The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts

Sarcoplasmic reticulum (SR) Ca2+ cycling is governed by the cardiac ryanodine receptor (RyR2) and SR Ca2+-ATPase (SERCA2a). Abnormal SR Ca2+ cycling is thought to be the primary cause of Ca2+ alternans that can elicit ventricular arrhythmias and sudden cardiac arrest. Although alterations in either RyR2 or SERCA2a function are expected to affect SR Ca2+ cycling, whether and to what extent altered RyR2 or SERCA2a function affects Ca2+ alternans is unclear. Here we employed a gain-of-function RyR2 variant (R4496C) and the phospholamban-knockout (PLB-KO) mouse model to assess the effect of genetically enhanced RyR2 or SERCA2a function on Ca2+ alternans. Confocal Ca2+ imaging revealed that RyR2-R4496C shortened SR Ca2+ release refractoriness and markedly suppressed rapid pacing-induced Ca2+ alternans. Interestingly, despite enhancing RyR2 function, intact RyR2-R4496C hearts exhibited no detectable spontaneous SR Ca2+ release events during pacing. Unlike for RyR2, enhancing SERCA2a function by ablating PLB exerted a relatively minor effect on Ca2+ alternans in intact hearts expressing RyR2 wildtype or a loss-of-function RyR2 variant, E4872Q, that promotes Ca2+ alternans. Furthermore, partial SERCA2a inhibition with 3 µM 2,5-di-tert-butylhydroquinone (tBHQ) also had little impact on Ca2+ alternans, while strong SERCA2a inhibition with 10 µM tBHQ markedly reduced the amplitude of Ca2+ transients and suppressed Ca2+ alternans in intact hearts. Our results demonstrate that enhanced RyR2 function suppresses Ca2+ alternans in the absence of spontaneous Ca2+ release and that RyR2, but not SERCA2a, is a key determinant of Ca2+ alternans in intact working hearts, making RyR2 an important therapeutic target for cardiac alternans.Peer ReviewedPostprint (published version

Role of FOXO3 Activated by HIV-1 Tat in HIV-Associated Neurocognitive Disorder Neuronal Apoptosis

There are numerous types of pathological changes in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), including apoptosis of neurons. HIV-1 transactivator of transcription (Tat) protein, which is encoded by HIV-1, may promote apoptosis in HAND. Forkhead box O3 (FOXO3) is a multispecific transcription factor that has roles in many biological processes, including cellular apoptosis. The aim of this study was to determine whether FOXO3 is activated by HIV-1 Tat and to investigate its role in neuronal apoptosis in HAND. We employed tissue staining and related molecular biological experimental methods to confirm our hypothesis. The in vivo experimental results demonstrated that the expression of nuclear FOXO3 increased in the apoptotic neurons of the cerebral cortexes of rhesus macaques infected with simian human immunodeficiency virus (SHIV). The in vitro investigation showed that HIV-1 Tat activated FOXO3, causing it to move from the cytoplasm to the nucleus via the c-Jun N-terminal kinase (JNK) signaling pathway in SH-SY5Y cells. Moreover, FOXO3 down-regulated expression of the anti-apoptosis gene B-cell lymphoma 2 (Bcl-2) and up-regulated the expression of the pro-apoptosis gene Bcl-2-like 11 (Bim) after entering the nucleus, eventually causing cellular apoptosis. Finally, reduction of nuclear FOXO3 reversed cellular apoptosis. Our results suggest that HIV-1 Tat induces FOXO3 to translocate from the cytoplasm to the nucleus via the JNK signaling pathway, leading to neuronal apoptosis. Agents targeting FOXO3 may provide approaches for restoring neuronal function in HAND

Ca 2+-CaM Dependent Inactivation of RyR2 Underlies Ca 2+ Alternans in Intact Heart

