Fueling the heartbeat: Dynamic regulation of intracellular ATP during excitation-contraction coupling in ventricular myocytes.

The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca2+ handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP]i in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]i. Notably, diastolic [ATP]i was <1 mM, which is eightfold to 10-fold lower than previously estimated. Accordingly, ATP-sensitive K+ (KATP) channels were active at physiological [ATP]i. Cells exhibited two distinct types of ATP fluctuations during an action potential: net increases (Mode 1) or decreases (Mode 2) in [ATP]i. Mode 1 [ATP]i increases necessitated Ca2+ entry and release from the sarcoplasmic reticulum (SR) and were associated with increases in mitochondrial Ca2+. By contrast, decreases in mitochondrial Ca2+ accompanied Mode 2 [ATP]i decreases. Down-regulation of the protein mitofusin 2 reduced the magnitude of [ATP]i fluctuations, indicating that SR-mitochondrial coupling plays a crucial role in the dynamic control of ATP levels. Activation of ß-adrenergic receptors decreased [ATP]i, underscoring the energetic impact of this signaling pathway. Finally, our work suggests that cross-bridge cycling is the largest consumer of ATP in a ventricular myocyte during an action potential. These findings provide insights into the energetic demands of EC coupling and highlight the dynamic nature of ATP concentrations in cardiac muscle.

Acute phosphatidylinositol 4,5 bisphosphate depletion destabilizes sarcolemmal expression of cardiac L-type Ca2+ channel CaV1.2.

CaV1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through Gq-coupled AT1 receptors, angiotensin II triggers a decrease in PIP2, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels. PIP2 depletion suppresses CaV1.2 currents in heterologous expression systems but the mechanism of this regulation and whether a similar phenomenon occurs in cardiomyocytes is unknown. Previous studies have shown that CaV1.2 currents are also suppressed by angiotensin II. We hypothesized that these two observations are linked and that PIP2 stabilizes CaV1.2 expression at the PM and angiotensin II depresses cardiac excitability by stimulating PIP2 depletion and destabilization of CaV1.2 expression. We tested this hypothesis and report that CaV1.2 channels in tsA201 cells are destabilized after AT1 receptor-triggered PIP2 depletion, leading to their dynamin-dependent endocytosis. Likewise, in cardiomyocytes, angiotensin II decreased t-tubular CaV1.2 expression and cluster size by inducing their dynamic removal from the sarcolemma. These effects were abrogated by PIP2 supplementation. Functional data revealed acute angiotensin II reduced CaV1.2 currents and Ca2+ transient amplitudes thus diminishing excitation-contraction coupling. Finally, mass spectrometry results indicated whole-heart levels of PIP2 are decreased by acute angiotensin II treatment. Based on these observations, we propose a model wherein PIP2 stabilizes CaV1.2 membrane lifetimes, and angiotensin II-induced PIP2 depletion destabilizes sarcolemmal CaV1.2, triggering their removal, and the acute reduction of CaV1.2 currents and contractility.

RAB6 and dynein drive post-Golgi apical transport to prevent neuronal progenitor delamination.

Radial glial (RG) cells are the neural stem cells of the developing neocortex. Apical RG (aRG) cells can delaminate to generate basal RG (bRG) cells, a cell type associated with human brain expansion. Here, we report that aRG delamination is regulated by the post-Golgi secretory pathway. Using in situ subcellular live imaging, we show that post-Golgi transport of RAB6+ vesicles occurs toward the minus ends of microtubules and depends on dynein. We demonstrate that the apical determinant Crumbs3 (CRB3) is also transported by dynein. Double knockout of RAB6A/A' and RAB6B impairs apical localization of CRB3 and induces a retraction of aRG cell apical process, leading to delamination and ectopic division. These defects are phenocopied by knockout of the dynein activator LIS1. Overall, our results identify a RAB6-dynein-LIS1 complex for Golgi to apical surface transport in aRG cells, and highlights the role of this pathway in the maintenance of neuroepithelial integrity.

