Rate of Convergence Towards Hartree Dynamics

We consider a system of N bosons interacting through a two-body potential with, possibly, Coulomb-type singularities. We show that the difference between the many-body Schr\"odinger evolution in the mean-field regime and the effective nonlinear Hartree dynamics is at most of the order 1/N, for any fixed time. The N-dependence of the bound is optimal.Comment: 26 page

Cyclic Tetrapyrrolic Photosensitisers from the leaves of Phaeanthus ophthalmicus

<p>Abstract</p> <p>Background</p> <p>Twenty-seven extracts from 26 plants were identified as photo-cytotoxic in the course of our bioassay guided screening program for photosensitisers from 128 extracts prepared from 64 terrestrial plants in two different collection sites in Malaysia - Royal Belum Forest Reserve in the State of Perak and Gunung Nuang in the State of Selangor. One of the photo-cytotoxic extracts from the leaves of <it>Phaeanthus ophtalmicus </it>was further investigated.</p> <p>Results</p> <p>The ethanolic extract of the leaves from <it>Phaeanthus ophtalmicus </it>was able to reduce the <it>in vitro </it>viability of leukaemic HL60 cells to < 50% when exposed to 9.6 J/cm²of a broad spectrum light at a concentration of 20 μg/mL. Dereplication of the photo-cytotoxic fractions from <it>P. ophthalmicus </it>extracts based on TLC R_fvalues and HPLC co-injection of reference tetrapyrrolic compounds enabled quick identification of known photosensitisers, pheophorbide-<it>a</it>, pheophorbide-<it>a </it>methyl ester, 13²-hydroxypheophorbide-<it>a </it>methyl ester, pheophytin-<it>a </it>and 15¹-hydroxypurpurin 7-lactone dimethyl ester. In addition, compound <b>1 </b>which was not previously isolated as a natural product was also identified as 7-formyl-15¹-hydroxypurpurin-7-lactone methyl ester using standard spectroscopic techniques.</p> <p>Conclusions</p> <p>Our results suggest that the main photosensitisers in plants are based on the cyclic tetrapyrrole structure and photosensitisers with other structures, if present, are present in very minor amounts or are not as active as those with the cyclic tetrapyrrole structure.</p

A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression

Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features transdifferentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin–LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. Significance: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration

Coronary artery calcification – distribution, extent and 1-year outcomes in patients with low to intermediate pre-test probability of coronary artery disease.

Background: Coronary artery calcium (CAC) is an established marker to predict major cardiovascular events (MACE), and has incremental value over traditional risk factors (CVRF). CAC is widely available, easily reproducible, and used in nearly all coronary computed tomography angiography (CCTA) assessment protocols for coronary artery disease (CAD). The distribution and extent of CAC, and its prognostic implications in local Malaysian patients with low to intermediate pre-test probability (LI-PTP) of CAD had not been established. Objectives: We aimed to establish the distribution, extent and prognostic implications of CAC in patients without known CAD, but with LI-PTP of CAD, undergoing CCTA for chest pain evaluation. Methods: Clinical information was obtained from consecutive patients who underwent CAC and CCTA examination from January 2020 to January 2021 at a single public access tertiary referral centre. The primary outcomes were the distribution and extent of CAC, and its relationship with MACE at 1 year. Results: Of 499 consecutive patients, 7 were excluded due to high PTP. CAC was present in 172/492 (35%). Within this group, 74/172 (41.3%) had CAC score of 1-100 (mild), 75/172 (42.4%) had a CAC of 101- 400 (moderate), 23/172 (13.4%) had CAC of >400 (high). 136 had suspected significant CAD and was offered conventional coronary angiography (CCA). 91/492 underwent CCA, and 38 were found to have significant CAD. Of those found to have significant CAD, 7/38 (18.4%) had CAC of zero, 8/38 (21.1%) had mild CAC, 12/38 (31.6%) moderate, and 11/38 (30%) high CAC. Severe CAC was associated with a higher rate of revascularization 11/23 (47.8%), compared to those with zero 7/320 (2.2%), mild 8/74 (10.8%) and moderate 12/75 (16%) CAC. Predictors of high CAC were age, male gender, and presence of cardiovascular disease risk factors. Of the 492 patients, 230 patients completed 1 year follow-up, and from this, 1 patient had a MACE. Conclusion In patients with LI-PTP risk of CAD, CAC was seen in approximately one third of our cohort. In the group with high CAC, a higher proportion required coronary revascularization, but MACE remained low at 1 year

Utility of Dutch Lipid Clinic Network Score to Estimate Prevalence of Familial Hypercholestrolemia in Patients with ST-Elevation Myocardial Infarction