Rationale: Ca2+ alternans plays an essential role in cardiac alternans that can lead to ventricular fibrillation, but the mechanism underlying Ca2+ alternans remains undefined. Increasing evidence suggests that Ca2+ alternans results from alternations in the inactivation of cardiac RyR2 (ryanodine receptor 2). However, what inactivates RyR2 and how RyR2 inactivation leads to Ca2+ alternans are unknown. Objective: To determine the role of CaM (calmodulin) on Ca2+ alternans in intact working mouse hearts. Methods and results: We used an in vivo local gene delivery approach to alter CaM function by directly injecting adenoviruses expressing CaM-wild type, a loss-of-function CaM mutation, CaM (1-4), and a gain-of-function mutation, CaM-M37Q, into the anterior wall of the left ventricle of RyR2 wild type or mutant mouse hearts. We monitored Ca2+ transients in ventricular myocytes near the adenovirus-injection sites in Langendorff-perfused intact working hearts using confocal Ca2+ imaging. We found that CaM-wild type and CaM-M37Q promoted Ca2+ alternans and prolonged Ca2+ transient recovery in intact RyR2 wild type and mutant hearts, whereas CaM (1-4) exerted opposite effects. Altered CaM function also affected the recovery from inactivation of the L-type Ca2+ current but had no significant impact on sarcoplasmic reticulum Ca2+ content. Furthermore, we developed a novel numerical myocyte model of Ca2+ alternans that incorporates Ca2+-CaM-dependent regulation of RyR2 and the L-type Ca2+ channel. Remarkably, the new model recapitulates the impact on Ca2+ alternans of altered CaM and RyR2 functions under 9 different experimental conditions. Our simulations reveal that diastolic cytosolic Ca2+ elevation as a result of rapid pacing triggers Ca2+-CaM dependent inactivation of RyR2. The resultant RyR2 inactivation diminishes sarcoplasmic reticulum Ca2+ release, which, in turn, reduces diastolic cytosolic Ca2+, leading to alternations in diastolic cytosolic Ca2+, RyR2 inactivation, and sarcoplasmic reticulum Ca2+ release (ie, Ca2+ alternans). Conclusions: Our results demonstrate that inactivation of RyR2 by Ca2+-CaM is a major determinant of Ca2+ alternans, making Ca2+-CaM dependent regulation of RyR2 an important therapeutic target for cardiac alternans.This work was supported by research grants from the Heart and Stroke Foundation of Canada (G-19-0026444), the Heart and Stroke Foundation Chair in Cardiovascular Research (END611955), the Canadian Institutes of Health Research to S.R.W. Chen (PJT-155940), the Spanish Ministry of Science Innovation and Universities SAF2017-88019-C3-1R, 2R, and 3R (to L. Hove-Madsen, R. Benitez, and B. Echebarria), Marato-TV3 20152030 (to L. Hove-Madsen) and 20151110 (to B. Echebarria), and Generalitat de Catalunya SGR2017-1769 (to L. Hove-Madsen).Peer reviewe

A BERT-Span model for Chinese named entity recognition in rehabilitation medicine

Background Due to various factors such as the increasing aging of the population and the upgrading of people’s health consumption needs, the demand group for rehabilitation medical care is expanding. Currently, China’s rehabilitation medical care encounters several challenges, such as inadequate awareness and a scarcity of skilled professionals. Enhancing public awareness about rehabilitation and improving the quality of rehabilitation services are particularly crucial. Named entity recognition is an essential first step in information processing as it enables the automated extraction of rehabilitation medical entities. These entities play a crucial role in subsequent tasks, including information decision systems and the construction of medical knowledge graphs. Methods In order to accomplish this objective, we construct the BERT-Span model to complete the Chinese rehabilitation medicine named entity recognition task. First, we collect rehabilitation information from multiple sources to build a corpus in the field of rehabilitation medicine, and fine-tune Bidirectional Encoder Representation from Transformers (BERT) with the rehabilitation medicine corpus. For the rehabilitation medicine corpus, we use BERT to extract the feature vectors of rehabilitation medicine entities in the text, and use the span model to complete the annotation of rehabilitation medicine entities. Result Compared to existing baseline models, our model achieved the highest F1 value for the named entity recognition task in the rehabilitation medicine corpus. The experimental results demonstrate that our method outperforms in recognizing both long medical entities and nested medical entities in rehabilitation medical texts. Conclusion The BERT-Span model can effectively identify and extract entity knowledge in the field of rehabilitation medicine in China, which supports the construction of the knowledge graph of rehabilitation medicine and the development of the decision-making system of rehabilitation medicine