Photophysical Rate Constants and Oxygen Dependence for Si and Ge Rhodamine Zwitterions.

The family of group XIV rhodamine zwitterions are fluorescence probes with carbon, silicon, germanium, or tin substituted in the 10-position of the xanthene ring. Because of their inherent near-infrared fluorescence, photostability and high quantum yields in aqueous solutions, the Si and Ge containing fluorophores in this class have become increasingly important for fluorescent labeling of proteins and biological molecules. This study fully characterizes photophysical rates derived from a model consisting of a singlet ground state, the lowest singlet excited state, and the lowest triplet excited state for two exemplar group XIV rhodamine zwitterions, one containing Si and the other Ge. Within a simple Jablonski diagram, all radiative and non-radiative rates, including intersystem crossing and triplet depopulation rates, were measured as a function of oxygen concentration. It was shown that the triplet depopulation rates are intrinsically fast in comparison with traditional xanthene containing fluorophores, probably due to the increased spin-obit coupling from the Si and Ge substitution in the xanthene ring. Dissolved oxygen increases both the intersystem crossing and triplet depopulation rates. Stern-Volmer analysis was conducted to estimate rates of quenching by oxygen. The experimental data was used to estimate the initial rates for reactive oxygen production by Si and Ge containing fluorophores in aqueous solutions containing different concentrations of dissolved O2. These estimates showed a significantly slower initial rate of reactive oxygen production in comparison with rhodamine 6G. This goes a long way to explaining their inherent photostability. Spectroscopic experiments were also conducted in 77 K viscous aqueous glasses where it was observed that the fluorescence spectra remained unchanged, and the quantum yields increased from 0.53 to 0.84 and from 0.52 to 0.89 for the Si and Ge containing fluorophores respectively; no phosphorescence was observed. All intersystem crossing and triplet depopulation rates were measured using fluorescence correlation spectroscopy (FCS) and analyzed using a new method that extrapolated the power dependence of the FCS curves to optical saturation. This method was verified using published data.

Inhibition of calcium/calmodulin (Ca2+ /CaM)-Calcium/calmodulin-dependent protein kinase II (CaMKII) axis reduces in vitro and ex vivo arrhythmias in experimental Chagas disease.

Chagasic cardiomyopathy (CCC) is one of the main causes of heart failure and sudden death in Latin America. To date, there is no available medication to prevent or reverse the onset of cardiac symptoms. CCC occurs in a scenario of disrupted calcium dynamics and enhanced oxidative stress, which combined, may favor the hyper activation of calcium/calmodulin (Ca2+ /CaM)-calcium/calmodulin-dependent protein kinase II (CaMKII) (Ca2+ /CaM-CaMKII) pathway, which is fundamental for heart physiology and it is implicated in other cardiac diseases. Here, we evaluated the association between Ca2+ /CaM-CaMKII in the electro-mechanical (dys)function of the heart in the early stage of chronic experimental Trypanosoma cruzi infection. We observed that in vitro and ex vivo inhibition of Ca2+ /CaM-CaMKII reversed the arrhythmic profile of isolated hearts and isolated left-ventricles cardiomyocytes. The benefits of the limited Ca2+ /CaM-CaMKII activation to cardiomyocytes' electrical properties are partially related to the restoration of Ca2+ dynamics in a damaged cellular environment created after T. cruzi infection. Moreover, Ca2+ /CaM-CaMKII inhibition prevented the onset of arrhythmic contractions on isolated heart preparations of chagasic mice and restored the responsiveness to the increase in the left-ventricle pre-load. Taken together, our data provide the first experimental evidence for the potential of targeting Ca2+ /CaM-CaMKII pathway as a novel therapeutic target to treat CCC.

Machine Learning for Hypertension Prediction: a Systematic Review.

