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Machine learning is an important applied research area in particle physics, beginning with applications to high-level physics analysis in the 1990s and 2000s, followed by an explosion of applications in particle and event identification and reconstruction in the 2010s. In this document we discuss promising future research and development areas in machine learning in particle physics with a roadmap for their implementation, software and hardware resource requirements, collaborative initiatives with the data science community, academia and industry, and training the particle physics community in data science. The main objective of the document is to connect and motivate these areas of research and development with the physics drivers of the High-Luminosity Large Hadron Collider and future neutrino experiments and identify the resource needs for their implementation. Additionally we identify areas where collaboration with external communities will be of great benefit.

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament-associated protein that binds tightly to myosin and has a potential role for modulating myocardial contraction. We tested the hypothesis that cMyBP-C 1) contributes to the enhanced in vivo contractile state following [beta]-adrenergic stimulation and 2) is necessary for myocardial adaptation to chronic increases in afterload. In vivo pressure-volume relations demonstrated that left ventricular (LV) systolic and diastolic function were compromised under basal conditions in cMyBP-[C.sup.-/-] compared with WT mice. Moreover, whereas [beta]-adrenergic treatment significantly improved ejection fraction, peak elastance, and the time to peak elastance in WT mice, these functional indexes remained unchanged in cMyBP-[C.sup.-/-] mice. Morphological and functional changes were measured through echocardiography in anesthetized mice following 5 wk of aortic banding. Adaptation to pressure overload was diminished in cMyBP-[C.sup.-/-] mice as characterized by a lack of an increase in posterior wall thickness, increased LV diameter, deterioration of fractional shortening, and prolonged isovolumic relaxation time. These results suggest that the absence of cMyBP-C significantly diminishes in vivo LV function and markedly attenuates the increase in LV contractility following [beta]-adrenergic stimulation or adaptation to pressure overload. aortic handing; pressure-volume relations; dobutamine

In this article the authors comment on a study on the measurement of right ventricular (RV) function in mice using admittance-derived pressure-volume loops. The authors assert that the study showed that it was possible to obtain or estimate pressure volume loops and to derive RV contractile function using mice models. They believe that RV response to chronic pressure overload can be fully understood through assessments of RV contractile function and reserve.

The small splice variant of the sulfonylurea receptor protein isoform 2 A (SUR2A-55) targets mitochondria and enhances mitoK ATP activity. In male mice the overexpression of this protein promotes cardioprotection, reducing myocardial injury after an ischemic insult. However, it is unclear what impact SUR2A-55 overexpression has on the female myocardium. To investigate the impact of SU2R2A-55 on the female heart, mice with cardiac specific transgenic overexpression of SUR2A-55 (TG SUR2A-55 ) were examined by resting echocardiography and histopathology. In addition, hearts were subjected to ischemia reperfusion (IR) injury. Female TG SUR2A-55 mice had resting LV dysfunction and worse hemodynamic recovery with increased infarct size after IR injury. RNA-seq analysis found 227 differential expressed genes between WT and TG SUR2A-55 female mouse hearts that were enriched in pathways of cellular metabolism. This was in direct contrast to male mice that had only four differentially expressed genes. Female TG SUR2A-55 mice compared to female WT mice had reduced cardiomyocyte mitochondrial membrane potential without a change in electron transport chain protein expression. In addition, isolated mitochondria from female TG SUR2A-55 hearts displayed reduced sensitivity to ATP and diazoxide suggestive of increased mitoK ATP activity. In conclusion, our data suggests that female TG SUR2A-55 mice are unable to tolerate a more active mitoK ATP channel leading to LV dysfunction and worse response to IR injury. This is in direct contrast to our prior report showing cardioprotection in male mice overexpressing SUR2A-55 in heart. Future research directed at examining the expression and activity of mitoK ATP subunits according to sex may elucidate different treatments for male and female patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Computational models provide an efficient paradigm for integrating and linking multiple spatial and temporal scales. However, these models are difficult to parameterize and match to experimental data. Recent advances in both data collection and model analyses have helped overcome this limitation. Here, we combine a multiscale, biventricular interaction model with mouse data before and after left ventricular (LV) ischemia. Sensitivity analyses are used to identify the most influential parameters on pressure and volume predictions. The subset of influential model parameters are calibrated to biventricular pressure-volume loop data (n=3) at baseline. Each mouse underwent left anterior descending coronary artery ligation, during which changes in fractional shortening and RV pressure-volume dynamics were recorded. Using the calibrated model, we simulate acute LV ischemia and contrast outputs at baseline and in simulated ischemia. Our baseline simulations align with the LV and RV data, and our predictions during ischemia complement recorded RV data and prior studies on LV function during myocardial infarction. We show that a model with both biventricular mechanical interaction and systems level cardiovascular dynamics can quantitatively reproduce in-vivo data and qualitatively match prior findings from animal studies on LV ischemia.