A polynomial algorithm for a lot sizing problem with backlogging, outsourcing models and limited inventory

International audienceThis paper addresses a real-life production planning problem arising in a manufacturer of luxury goods. This problem can be modeled as a single item dynamic lot-sizing model with backlogging, outsourcing and inventory capacity. Setup cost is included in the production cost function, and the production level at each period is unbounded. The holding, backlogging and outsourcing cost functions are assumed to be linear. The backlogging level at each period is also limited. The goal is to satisfy all demands in the planning horizon at minimal total cost. We show that this problem can be solved in O(T4 log T) time where T is the number of periods in the planning horizon

Polynomial dynamic programming algorithms for lot sizing models with bounded inventory and stockout and/or backlogging

International audienceThis paper addresses a dynamic lot sizing problem with bounded inventory and stockout where both no backlogging and backlogging allowed cases are considered. The stockout option means that there is outsourcing in a period only when the inventory level at that period is non-positive. The production capacity is unlimited and production cost functions are linear but with fixed charges. The problem is that of satisfying all demands in the planning horizon at minimal total cost. We show that the no backlogging case can be solved in ) O(T2) time with general concave inventory holding and outsourcing cost functions where T is the length of the planning horizon. The complexity can be reduced to O(T) when the inventory holding cost functions are also linear and have some realistic properties, even if the outsourcing cost functions remain general concave functions. When the inventory holding and outsourcing cost functions are linear, the backlogging case can be solved in O(T3logT) time whether the outsourcing level at each period is bounded by the sum of the demand of that period and backlogging level from previous periods, or only by the demand of that period

A Polynomial Algorithm for a Lot-Sizing Problem with Backlogging

a b s t r a c t This paper addresses a real-life production planning problem arising in a manufacturer of luxury goods. This problem can be modeled as a single item dynamic lot-sizing model with backlogging, outsourcing and inventory capacity. Setup cost is included in the production cost function, and the production level at each period is unbounded. The holding, backlogging and outsourcing cost functions are assumed to be linear. The backlogging level at each period is also limited. The goal is to satisfy all demands in the planning horizon at minimal total cost. We show that this problem can be solved in O(T 4 log T) time where T is the number of periods in the planning horizon

2006: Can CGCMs simulate the Twentieth Century “warming hole” in the central United States

ABSTRACT The observed lack of twentieth-century warming in the central United States (CUS), denoted here as the "warming hole," was examined in 55 simulations driven by external historical forcings and in 19 preindustrial control (unforced) simulations from 18 coupled general circulation models (CGCMs). Twentiethcentury CUS trends were positive for the great majority of simulations, but were negative, as observed, for seven simulations. Only a few simulations exhibited the observed rapid rate of warming (cooling) during 1901-40 (1940-79). Those models with multiple runs (identical forcing but different initial conditions) showed considerable intramodel variability with trends varying by up to 1.8°C century Ϫ1 , suggesting that internal dynamic variability played a major role at the regional scale. The wide range of trend outcomes, particularly for those models with multiple runs, and the small number of simulations similar to observations in both the forced and unforced experiments suggest that the warming hole is not a robust response of contemporary CGCMs to the estimated external forcings. A more likely explanation based on these models is that the observed warming hole involves external forcings combined with internal dynamic variability that is much larger than typically simulated. The observed CUS temperature variations are positively correlated with North Atlantic (NA) sea surface temperatures (SSTs), and both NA SSTs and CUS temperature are negatively correlated with central equatorial Pacific (CEP) SSTs. Most models simulate rather well the connection between CUS temperature and NA SSTs. However, the teleconnections between NA and CEP SSTS and between CEP SSTs and CUS temperature are poorly simulated and the models produce substantially less NA SST variability than observed, perhaps hampering their ability to reproduce the warming hole