PURPOSE OF REVIEW: To provide an overview of the literature regarding the use of machine learning algorithms to predict hypertension. A systematic review was performed to select recent articles on the subject. RECENT FINDINGS: The screening of the articles was conducted using a machine learning algorithm (ASReview). A total of 21 articles published between January 2018 and May 2021 were identified and compared according to variable selection, train-test split, data balancing, outcome definition, final algorithm, and performance metrics. Overall, the articles achieved an area under the ROC curve (AUROC) between 0.766 and 1.00. The algorithms most frequently identified as having the best performance were support vector machines (SVM), extreme gradient boosting (XGBoost), and random forest. Machine learning algorithms are a promising tool to improve preventive clinical decisions and targeted public health policies for hypertension. However, technical factors such as outcome definition, availability of the final code, predictive performance, explainability, and data leakage need to be consistently and critically evaluated.

Natural and artificial pollination of white-fleshed pitaya.

To produce pitaya (Hylocereus spp.), it is essential that pollination occur, either artificially or by pollinating agents. This study evaluated the viability of self-pollination, cross-pollination, and natural pollination, as well as pollen viability, stigma receptivity and ideal pollination window in pitaya flowers (Hylocereus spp.). An experiment was conducted with a randomized block design consisting of four treatments: T1: manual self-pollination; T2: nocturnal open pollination; T3: diurnal open pollination; and T4: manual cross-pollination - red-fleshed pitaya [ Hylocereus polyrhizus] pollen placed on white-fleshed pitaya [ Hylocereus undatus] stigma. The experiment had four replicates, with two plants per replicate (two flowers per plant), totaling 16 flowers per treatment. The analyzed variables were fruit weight, length, diameter, titratable acidity, pH, soluble solids, and SS/TA ratio; the germination percentage of pollen grains; and the receptivity of stigmas. Artificial pollination (self- and cross-pollination) of white-fleshed pitaya (Hylocereus undatus) is viable, resulting in larger fruits than natural pollination, with cross-pollination being the most recommended. Throughout the floral opening period, the pitaya flower (Hylocereus spp.) has receptive stigma capable of receiving pollen. The flowers exhibit the highest pollen germination rate at 7 p.m, which is the ideal pollination window for pitaya.

Bacterial Cellulose as a Versatile Biomaterial for Wound Dressing Application.

Chronic ulcers are among the main causes of morbidity and mortality due to the high probability of infection and sepsis and therefore exert a significant impact on public health resources. Numerous types of dressings are used for the treatment of skin ulcers-each with different advantages and disadvantages. Bacterial cellulose (BC) has received enormous interest in the cosmetic, pharmaceutical, and medical fields due to its biological, physical, and mechanical characteristics, which enable the creation of polymer composites and blends with broad applications. In the medical field, BC was at first used in wound dressings, tissue regeneration, and artificial blood vessels. This material is suitable for treating various skin diseases due its considerable fluid retention and medication loading properties. BC membranes are used as a temporary dressing for skin treatments due to their excellent fit to the body, reduction in pain, and acceleration of epithelial regeneration. BC-based composites and blends have been evaluated and synthesized both in vitro and in vivo to create an ideal microenvironment for wound healing. This review describes different methods of producing and handling BC for use in the medical field and highlights the qualities of BC in detail with emphasis on biomedical reports that demonstrate its utility. Moreover, it gives an account of biomedical applications, especially for tissue engineering and wound dressing materials reported until date. This review also includes patents of BC applied as a wound dressing material.

Lipopolysaccharide-induced epididymitis modifies the transcriptional profile of Wfdc genes in mice†.

