ERK1/2 Activity Is Critical for the Outcome of Ischemic Stroke

Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2wt) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood–brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIPwt) and its phosphorylation-deficient mutant RKIPS153A, known inhibitors of the ERK1/2 signaling cascade. RKIPwt and RKIPS153A attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.

COVID-19 outbreaks in nursing homes: A strong link with the coronavirus spread in the surrounding population, France, March to July 2020

Background Worldwide, COVID-19 outbreaks in nursing homes have often been sudden and massive. The study investigated the role SARS-CoV-2 virus spread in nearby population plays in introducing the disease in nursing homes. Material and methods This was carried out through modelling the occurrences of first cases in each of 943 nursing homes of Auvergne-Rhône-Alpes French Region over the first epidemic wave (March-July, 2020). The cumulative probabilities of COVID-19 outbreak in the nursing homes and those of hospitalization for the disease in the population were modelled in each of the twelve Départements of the Region over period March-July 2020. This allowed estimating the duration of the active outbreak period, the dates and heights of the peaks of outbreak probabilities in nursing homes, and the dates and heights of the peaks of hospitalization probabilities in the population. Spearman coefficient estimated the correlation between the two peak series. Results The cumulative proportion of nursing homes with COVID-19 outbreaks was 52% (490/943; range: 22–70% acc. Département). The active outbreak period in the nursing homes lasted 11 to 21 days (acc. Département) and ended before lockdown end. Spearman correlation between outbreak probability peaks in nursing homes and hospitalization probability peaks in the population (surrogate of the incidence peaks) was estimated at 0.71 (95% CI: [0.66; 0.78]). Conclusion The modelling highlighted a strong correlation between the outbreak in nursing homes and the external pressure of the disease. It indicated that avoiding disease outbreaks in nursing homes requires a tight control of virus spread in the surrounding populations.

Minigene as a Novel Regulatory Element in Toxin-Antitoxin Systems

The axe-txe type II toxin-antitoxin (TA) system is characterized by a complex and multilayered mode of gene expression regulation. Precise and tight control of this process is crucial to keep the toxin in an appropriate balance with the cognate antitoxin until its activation is needed for the cell. In this report, we provide evidence that a minigene encoded within the axe-txe operon influences translation of the Txe toxin. This is the first example to date of such a regulatory mechanism identified in the TA modules. Here, in a series of genetic studies, we employed translational reporter gene fusions to establish the molecular basis of this phenomenon. Our results show that translation of the two-codon mini-ORF displays an in cis mode of action, and positively affects the expression of txe, possibly by increasing its mRNA stability through protection from an endonuclease attack. Moreover, we established that the reading frame in which the two cistrons are encoded, as well as the distance between them, are critical parameters that affect the level of such regulation. In addition, by searching for two-codon ORFs we found sequences of several potential minigenes in the leader sequences of several other toxins belonging to the type II TA family. These findings suggest that this type of gene regulation may not only apply for the axe-txe cassette, but could be more widespread among other TA systems.

Teamwork, Targets, Technology, and Tight Control in Newly Diagnosed Type 1 Diabetes: Pilot 4T Study

Context Youth with type 1 diabetes (T1D) do not meet hemoglobin A1c (HbA1c) targets. Objective To assess HbA1c outcomes in children with new onset T1D enrolled in the Teamwork, Targets, Technology and Tight Control (4T) Study. Method HbA1c levels were compared between the 4T and Historical cohorts. HbA1c differences between cohorts were estimated using locally estimated scatter plot smoothing (LOESS). The change from nadir HbA1c (month 4) to 12 months post-diagnosis was estimated by cohort using a piecewise mixed effects regression model accounting for age at diagnosis, sex, ethnicity, and insurance type. Setting and Participants We recruited 135 youth with newly diagnosed T1D at Stanford Children’s Health. Intervention Starting July 2018, all youth within the first month of T1D diagnosis were offered continuous glucose monitoring (CGM) initiation and remote CGM data review was added in March 2019. Main Outcome Measure HbA1c. Results HbA1c at 6, 9, and 12 months post-diagnosis was lower in the 4T cohort than in the Historic cohort (-0.54%, -0.52%, and -0.58%, respectively). Within the 4T cohort, HbA1c at 6, 9, and 12 months post-diagnosis was lower in those patients with Remote Monitoring than those without (-0.14%, -0.18%, -0.14%, respectively). Multivariable regression analysis showed that the 4T cohort experienced a significantly lower increase in HbA1c between months 4 and 12 (p < 0.001). Conclusions A technology-enabled team-based approach to intensified new onset education involving target setting, CGM initiation, and remote data review significantly decreased HbA1c in youth with T1D 12 months post-diagnosis.