Background Hypercholesterolaemia is prevalent in the Malaysian population, and its treatment control rates remain suboptimal1. Familial hypercholesterolemia (FH) is an autosomal dominant condition that leads to accelerated arteriosclerotic cardiovascular disease (ASCVD). The prevalence of FH in the general population worldwide has been postulated to be 1:3132 and 1:100 in the Malaysian community3. It has been proposed that lipid lowering treatment prevents further increase in total cardiovascular risk of FH patients, and this recommendation is extensible for FH patients plus atherosclerotic CAD (coronary artery disease). However, despite its implication in CAD, FH is still an underdiagnosed and undertreated condition2-4. To date, the prevalence of FH in the STEMI (ST-elevation myocardial infarction) population in Malaysia is not studied. Establishing the prevalence of FH among patients with CAD and comparing this with the general population would help future efforts at identifying subjects with FH. Objective We aim to estimate the prevalence of FH in patients with STEMI in Sarawak using Dutch Lipid Clinic Network (DLCN) score. Materials and Methods Patients who were admitted for type-1 STEMI from April 2021 until July 2021 to Pusat Jantung Sarawak were recruited. History taking and physical examination were carried out on-site. FH was screened clinically using DLCN score. Results Out of the recruited patients, 45% of the cohort was clinically categorized into probable/ possible FH without genetic testing. Mean age and low density lipoprotein (LDL) were 52.7 and 3.38mmol/l respectively. Prevalence of premature CAD was 63%. Male gender, smoking, high BMI was the most frequent risk factor observed. Conclusions Prevalence of probable/possible familial hypercholesterolemia in a STEMI cohort using DLCN score is 45%. DLCN score in the STEMI cohort is not related to LDL levels

Prevalence of Acid alpha-Glucosidase (GAA) Pseudodefiency Allele and It’s Clinical Significance Among Patients with Cardiomyopathy

Background: Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of lysosomal acid alpha-glucosidase (GAA) activity, leading to the progressive accumulation of glycogen in lysosomes of the skeletal and cardiac muscles. An alpha-glucosidase (GAA) pseudodeficiency allele is a change in the GAA gene sequence that results in GAA enzyme activity reduction, but does not cause Pompe disease. In Japan and Taiwan, there is high prevalence of pseudodeficiency allele (c.1725G>A and c.2065G>A) detected from their newborn screening. We observed similar prevalence of pseudodeficiency allele among our patients who had genetic test performed for suspected hereditary cardiomyopathy. Objectives: To report the prevalence of GAA pseudodeficiency allele, and to ascertain its clinical significance among patients with cardiomyopathy. Methods: The clinical data of the patients with GAA mutations were retrieved. Patients were called back for neurological examination, lung function test, measurement of creatine kinase (CK) level and dried-blood-spot for GAA enzymatic activity. Results: From January to December 2021, 33 patients underwent genetic testing. 23 out of the 33 genetic analyses included GAA mutation. 9 (39.13%) out of 23 were tested positive for pseudodeficiency allele. Their median age was 53 years (range 29-82), 44.4% were males with equal ethnic distribution (33.3% Malay, 33.3% Chinese, 33.3% Dayaks). All were heterozygous for the pseudodeficiency allele: 5 (55.6%) with c.[1726A; 2065A] allele, the other 4 (44.4%) c.2065G>A. The underlying cardiomyopathy phenotypes were hypertrophic (44.4%), transthyretin amyloid (22.2%), hypertensive (22.2%) and Fabry (11.1%). 1 patient (11.1%) with transthyretin amyloid cardiomyopathy died of advanced heart failure at age 79 years. 1 patient had mild motor weakness of the limbs attributable to thyrotoxicosis, while the other 7 patients had normal skeletal motor function. Their median predicted forced vital capacity was 87.5% (range 76-103), median CK level was 103 U/L (range 39-297) and median GAA activity was 4.8 micromol/l/h (range 3.2-9.2) [normal > 2.0]. Conclusion: The prevalence of GAA pseudodeficiency allele among patients with cardiomyopathy is 39.13%. None of the patients exhibit significant muscle weakness or respiratory insufficiency despite low normal enzymatic activity. Whether the presence of pseudodeficiency allele affects the prognosis of the underlying cardiomyopathy remains uncertain

Coronary Computed Tomography Angiography as part of initial strategy, in assessment of patients with chest pain – clinical experience and 1 year prognosis.