Objective: We meta-analyzed studies comparing perceptual timing abilities in the range of milliseconds to several seconds in persons with attention-deficit/hyperactivity disorder (ADHD) and neurotypical participants, using the well-established time discrimination, time estimation, time production, and time reproduction paradigms., Method: We searched PubMed, OVID databases, and Web of Knowledge through September 17, 2020. From 2,266 records, 55 studies were retained and meta-analyzed with random effects models. We conducted meta-regression analyses to explore moderating effects of task parameters and neuropsychological measures of working memory, attention, and inhibition on timing performance., Results: Compared with persons without ADHD, those with ADHD had significantly more severe difficulties in discriminating stimuli of very brief durations, especially in the sub-second range. They also had more variability in estimating the duration of stimuli lasting several seconds. Moreover, they showed deficits in time estimation and time production accuracy, indicative of an accelerated internal clock. Additional deficits in persons with ADHD were also found in the time reproduction paradigm, involving attentional (slower counting at short time intervals due to distraction) and motivational (faster counting at long time intervals due to increased delay aversion) functions., Conclusion: There is meta-analytic evidence of a broad range of timing deficits in persons with ADHD. Results have implications for advancing our knowledge in the field (eg, for refinement of recent timing models in ADHD) and clinical practice (eg, testing timing functions to characterize the clinical phenotype of the patient and implementation of interventions to improve timing abilities)., (Copyright © 2021 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Dilated cardiomyopathy (DCM) is a heritable and genetically heterogenous disease often idiopathic and a leading cause of heart failure with high morbidity and mortality. DCM caused by RNA binding motif protein 20 (RBM20) mutations is diverse and needs a more complete mechanistic understanding. RBM20 mutation S637G (S639G in mice) is linked to severe DCM and early death in human patients. In this study, we generated a RBM20 S639G mutation knock-in (KI) mouse model to validate the function of S639G mutation and examine the underlying mechanisms. KI mice exhibited severe DCM and premature death with a ~ 50% mortality in two months old homozygous (HM) mice. KI mice had enlarged atria and increased ANP and BNP biomarkers. The S639G mutation promoted RBM20 trafficking and ribonucleoprotein (RNP) granules in the sarcoplasm. RNA Seq data revealed differentially expressed and spliced genes were associated with arrhythmia, cardiomyopathy, and sudden death. KI mice also showed a reduction of diastolic stiffness and impaired contractility at both the left ventricular (LV) chamber and cardiomyocyte levels. Our results indicate that the RBM20 S639G mutation leads to RNP granules causing severe heart failure and early death and this finding strengthens the novel concept that RBM20 cardiomyopathy is a RNP granule disease., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Piezoelectric biomaterials are intrinsically suitable for coupling mechanical and electrical energy in biological systems to achieve in vivo real-time sensing, actuation, and electricity generation. However, the inability to synthesize and align the piezoelectric phase at a large scale remains a roadblock toward practical applications. We present a wafer-scale approach to creating piezoelectric biomaterial thin films based on γ-glycine crystals. The thin film has a sandwich structure, where a crystalline glycine layer self-assembles and automatically aligns between two polyvinyl alcohol (PVA) thin films. The heterostructured glycine-PVA films exhibit piezoelectric coefficients of 5.3 picocoulombs per newton or 157.5 × 10 -3 volt meters per newton and nearly an order of magnitude enhancement of the mechanical flexibility compared with pure glycine crystals. With its natural compatibility and degradability in physiological environments, glycine-PVA films may enable the development of transient implantable electromechanical devices., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Sickle cell disease (SCD) is a hereditary blood disorder affecting millions of people in which red blood cells (RBCs) become sickled and lyse easily driven by polymerization of hemoglobin. Chronically, SCD causes anemia and biventricular dysfunction. GBT440 is an experimental treatment for SCD that prevents hemoglobin polymerization. We hypothesized that 17-month-old Berkeley SCD mice treated with GBT440 would have increased hematocrit (Hct) and better biventricular function compared to vehicle treated SCD mice. Our results demonstrate that 3 weeks of GBT440 treatment eliminated chronic anemia, increased left ventricular ejection fraction (LVEF) and stroke volume index, and improved right ventricular function. Overall, our findings support a therapeutic effect of GBT440 in vivo in a small animal model of SCD. Next steps in investigating mechanisms of improved cardiac function are warranted., (Copyright © 2021 by ASME.)

Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging., Competing Interests: CONFLICT OF INTEREST STATEMENT D.W.L has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. The University of Wisconsin-Madison has applied for a patent for the use of branched-chain amino acid restricted diets to promote metabolic health, for which NER and DWL are inventors.

Objective: Impulsive choices can lead to suboptimal decision making, a tendency which is especially marked in individuals with ADHD. We compared two different paradigms assessing impulsive choice: the simple choice paradigm (SCP) and the temporal discounting paradigm (TDP). Method: Random effects meta-analyses on 37 group comparisons (22 SCP; 15 TDP) consisting of 3.763 participants (53% ADHD). Results: Small-to-medium effect sizes emerged for both paradigms, confirming that participants with ADHD choose small immediate over large delayed rewards more frequently than controls. Moderation analyses show that offering real rewards in the SCP almost doubled the odds ratio for participants with ADHD. Conclusion: We suggest that a stronger than normal aversion toward delay interacts with a demotivating effect of hypothetical rewards, both factors promoting impulsive choice in participants with ADHD. Furthermore, we suggest the SCP as the paradigm of choice due to its larger ecological validity, contextual sensitivity, and reliability.

Emotional interference control refers to the ability to remain focused on goal-oriented processes when confronted with disrupting but irrelevant emotional stimuli, a process that may be impaired in children and adults with attention deficit/hyperactivity disorder (ADHD). However, emotional interference levels are known to be associated with trait anxiety, and patients with ADHD often display elevated levels of trait anxiety, such as these may have confounded previous findings of decreased emotional interference control in this population. In the present study, male and female 8-13 years old (mean =11.0 years) children with ADHD (n=33) and typically developing (TD) children (n=24) performed a visual emotional working memory (n-back) task with 2 memory loads and three different background pictures (neutral/positive/negative), and trait anxiety measures were obtained. Children with ADHD performed less well, and displayed increased emotional interference in the presence of aversive distractors when compared with TD children. Contrary to our expectations, trait anxiety did not mediate the association between diagnostic group membership and the degree of emotional interference control; however, co-morbid ODD was associated with decreased levels of emotional interference in ADHD. Future research should aim at characterizing the mechanisms subtending decreased emotional interference control in the ADHD population., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)