Insect-host control of obligate, intracellular symbiont density

Many insects rely on intracellular bacterial symbionts to supplement their specialized diets with micronutrients. Using data from diverse and well-studied insect systems, we propose three lines of evidence suggesting that hosts have tight control over the density of their obligate, intracellular bacterial partners. First, empirical studies have demonstrated that the within-host symbiont density varies depending on the nutritional and developmental requirements of the host. Second, symbiont genomes are highly reduced and have limited capacity for self-replication or transcriptional regulation. Third, several mechanisms exist for hosts to tolerate, regulate and remove symbionts including physical compartmentalization and autophagy. We then consider whether such regulation is adaptive, by discussing the relationship between symbiont density and host fitness. We discuss current limitations of empirical studies for exploring fitness effects in host–symbiont relationships, and emphasize the potential for using mathematical models to formalize evolutionary hypotheses and to generate testable predictions for future work.

Comparison of chronic widespread pain prevalence with different criteria in two cohorts of rheumatoid arthritis

Objective This study aims to investigate chronic widespread pain with the 1990 (CWP1990) and 2019 (CWP2019) definitions 6 years after the onset of rheumatoid arthritis (RA), in one patient cohort with tight controls and one conventional cohort, and factors associated with reporting CWP1990 and CWP2019, respectively. Methods A cohort of 80 RA patients with monthly visits to the physician the first 6 months was compared to a cohort of 101 patients from the same clinic with conventional follow-up. Both cohorts had early RA (< 13 months). The prevalence of CWP1990 and the more stringent CWP2019 were in a 6-year follow-up investigated with a questionnaire, including a pain mannequin and a fear-avoidance beliefs questionnaire. Results In the tight control cohort, 10% reported CWP2019 after 6 years compared to 23% in the conventional cohort (p = 0.026). There was no difference when using the CWP1990 definition (27% vs 31%, p = 0.546). When adjusted for important baseline data, the odds ratio for having CWP2019 was 2.57 (95% CI 1.02–6.50), in the conventional group compared to the tight control group (p = 0.046). A high level of fear-avoidance behaviour towards physical activity was associated with CWP2019, OR 10.66 (95% CI 1.01–112.14), but not with CWP1990 in the tight control cohort. Conclusion A more stringent definition of CWP identifies patients with a more serious pain condition, which potentially could be prevented by an initial tight control management. Besides tight control, caregivers should pay attention to fear-avoidance behaviour and tailor treatment. Key Points • CWP2019 is a more stringent definition of chronic widespread pain and identifies patients with a more serious pain condition. • Patients with a serious pain condition could be helped by frequent follow-ups. • This study suggests that a special attention of fear-avoidance behaviour towards physical activity in patients with RA is needed.

Auto Gear Teeth Burnishing Machine Using Servo Control

A typical vehicle transmission is comprised of between five and six gear sets and a series of gear trains that allows a driver to control how much power is delivered to the vehicle without changing how fast the engine runs. This transmission makes noise such as burrs, nicks, high points and heat treat scales are the leading causes of noise in power transmission. There are many different causes of gear noise, all of them theoretically preventable. Unfortunately, the prevention methods can be costly, both in equipment and manpower. If the design of the gear and its application are appropriate, in theory all that is necessary is to have a tight control on the process of producing the finished gear. In reality, there are many variables that can cause a process, no matter how well-controlled, to deteriorate, and thus cause errors, some of which will cause a gear to produce unwanted noise when put to use. The effective way to eliminate this noise the process known as "Gear Burnishing". The proposed system uses gear shaving cutter as a master for burnishing or deburring operation of gear teeth with servo mechanism (includes servo motor and servo drivers), Programmable logic controller (PLC), Human machine interface (HMI) to remove gear inaccuracies and so as to reduce or eliminate transmission noise and provide more life and reliability to transmissions in vehicles resulted into noise free vehicles.