Background: Coronary computed tomography angiography (CCTA) has been showed to have high specificity and sensitivity for detecting coronary artery disease (CAD). In Malaysia, national guidelines state that CCTA may be used in low- to intermediate pre-test probability (LI-PTP) of CAD, who have an equivocal functional test result, and who are asymptomatic or mildly symptomatic with good exercise capacity. Recent evidence suggested a ‘CCTA-first’ strategy in the evaluation of a patient with chest pain could provide prognostic benefits. Prognostic benefits of adopting this strategy in Malaysia has not been well studied. Objectives: We aimed to evaluate 12-month clinical outcomes of patients with LI-PTP, using the CCTA as an initial strategy, or as part of the work-up for, chest pain assessment. Methods: Consecutive patients who underwent CCTA examination from January 2020 to January 2021 were enrolled. Clinical information was then extracted. Primary outcome was defined as presence of stenosis of >50% in a major epicardial coronary artery; and secondary outcome defined as a composite of all-cause mortality, non-fatal myocardial infarction (MI) and coronary revascularisation. Results: Among the initial 499 patients, 7 were excluded as they were high in PTP. The mean PTP was 47.1±26.3. Baseline characteristics were available in 300 patients. The mean age was 53.5±11.4 years, 59.3% were male, 18.6% were diabetic, 71.2% had hypertension, and 50.8% had hypercholestrolaemia. 1.9% had an equivocal functional test for ischaemia. Of the 492 LI-PTP patients who underwent CCTA, 136 patients were suspected to have significant CAD, and recommended conventional coronary angiography (CCA). Of these, 91 patients underwent CCA. From this group 38 were found to have significant CAD which warranted revascularisation – 32 by percutaneous coronary intervention (PCI) and 6 referred for coronary artery bypass surgery (CABG). Therefore, utilising this strategy, 7.7% (38/492) of patients met the primary outcome. Of the original cohort of 492 LI-PTP patients, only 230 completed 1 year follow up, and from this, one patient met the secondary outcome. Conclusion Incorporation of CCTA into contemporary chest pain evaluation identified significant number of patients with significant CAD and was also associated with a low cardiac event rate at 1 year follow-up

Dynamically-Driven Inactivation of the Catalytic Machinery of the SARS 3C-Like Protease by the N214A Mutation on the Extra Domain

Despite utilizing the same chymotrypsin fold to host the catalytic machinery, coronavirus 3C-like proteases (3CLpro) noticeably differ from picornavirus 3C proteases in acquiring an extra helical domain in evolution. Previously, the extra domain was demonstrated to regulate the catalysis of the SARS-CoV 3CLpro by controlling its dimerization. Here, we studied N214A, another mutant with only a doubled dissociation constant but significantly abolished activity. Unexpectedly, N214A still adopts the dimeric structure almost identical to that of the wild-type (WT) enzyme. Thus, we conducted 30-ns molecular dynamics (MD) simulations for N214A, WT, and R298A which we previously characterized to be a monomer with the collapsed catalytic machinery. Remarkably, three proteases display distinctive dynamical behaviors. While in WT, the catalytic machinery stably retains in the activated state; in R298A it remains largely collapsed in the inactivated state, thus implying that two states are not only structurally very distinguishable but also dynamically well separated. Surprisingly, in N214A the catalytic dyad becomes dynamically unstable and many residues constituting the catalytic machinery jump to sample the conformations highly resembling those of R298A. Therefore, the N214A mutation appears to trigger the dramatic change of the enzyme dynamics in the context of the dimeric form which ultimately inactivates the catalytic machinery. The present MD simulations represent the longest reported so far for the SARS-CoV 3CLpro, unveiling that its catalysis is critically dependent on the dynamics, which can be amazingly modulated by the extra domain. Consequently, mediating the dynamics may offer a potential avenue to inhibit the SARS-CoV 3CLpro

AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production

Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-kappa B activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36 alpha, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.Peer reviewe

Outcome measures for the evaluation of treatment response in hidradenitis suppurativa for clinical practice

Importance Although several clinician- and patient-reported outcome measures have been developed for trials in hidradenitis suppurativa (HS), there is currently no consensus on which measures are best suited for use in clinical practice. Identifying validated and feasible measures applicable to the practice setting has the potential to optimize treatment strategies and generate generalizable evidence that may inform treatment guidelines. Objective To establish consensus on a core set of clinician- and patient-reported outcome measures recommended for use in clinical practice and to establish the appropriate interval within which these measures should be applied. Evidence Review Clinician- and patient-reported HS measures and studies describing their psychometric properties were identified through literature reviews. Identified measures comprised an item reduction survey and subsequent electronic Delphi (e-Delphi) consensus rounds. In each consensus round, a summary of outcome measure components and scoring methods was provided to participants. Experts were provided with feasibility characteristics of clinician measures to aid selection. Consensus was achieved if at least 67% of respondents agreed with use of a measure in clinical practice. Findings Among HS experts, response rates for item reduction, e-Delphi round 1, and e-Delphi round 2 surveys were 76.4% (42 of 55), 90.5% (38 of 42), and 92.9% (39 of 42), respectively; among patient research partners (PRPs), response rates were 70.8% (17 of 24), 100% (17 of 17), and 82.4% (14 of 17), respectively. The majority of experts across rounds were practicing dermatologists with 18 to 19 years of clinical experience. In the final e-Delphi round, most PRPs were female (12 [85.7%] vs 2 males [11.8%]) and aged 30 to 49 years. In the final e-Delphi round, HS experts and PRPs agreed with the use of the HS Investigator Global Assessment (28 [71.8%]) and HS Quality of Life score (13 [92.9%]), respectively. The most expert-preferred assessment interval in which to apply these measures was 3 months (27 [69.2%]). Conclusions and Relevance An international group of HS experts and PRPs achieved consensus on a core set of HS measures suitable for use in clinical practice. Consistent use of these measures may lead to more accurate assessments of HS disease activity and life outcomes, facilitating shared treatment decision-making in the practice setting