Whey-acidic protein four-disulfide core domain (WFDC) genes display putative roles in innate immunity and fertility. In mice, a locus on chromosome 2 contains 5 and 11 Wfdc genes in its centromeric and telomeric subloci, respectively. Although Wfdc genes are highly expressed in the epididymis, their contributions to epididymal function remain elusive. Here, we investigated whether Wfdc genes are regulated in response to lipopolysaccharide (LPS)-induced epididymitis, an inflammatory condition that impairs male fertility. We induced epididymitis in mice via (i) interstitial LPS injection into epididymal initial segment and (ii) intravasal LPS injection into the vas deferens towards cauda epididymis. Interstitial and intravasal LPS induced a differential upregulation of inflammatory mediators (interleukin 1 beta, interleukin 6, tumor necrosis factor, interferon gamma, and interleukin 10) in the initial segment and cauda epididymis within 72 h post-treatment. These changes were accompanied by a time-dependent endotoxin clearance from the epididymis. In the initial segment, interstitial LPS upregulated all centromeric (Slpi, Wfdc5, Wfdc12, Wfdc15a, and Wfdc15b) and five telomeric (Wfdc2, Wfdc3, Wfdc6b, Wfdc10, and Wfdc13) Wfdc transcripts at 24 and 72 h. In the cauda epididymis, intravasal LPS upregulated Wfdc5 and Wfdc2 transcripts at 24 h, followed by a downregulation of Wfdc15b and three telomeric (Wfdc6a, Wfdc11, and Wfdc16) gene transcripts at 72 h. Pharmacological inhibition of nuclear factor kappa B activation prevented LPS-induced upregulation of centromeric and telomeric Wfdc genes depending on the epididymal region. We show that LPS-induced inflammation differentially regulated the Wfdc locus in the proximal and distal epididymis, indicating region-specific roles for the Wfdc family in innate immune responses during epididymitis.

Relationship between cocaine and cocaethylene blood concentration with the severity of clinical manifestations.

BACKGROUND: Poisonings resulting from the abuse of drugs currently represent a serious problem for public health. Among the main agents involved, cocaine stands out. It became one of the most abused drugs around the world, and one of the main reasons for visits to the emergency department due to the use of illicit substances. The use of cocaine is primarily in combination with alcoholic beverages. There are few studies that correlate cocaine blood concentration and the severity of clinical manifestations in patients evaluated at Emergency Department. The aim of the present study was to verify the possible relationship between the blood concentration of cocaine and cocaethylene (product of the interaction of cocaine with ethanol) with the severity of the clinical manifestations presented by patients with cocaine intoxication. METHODS: Blood levels were measured by high-performance liquid chromatography (HPLC) and the severity of clinical manifestations was assessed using the Stimulant Intoxication Score (SIS). To establish this relationship, Pearson's chi-square statistical test (x2) was used for categorical variables and Student's t for continuous variables, with statistical significance of 5% (p < 0.05). RESULTS: Of the 81 patients included in the study, 77.8% were men with a mean age of 32.5 years ± 8.5 and mean of SIS 3.4 ± 2.5. Considering the toxicological analysis results, 24.7% of the blood samples were positive. The mean of cocaine and cocaethylene concentrations were 0.34 µg/mL ± 0.45 and 0.38 µg/mL ± 0.34, respectively. The blood concentration of cocaine and cocaethylene has not been shown to be useful information for the treatment and prognosis of patients, but blood levels of these substances at the time of treatment, regardless of their concentration, may be an indicator of severity, showing that any concentrations of these substances should be considered as potentially toxic. CONCLUSION: The application of the SIS score proved to be an important alternative capable of predicting the severity of the patients due to cocaine intoxication in a fast and simplified way.

Neonatal mortality prediction with routinely collected data: a machine learning approach.

BACKGROUND: Recent decreases in neonatal mortality have been slower than expected for most countries. This study aims to predict the risk of neonatal mortality using only data routinely available from birth records in the largest city of the Americas. METHODS: A probabilistic linkage of every birth record occurring in the municipality of São Paulo, Brazil, between 2012 e 2017 was performed with the death records from 2012 to 2018 (1,202,843 births and 447,687 deaths), and a total of 7282 neonatal deaths were identified (a neonatal mortality rate of 6.46 per 1000 live births). Births from 2012 and 2016 (N = 941,308; or 83.44% of the total) were used to train five different machine learning algorithms, while births occurring in 2017 (N = 186,854; or 16.56% of the total) were used to test their predictive performance on new unseen data. RESULTS: The best performance was obtained by the extreme gradient boosting trees (XGBoost) algorithm, with a very high AUC of 0.97 and F1-score of 0.55. The 5% births with the highest predicted risk of neonatal death included more than 90% of the actual neonatal deaths. On the other hand, there were no deaths among the 5% births with the lowest predicted risk. There were no significant differences in predictive performance for vulnerable subgroups. The use of a smaller number of variables (WHO's five minimum perinatal indicators) decreased overall performance but the results still remained high (AUC of 0.91). With the addition of only three more variables, we achieved the same predictive performance (AUC of 0.97) as using all the 23 variables originally available from the Brazilian birth records. CONCLUSION: Machine learning algorithms were able to identify with very high predictive performance the neonatal mortality risk of newborns using only routinely collected data.

Whistles of the pantropical spotted dolphin (Stenella attenuata) in Santos Basin, western South Atlantic Ocean.

The vocal repertoire of the pantropical spotted dolphin (Stenella attenuata) is poorly documented, with no published information about acoustic signals from South Atlantic Ocean populations. We conducted passive acoustic monitoring and recording of S. attenuata population in the Santos Basin, Brazil, using a towed hydrophone array during line-transects surveys. Our monitoring yielded whistle samples derived from eight groups of S. attenuata, from which we selected 155 whistles for further analysis. Approximately 48% of the whistles presented ultrasonic frequency values, with maximum frequencies up to 31.1 kHz. Across the sample, the number of steps ranged from 0 to 20 and inflection points ranged from 0 to 8. On average, end frequencies were higher than start frequencies, and whistles generally presented wide frequency ranges, with an average of 11.3 kHz. The most predominant whistle contour category was "ascending-descending." Our study provides new information regarding the acoustic repertoire of this poorly documented species and will aid efforts for using acoustics to identify and monitor cetaceans in this region.

Measurement of Azimuthal Anisotropy of Muons from Charm and Bottom Hadrons in pp Collisions at sqrt[s]=13 TeV with the ATLAS Detector.

The elliptic flow of muons from the decay of charm and bottom hadrons is measured in pp collisions at sqrt[s]=13 TeV using a data sample with an integrated luminosity of 150 pb^{-1} recorded by the ATLAS detector at the LHC. The muons from heavy-flavor decay are separated from light-hadron decay muons using momentum imbalance between the tracking and muon spectrometers. The heavy-flavor decay muons are further separated into those from charm decay and those from bottom decay using the distance-of-closest-approach to the collision vertex. The measurement is performed for muons in the transverse momentum range 4-7 GeV and pseudorapidity range |η|<2.4. A significant nonzero elliptic anisotropy coefficient v_{2} is observed for muons from charm decays, while the v_{2} value for muons from bottom decays is consistent with zero within uncertainties.

Search for Magnetic Monopoles and Stable High-Electric-Charge Objects in 13 Tev Proton-Proton Collisions with the ATLAS Detector.

A search for magnetic monopoles and high-electric-charge objects is presented using 34.4 fb^{-1} of 13 TeV pp collision data collected by the ATLAS detector at the LHC during 2015 and 2016. The considered signature is based upon high ionization in the transition radiation tracker of the inner detector associated with a pencil-shape energy deposit in the electromagnetic calorimeter. The data were collected by a dedicated trigger based on the tracker high-threshold hit capability. The results are interpreted in models of Drell-Yan pair production of stable particles with two spin hypotheses (0 and 1/2) and masses ranging from 200 to 4000 GeV. The search improves by approximately a factor of 5 the constraints on the direct production of magnetic monopoles carrying one or two Dirac magnetic charges and stable objects with electric charge in the range 20≤|z|≤60 and extends the charge range to 60<|z|≤100.

Multiomics Analyses Identify Genes and Pathways Relevant to Essential Tremor.

INTRODUCTION: The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown. OBJECTIVE: The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches. METHODS: Case-control RNA sequencing of 2 cerebellar regions was done for 64 samples. A phenome-wide association study (pheWAS) of the differentially expressed genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. Finally, a transcriptome-wide association study (TWAS) was done to identify novel risk genes for ET. RESULTS: We identified several novel dysregulated genes, including CACNA1A and SHF. Pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. The ET GWGAS data found calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. The TWAS also found calcium and olfactory pathways enriched. The pheWAS identified that the underexpressed differentially expressed gene, SHF, is associated with a blood pressure medication (P = 9.3E-08), which is used to reduce tremor in ET patients. Treatment of cerebellar DAOY cells with the ET drug propranolol identified increases in SHF when treated, suggesting it may rescue the underexpression. CONCLUSION: We found that calcium-related pathways were enriched across the GWGAS, TWAS, and transcriptome. SHF was shown to have significantly decreased expression, and the pheWAS showed it was associated with blood pressure medication. The treatment of cells with propranolol showed that the drug restored levels of SHF. Overall, our findings highlight the power of integrating multiple different approaches to prioritize ET pathways and genes. © 2020 International Parkinson and Movement Disorder Society.

Alkynyl Linkers as a Design Tool to Gain Control over the Self-Assembly of Meso-Substituted Porphyrins on HOPG.

Self-assembled monolayers (SAMs) fall generally into two broad categories: those that are covalently bound either to the surface or to each other and those that rely on weaker forces such as hydrogen bonding or van der Waals forces. The engineering of the structure of SAMs formed from weaker forces is an exciting and complex field that often utilizes long alkane substituents bound to core moieties. The core provides the unique optical, electronic, or catalytic property desired, while the interdigitation of the alkane chains provides the means for creating well-regulated patterns of cores on the substrate. This design technique sometimes fails because some of the alkane substituents remain extended into solution rather than become interdigitated on the substrate. One contributor to this is steric hindrance between elements of the core and of the alkane chain. It is shown that the use of an alkyne linker between the core and the alkane chain can, in the case of meso-substituted porphyrins, significantly reduce this steric barrier and allow more stable and predictable surface structures to form. In particular, 5,15-bis(1-octynyl)porphyrin and 5,15-bis(1-tetradecynyl)porphyrin are shown to form significantly more stable SAMs than their alkane-linked counterparts. Scanning tunneling microscopy is used to provide detailed surface structures. Temperature and solution concentration dependence of the surface coverage is also reported. Density functional theory (DFT) is used to determine the energetic effects associated with alkane substitution at both the meso and ß positions and the beneficial energetic effects of the alkyne linker.

Diagnostic Validity of an Isokinetic Testing to Identify Partial Anterior Cruciate Ligament Injuries.

OBJECTIVE: To assess the diagnostic validity of an isokinetic testing to detect partial injuries on the anterior cruciate ligament (ACL). DESIGN: Prospective diagnostic study. SETTINGS: Orthopedic clinic, physiotherapy clinic, orthopedic hospital, and diagnostic/image clinic. PARTICIPANTS: Consecutive patients (n = 29) with unilateral knee complaint submitted to physical examination, magnetic resonance images (MRIs), and isokinetic testing prior to surgery of ACL reconstruction. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The isokinetic torque curves data from extensor and flexor muscles were converted to frequency domain by fast Fourier transformation and compared with healthy contralateral limb. Differences were categorized as unstable knees and these conclusions were compared with patient's physical examinations (doctor's conclusion on ACL integrity) and MRIs (as the radiologist conclusions on ACL integrity). After surgery, all intraoperatively confirmed partial injured patient's data were collected. The diagnostic accuracy measures to compare the conclusions of all 3 professionals included sensitivity, specificity, positive predictive value, negative predictive value, disease prevalence, positive likelihood ratio, and accuracy-all using a confidence interval of 95%. RESULTS: Compared with MRI, the sensitivity of isokinetic test for an ACL partial injury was 90.00%, specificity 83.33%, positive predictive value 52.94%, negative predictive value 97.56%, and accuracy 84.48%. Compared with physical examination, the sensitivity of isokinetic test for an ACL partial injury was 85.71%, specificity 78.43%, positive predictive value 35.29%, negative predictive value 97.56%, and accuracy 79.31%. CONCLUSIONS: This method of isokinetic data analysis through fast Fourier transformation can be used to improve diagnostic accuracy of a difficult detection injury. Even present, a partial ACL injury can produce a stable knee during isokinetic testing and could be used to detect candidates for conservative treatment based on strengthening exercises, reducing surgery risks, and financial and social impact on patient's life.

Annexin A1-derived peptide Ac2-26 in a pilocarpine-induced status epilepticus model: anti-inflammatory and neuroprotective effects.

BACKGROUND: The inflammatory process has been described as a crucial mechanism in the pathophysiology of temporal lobe epilepsy. The anti-inflammatory protein annexin A1 (ANXA1) represents an interesting target in the regulation of neuroinflammation through the inhibition of leukocyte transmigration and the release of proinflammatory mediators. In this study, the role of the ANXA1-derived peptide Ac2-26 in an experimental model of status epilepticus (SE) was evaluated. METHODS: Male Wistar rats were divided into Naive, Sham, SE and SE+Ac2-26 groups, and SE was induced by intrahippocampal injection of pilocarpine. In Sham animals, saline was applied into the hippocampus, and Naive rats were only handled. Three doses of Ac2-26 (1 mg/kg) were administered intraperitoneally (i.p.) after 2, 8 and 14 h of SE induction. Finally, 24 h after the experiment-onset, rats were euthanized for analyses of neuronal lesion and inflammation. RESULTS: Pilocarpine induced generalised SE in all animals, causing neuronal damage, and systemic treatment with Ac2-26 decreased neuronal degeneration and albumin levels in the hippocampus. Also, both SE groups showed an intense influx of microglia, which was corroborated by high levels of ionised calcium binding adaptor molecule 1(Iba-1) and monocyte chemoattractant protein-1 (MCP-1) in the hippocampus. Ac2-26 reduced the astrocyte marker (glial fibrillary acidic protein; GFAP) levels, as well as interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and growth-regulated alpha protein (GRO/KC). These effects of the peptide were associated with the modulation of the levels of formyl peptide receptor 2, a G-protein-coupled receptor that binds to Ac2-26, and the phosphorylated extracellular signal-regulated kinase (ERK) in the hippocampal neurons. CONCLUSIONS: The data suggest a neuroprotective effect of Ac2-26 in the epileptogenic processes through downregulation of inflammatory mediators and neuronal loss.

Observation of Light-by-Light Scattering in Ultraperipheral Pb+Pb Collisions with the ATLAS Detector.

This Letter describes the observation of the light-by-light scattering process, γγ→γγ, in Pb+Pb collisions at sqrt[s_{NN}]=5.02 TeV. The analysis is conducted using a data sample corresponding to an integrated luminosity of 1.73 nb^{-1}, collected in November 2018 by the ATLAS experiment at the LHC. Light-by-light scattering candidates are selected in events with two photons produced exclusively, each with transverse energy E_{T}^{γ}>3 GeV and pseudorapidity |η_{γ}|<2.4, diphoton invariant mass above 6 GeV, and small diphoton transverse momentum and acoplanarity. After applying all selection criteria, 59 candidate events are observed for a background expectation of 12±3 events. The observed excess of events over the expected background has a significance of 8.2 standard deviations. The measured fiducial cross section is 78±13(stat)±7(syst)±3(lumi) nb.

Combination of Searches for Invisible Higgs Boson Decays with the ATLAS Experiment.

Dark matter particles, if sufficiently light, may be produced in decays of the Higgs boson. This Letter presents a statistical combination of searches for H→invisible decays where H is produced according to the standard model via vector boson fusion, Z(ℓℓ)H, and W/Z(had)H, all performed with the ATLAS detector using 36.1 fb^{-1} of pp collisions at a center-of-mass energy of sqrt[s]=13 TeV at the LHC. In combination with the results at sqrt[s]=7 and 8 TeV, an exclusion limit on the H→invisible branching ratio of 0.26(0.17_{-0.05}^{+0.07}) at 95% confidence level is observed (expected).