < 0.001), ponderal index (P < 0.001), birth weight (P < 0.01), insulin levels (P < 0.05), the insulin/cortisol ratio (P < 0.05), HOMA-R (P < 0.05) and Apo B values (P < 0.01), but higher oxidised LDL (LDLox) values and a higher LDLox/low-density lipoprotein (LDL) ratio (both P < 0.05) than S-homozygous newborns. The APOA5 S19W polymorphism was associated with foetal growth as well as with glucose and lipoprotein metabolism in the neonates. Concurrence of the S19W polymorphism in neonates and their mothers did not affect neonatal lipid and lipoprotein concentrations but was associated with impaired foetal growth. Specifically, W allele carriers displayed a higher degree of LDL oxidation and lower body weight, plasma insulin values, insulin/cortisol ratio and Apo B concentrations than homozygotes for the common S allele. In conclusion, these findings suggest that the W allele carriers received a less optimal nutrition during gestation and that their lipoprotein antioxidant status was inferior to that of their homozygous S allele counterparts.

Sirt1 protects against high-fat diet-induced metabolic damage.

The identification of new pharmacological approaches to effectively prevent, treat, and cure the metabolic syndrome is of crucial importance. Excessive exposure to dietary lipids causes inflammatory responses, deranges the homeostasis of cellular metabolism, and is believed to constitute a key initiator of the metabolic syndrome. Mammalian Sirt1 is a protein deacetylase that has been involved in resveratrol-mediated protection from high-fat diet-induced metabolic damage, but direct proof for the implication of Sirt1 has remained elusive. Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipid-induced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1alpha, and lower activation of proinflammatory cytokines, such as TNFalpha and IL-6, via down-modulation of NFkappaB activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet.

Diagnostic Characteristics of Lactate Dehydrogenase on a Multiplex Assay for Malaria Detection Including the Zoonotic Parasite Plasmodium knowlesi.

Plasmodium lactate dehydrogenase (pLDH) is a common target in malaria rapid diagnostic tests (RDTs). These commercial antibody capture assays target either Plasmodium falciparum-specific pLDH (PfLDH), P. vivax-specific pLDH (PvLDH), or a conserved epitope in all human malaria pLDH (PanLDH). However, there are no assays specifically targeting P. ovale, P. malariae or zoonotic parasites such as P. knowlesi and P. cynomolgi. A malaria multiplex array, carrying the specific antibody spots for PfLDH, PvLDH, and PanLDH has been previously developed. This study aimed to assess potential cross-reactivity between pLDH from various Plasmodium species and this array. We tested recombinant pLDH proteins, clinical samples for P. vivax, P. falciparum, P. ovale curtisi, and P. malariae; and in vitro cultured P. knowlesi and P. cynomolgi. P. ovale-specific pLDH (PoLDH) and P. malariae-specific pLDH (PmLDH) cross-reacted with the PfLDH and PanLDH spots. Plasmodium Knowlesi-specific pLDH (PkLDH) and P. cynomolgi-specific pLDH (PcLDH) cross-reacted with the PvLDH spot, but only PkLDH was recognized by the PanLDH spot. Plasmodium ovale and P. malariae can be differentiated from P. falciparum by the concentration ratios of PanLDH/PfLDH, which had mean (range) values of 4.56 (4.07-5.16) and 4.56 (3.43-6.54), respectively, whereas P. falciparum had a lower ratio of 1.12 (0.56-2.61). Plasmodium knowlesi had a similar PanLDH/PvLDH ratio value, with P. vivax having a mean value of 2.24 (1.37-2.79). The cross-reactivity pattern of pLDH can be a useful predictor to differentiate certain Plasmodium species. Cross-reactivity of the pLDH bands in RDTs requires further investigation.

What Are University Professors' Motivations? A Realistic Approach to Self-Perception of a Group of Spanish University Professors Belonging to the G-9 Group of Universities.

Universities face challenges on a number of levels. In this scenario, university professors play an important role as facilitators of knowledge. The main objective of this study was to analyse the motivations that influence the professional performance in a sample of 102 university professors from nine Spanish public universities (Male: 54 (52.9%); Female: 48 (47.1%)). For this purpose, a questionnaire of 22 closed-ended Likert-type questions was designed, in which scores ranged from 0 to 10 (do not agree at all, strongly agree). Following analysis, the final questionnaire was composed of 17 items, and showed good internal consistency (Cronbach's alpha = 0.858). The validity analysis showed a value of 0.822 (>0.5) in the sample adequacy measure of Kaiser-Meyer-Olkin and Bartlett's sphericity test (p < 0.0001). The exploratory factor analysis showed a clustering in four factors (two for intrinsic motivations and two for extrinsic motivations), explaining 64.33% of the total variance. Comparisons between each factor score by gender (male and female) showed statistically significant differences for factor F1 (higher for females) and F2 (higher for males). Finally, Q1 and Q13 showed a statistically significant correlation (p ≤ 0.05) with years of teaching experience. The motivations of Spanish university professors appear to be associated with the age and gender of the teacher.

Disparities in Remote Learning Faced by First-Generation and Underrepresented Minority Students during COVID-19: Insights and Opportunities from a Remote Research Experience.

The COVID-19 pandemic forced an unprecedented shift to remote instruction across higher education, reducing access to critically important undergraduate research experience and potentially magnifying inequities faced by first-generation and underrepresented minority (URM) students in higher education. Through a novel course-based undergraduate research experience (CURE) at UCLA, delivered completely online, results of a unique, student-generated survey showed that the transition to remote learning was challenging for all students, increasing student workload, decreasing ability to focus on school, and limiting their ability to succeed. However, results showed significant disparities in remote learning that disproportionately impacted URM and first-generation students. These students had significantly greater expectations to help siblings with remote learning,; URM and first-generation students also suffered greater economic and food insecurity related to COVID-19. At the same time, this study demonstrates how student voices in survey development provide novel and actionable insights. While access to CUREs is often limited by laboratory space, by focusing on the research process, rather than specific laboratory skills, this study provides a scalable pedagogical model for remote undergraduate research experiences. Importantly, this model fostered student engagement and increased interest in further undergraduate research, including topics not directly related to the subject of this study, suggesting that online CUREs can be effective and impactful.

Mouse tumor model for neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by increased incidence of benign and malignant tumors of neural crest origin. Mutations that activate the protooncogene ras, such as loss of Nf1, cooperate with inactivating mutations at the p53 tumor suppressor gene during malignant transformation. One hundred percent of mice harboring null Nf1 and p53 alleles in cis synergize to develop soft tissue sarcomas between 3 and 7 months of age. These sarcomas exhibit loss of heterozygosity at both gene loci and express phenotypic traits characteristic of neural crest derivatives and human NF1 malignancies.

Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin.

Cellular senescence is emerging as an important in vivo anticancer response elicited by multiple stresses, including currently used chemotherapeutic drugs. Nutlin-3a is a recently discovered small-molecule antagonist of the p53-destabilizing protein murine double minute-2 (MDM2) that induces cell cycle arrest and apoptosis in cancer cells with functional p53. Here, we report that nutlin-3a induces cellular senescence in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. No evidence of drug-induced apoptosis was observed in any case. Nutlin-induced senescence was strictly dependent on the presence of functional p53 as revealed by the fact that cells lacking p53 were completely insensitive to the drug, whereas cells lacking the tumor suppressor alternative reading frame product of the CDKN2A locus underwent irreversible cell cycle arrest. Interestingly, irreversibility was achieved in neoplastic cells faster than in their corresponding parental primary cells, suggesting that nutlin-3a and oncogenic signaling cooperate in activating p53. Our current results suggest that senescence could be a major cellular outcome of cancer therapy by antagonists of the p53-MDM2 interaction, such as nutlin-3a.

Smartwatch for the analysis of rest tremor in patients with Parkinson's disease.

Wearable technology used in Parkinson's disease (PD) research has become an increasing focus of interest in this field. Our group assessed the feasibility, clinical correlation, reliability, and acceptance of smartwatches in order to quantify arm resting tremors in PD patients. An Android application on a smartwatch was used to obtain raw data from the smartwatch's gyroscopes. Twenty-two PD patients were consecutively recruited and followed for 1 year. Arm rest tremors were video filmed and scored by two independent raters using the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS-III). The tremor intensity parameter was defined by the root mean square of the angular speed measured by the smartwatch at the wrist. Sixty-four smartwatch evaluations were completed. The Spearman coefficient among the mean of the resting tremor (UPDRS-III) scores and smartwatch measurements for tremor intensity was 0.81 (p < .001); smartwatch reliability to quantify tremors was checked by intraclass reliability coefficient with a resting tremor = 0.89, minimum detectable change = 59.03%. Good acceptance of the system was shown. Smartwatch use for PD tremor analysis is possible, reliable, well-correlated with clinical scores, and well-accepted by patients for clinical follow-up. The results from these experiments suggest that this commodity hardware has the potential to quantify PD patients' tremors objectively in a consulting-room.