Synapse elimination activates a coordinated homeostatic presynaptic response in an autaptic circuit

The number of synapses present in a neuronal circuit is not fixed. Neurons must compensate for changes in connectivity caused by synaptic pruning, learning processes or pathological conditions through the constant adjustment of the baseline level of neurotransmission. Here, we show that cholinergic neurons grown in an autaptic circuit in the absence of glia sense the loss of half of their synaptic contacts triggered by exposure to peptide p4.2, a C-terminal fragment of SPARC. Synaptic elimination is driven by a reorganization of the periodic F-actin cytoskeleton present along neurites, and occurs without altering the density of postsynaptic receptors. Neurons recover baseline neurotransmission through a homeostatic presynaptic response that consists of the coordinated activation of rapid synapse formation and an overall potentiation of presynaptic calcium influx. These results demonstrate that neurons establishing autaptic connections continuously sense and adjust their synaptic output by tweaking the number of functional contacts and neurotransmitter release probability

SUMMATIVE ASSESSMENTS IN ENGLISH FOR SENIOR HIGH SCHOOL

Introduction: Language ability information is important and necessary. Universities are unlikely to admit students without some understanding of their English competence or competency. The same can be said for companies that hire interpreters or translators. These entities certainly need dependable measures of language ability. Methods: This descriptive research design aimed to develop summative assessments to address the least mastered competencies in English among Senior High School students based on the level of English competencies as perceived by the Senior High School English teachers and the problems encountered by teachers in teaching the English competencies. The study employed a validated questionnaire to gather data. The teacher respondents were selected using random sampling. Frequency and percentage were used to analyze the data. Results: The study found out that teachers perceived learners to be at emerging level in listening competency, expanding level in reading, and viewing competency, and emerging level in writing competency. Moreover, all the English competencies were rated serious as to the problems encountered by teachers in teaching the English competencies. Conclusions: Based on the results of the survey conducted to SHS English teachers, the following English language competencies, namely, reading, writing, and listening may be considered in the constructing of summative assessments. These English competencies were perceived by the teachers to have the lowest levels and contain weak points that need to be addressed through assessment tools. In like manner, serious cases of problems encountered in teaching these competencies may also be considered

Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG- binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763

In Vivo Photocontrol of Microtubule Dynamics and Integrity, Migration and Mitosis, by the Potent GFP-Imaging-Compatible Photoswitchable Reagents SBTubA4P and SBTub2M

Photoswitchable reagents are powerful tools for high-precision studies in cell biology. When these reagents are globally administered yet locally photoactivated in two-dimensional (2D) cell cultures, they can exert micron- and millisecond-scale biological control. This gives them great potential for use in biologically more relevant three-dimensional (3D) models and in vivo, particularly for studying systems with inherent spatiotemporal complexity, such as the cytoskeleton. However, due to a combination of photoswitch isomerization under typical imaging conditions, metabolic liabilities, and insufficient water solubility at effective concentrations, the in vivo potential of photoswitchable reagents addressing cytosolic protein targets remains largely unrealized. Here, we optimized the potency and solubility of metabolically stable, druglike colchicinoid microtubule inhibitors based on the styrylbenzothiazole (SBT) scaffold that are nonresponsive to typical fluorescent protein imaging wavelengths and so enable multichannel imaging studies. We applied these reagents both to 3D organoids and tissue explants and to classic model organisms (zebrafish, clawed frog) in one- and two-protein imaging experiments, in which spatiotemporally localized illuminations allowed them to photocontrol microtubule dynamics, network architecture, and microtubule-dependent processes in vivo with cellular precision and second-level resolution. These nanomolar, in vivo capable photoswitchable reagents should open up new dimensions for high-precision cytoskeleton research in cargo transport, cell motility, cell division, and development. More broadly, their design can also inspire similarly capable optical reagents for a range of cytosolic protein targets, thus bringing in vivo photopharmacology one step closer to general realization

Minimal Flavour Violation Waiting for Precise Measurements of Delta M_s, S_{psi phi}, A^s_SL, |V_ub|, gamma and B^0_{s,d} -> mu+ mu-

We emphasize that the recent measurements of the B^0_s - bar B^0_s mass difference Delta M_s by the CDF and D0 collaborations offer an important model independent test of minimal flavour violation (MFV). The improved measurements of the angle gamma in the unitarity triangle and of |V_ub| from tree level decays, combined with future accurate measurements of Delta M_s, S_{psi K_S}, S_{psi phi}, Br(B_{d,s} -> mu+ mu-), Br(B -> X_{d,s} nu bar nu), Br(K+ -> pi+ nu bar nu) and Br(K_L -> pi^0 nu bar nu) and improved values of the relevant non-perturbative parameters, will allow to test the MFV hypothesis in a model independent manner to a high accuracy. In particular, the difference between the reference unitarity triangle obtained from tree level processes and the universal unitarity triangle (UUT) in MFV models would signal either new flavour violating interactions and/or new local operators that are suppressed in MFV models with low tan(beta), with the former best tested through S_{psi phi} and K_L -> pi^0 nu bar nu. A brief discussion of non-MFV scenarios is also given. In this context we identify in the recent literature a relative sign error between Standard Model and new physics contributions to S_{psi phi}, that has an impact on the correlation between S_{psi phi} and A^s_SL. We point out that the ratios S_{psi phi}/A^s_SL and (Delta M_s)/(Delta Gamma_s) will allow to determine (Delta M_s)/(Delta M_s)^SM. Similar proposals for the determination of (Delta M_d)/(Delta M_d)^SM are also given.Comment: 22 pages, 8 figures, 1 table. Extended discussion of the correlation between S_{psi phi} and A^s_SL and new proposals to determine Delta M_q/(Delta M_q)^SM from future measurements, with respect to the first version. Minor changes and few references adde

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Epidemiological trends of HIV/HCV coinfection in Spain, 2015-2019

Altres ajuts: Spanish AIDS Research Network; European Funding for Regional Development (FEDER).Objectives: We assessed the prevalence of anti-hepatitis C virus (HCV) antibodies and active HCV infection (HCV-RNA-positive) in people living with HIV (PLWH) in Spain in 2019 and compared the results with those of four similar studies performed during 2015-2018. Methods: The study was performed in 41 centres. Sample size was estimated for an accuracy of 1%. Patients were selected by random sampling with proportional allocation. Results: The reference population comprised 41 973 PLWH, and the sample size was 1325. HCV serostatus was known in 1316 PLWH (99.3%), of whom 376 (28.6%) were HCV antibody (Ab)-positive (78.7% were prior injection drug users); 29 were HCV-RNA-positive (2.2%). Of the 29 HCV-RNA-positive PLWH, infection was chronic in 24, it was acute/recent in one, and it was of unknown duration in four. Cirrhosis was present in 71 (5.4%) PLWH overall, three (10.3%) HCV-RNA-positive patients and 68 (23.4%) of those who cleared HCV after anti-HCV therapy (p = 0.04). The prevalence of anti-HCV antibodies decreased steadily from 37.7% in 2015 to 28.6% in 2019 (p < 0.001); the prevalence of active HCV infection decreased from 22.1% in 2015 to 2.2% in 2019 (p < 0.001). Uptake of anti-HCV treatment increased from 53.9% in 2015 to 95.0% in 2019 (p < 0.001). Conclusions: In Spain, the prevalence of active HCV infection among PLWH at the end of 2019 was 2.2%, i.e. 90.0% lower than in 2015. Increased exposure to DAAs was probably the main reason for this sharp reduction. Despite the high coverage of treatment with direct-acting antiviral agents, HCV-related cirrhosis remains significant in this population

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe