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Title Abstract Introduction Role of therapeutics Conclusion
Submitted: August 04, 2021 | Approved: August 16, 2021 | Published: August 17, 2021
How to cite this article: D'Souza SM, Yoo BS, Houston KV, Patel AJ, Parekh PJ, et al. Non-alcoholic fatty liver disease: Update on treatment options and translational implications of sleep disruption. Ann Clin Gastroenterol Hepatol. 2021; 5: 032-038.
DOI: 10.29328/journal.acgh.1001030
D'Souza SM: orcid.org/0000-0003-3772-2616
Yoo BS: orcid.org/0000-0002-8501-7922
Houston KV: orcid.org/0000-0002-8441-0132
Patel AJ: orcid.org/0000-0002-6981-3427
Parekh PJ: orcid.org/0000-0003-4750-775X
Johnson DA: orcid.org/0000-0002-8737-0711
Copyright License: © 2021 D'Souza SM, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Non-alcoholic fatty liver disease; Sleep; Circadian rhythms; Dysbiosis; Microbiome
Non-alcoholic fatty liver disease: Update on treatment options and translational implications of sleep disruption
Steve M D'Souza, Byung S Yoo, Kevin V Houston, Ankit J Patel, Parth J Parekh and David A Johnson*
Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA, USA
*Address for Correspondence: David A Johnson MD, MACG, FASGE, MACP, Professor of Medicine/Chief of Gastroenterology, Eastern VA Medical School, Norfolk, VA, USA, Tel: 757 641 6685; Email: dajevms@aol.com
Non-alcoholic fatty liver disease (NAFLD) is a condition that is associated with cirrhosis and hepatocellular carcinoma, and is increasing in prevalence worldwide. Sleep disruptions are commonly seen in NAFLD, and the disease process is associated with sleep disorders, including obstructive sleep apnea, circadian rhythm disorders, and insufficient sleep. The intermittent hypoxia seen in obstructive sleep apnea may contribute to fibrotic changes in the liver.
A major component of this linkage may be related to gut microbiome changes. One notable change is increase in Bacteroidetes/Firmicutes ratio, and decrease in flora that ferment fiber into anti-inflammatory short-chain fatty acids. Several therapeutic options exist for NAFLD that target both sleep and NAFLD, including non-pharmacological factors, such as lifestyle modification (mainly diet and exercise). Pharmacological options include melatonin, Vitamin E, thiazolidinediones, and fecal microbiota transplantation.
The pathogenesis of non-alcoholic fatty liver disease is closely tied to sleep and circadian rhythm abnormalities, through shared inflammatory pathways and altered metabolism. This review explores the pathogenesis of NAFLD in the context of sleep and circadian abnormalities. The associated inflammatory response is linked to changes in gut-microbiome interactions that contribute to the disease process. Understanding of this linkage has implications for various therapies for disease mitigation.
Fatty liver disease is a condition involving lipid accumulation within hepatocytes and has become the most common liver disease worldwide [1]. Non-alcoholic fatty liver disease (NAFLD) is a subset of fatty liver disease and is defined as hepatic steatosis without a cause of secondary fat accumulation such as excessive alcohol consumption, drug-induced etiologies, or hereditary disorders [2]. This subset of fatty liver disease affects an estimated 30% of adults in the United States and a median of 20% adults worldwide [1].
Pathogenesis of NAFLD
Non-alcoholic fatty liver disease is further subdivided into non-alcoholic fatty liver (steatosis) and non-alcoholic steatohepatitis (NASH). The former is an isolated, non-alcoholic fatty liver that histologically involves greater than 5% of the liver parenchyma without inflammation or chronic hepatocyte injury [2]. This is in contrast to the latter, NASH, defined histologically as a necro-inflammatory process where greater than 5% of the liver parenchyma is involved and the hepatocytes become injured in a background of steatosis [2]. This process has been demonstrated to be progressive, with NASH leading to scarring, fibrosis and an increased risk of cirrhosis and hepatocellular carcinoma [3-5].
The pathogenesis of NAFLD involves the accumulation of fat, or lipids, within hepatocytes in the form of triglycerides. The primary reasons for this remain poorly understood, as some patients may have only isolated fat accumulation while others progress to NASH and have more progressive disease [6]. Current understanding involves alterations in metabolic pathways of hepatic lipid metabolism resulting from systemic insulin resistance, oxidative stress, and lipotoxicity [6]. A two-hit hypothesis helps to contextualize the current pathogenesis of NASH: the 'first-hit' consisting of excess hepatic triglyceride accumulation due to dysregulation of fatty acids and insulin resistance in the absence of other causes and the 'second-hit' consisting of oxidative stress and cytokine expression leading to a shift from steatosis to NASH [7,8].
Sleep disruption has been a point of interest in regard to NAFLD, although the exact mechanisms have been poorly understood. Recent studies into NAFLD and various forms of sleep disruption in animal models and the transition to clinical practice will be explored in this article.
Normal circadian function
The human circadian rhythm is marked by the diurnal oscillation of function, affecting sleep, metabolism, and immune response [9-12]. The central regulator of circadian function is the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives light-dark input from the retinohypothalamic tract to regulate circadian function through inhibition/activation of pineal gland production of melatonin, and through production and downstream effects of Circadian Locomotor Output Cycles Kaput (CLOCK) protein [13]. In addition, various tissues, including the liver and pancreas, display circadian automaticity in function, and are referred to as peripheral tissue oscillators [13]. Gastrointestinal circadian function is regulated by timing and frequency of food intake, and can affect the efficiency of nutrient absorption and processing, daily oscillation of gut microbial composition, and the related metabolic and immune consequences [14,15]. Clock protein dimerizes with Bmal1, and binds to an E-box, a DNA-response element site, to increase production of proteins including PER-1, PER-2, CRY-1, and CRY-2, which regulate various metabolic processes as well as provide periodic CLOCK gene inhibition [16,17]. Misalignment between central and peripheral rhythms, such as that seen in night-shift workers, are referred to as circadian dysrhythmia, and can be associated with loss of normal circadian function and metabolic derangements.
OSA and Sleep Disruption in NAFLD
Obstructive sleep apnea (OSA) has been well studied in its relationship to NAFLD. OSA is a sleep disorder characterized by repetitive episodes of non-breathing throughout the night, typically due to an upper airway obstruction or other anatomical abnormality and resulting in either hypopnea or apnea [18]. These episodes lead to wide ranging effects including chronic hypoxia during sleep or activation of the sympathetic nervous system and can have profound effects on the cardiovascular system, endocrine system, central nervous system [18]. Furthermore, this chronic hypoxia may lead to induction of oxidative stress and subsequent lipid peroxidation which could lead to hepatocyte necrosis and apoptosis, a has been postulated to be a key factor in the "second hit" in the pathogenesis of NAFLD [19].
Evidence has shown OSA to be a potential risk factor for the development and progression of NAFLD due to a hypoxia-induced mechanism [20,21]. Chronic hypoxia leads to oxidative stress, lipid peroxidation, and systemic inflammation leading to an imbalance between oxidant and antioxidant agents and a progression of NASH through liver fibrosis. One study evaluated patients with NAFLD through polysomnography and serum analysis [20]. The participants were divided into control, moderate OSA, and severe OSA. The results revealed a significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, low density lipoprotein-cholesterol, and high-sensitivity C-reactive protein with increased severity of OSA. These findings were independent of factors such as age, gender, obesity, inflammation, blood pressure, serum glucose, and lipid profile suggesting nocturnal hypoxia as a risk factor in progression of NAFLD.
While the exact pathophysiologic mechanisms involved in the relationship of OSA and NAFLD are still being investigated, there have been several factors that seem to be at play in this multifactorial process. There is evidence that the chronic intermittent hypoxia may trigger liver injury, induce a systemic inflammatory state, and lead to fibrogenesis [22]. A key factor may be hypoxia-inducible factor 1-alpha (HIF-1a), a transcription factor involved in the cellular response to hypoxia. One study comparing HIF-1a knockout to wild-type mice, after inducing NAFLD through a high trans-fat diet for 6 months, the wild-type mice had 80% more hepatic collagen [23]. Furthermore, this study induced the hepatocytes to a sustained hypoxic state vs normoxia and found that those under hypoxic conditions allowed for avid collagen cross-linking whereas knockout mice did not have significant cross-linking. Thus, hepatocyte HIF-1a appears to be a key mediator in the increase in hypoxia-induced liver fibrosis, and decrease may be protective from fibrosis [24]. HIF-1a activation seems to also have a close relationship to lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1),
a cell surface protein that is involved in endocytosis of lipoproteins into endothelial cells. It has been shown that LOX-1 levels are higher in patients with OSA compared to the normal population and this is important in regard to NAFLD pathogenesis because oxidative-LDL stimulates production of LOX-1 through a ROS/NF-κB signaling pathway and mediates ox-LDL induced endothelial injury and defenestration of human liver sinusoidal cells [25]. Thus it is reasonable to postulate the progression of NAFLD is mediated by a HIF-1a and its downstream effect on LOX-1 expression causing hepatocyte injury.
Another study analyzed the association between chronic intermittent hypoxia (CIH), morbid obesity, and the effect on liver and adipose tissue [21]. Across 101 morbidly obese subjects, histopathologic analysis of liver biopsies showed NAFLD lesions, NAFLD activity score, and fibrosis were significantly more severe in patients with higher oxygen desaturation index (a quantified severity of nocturnal CIH). This suggests that there is a dose-response relationship between the amount of nocturnal oxygen desaturations and the severity of hepatic lesions found, all of which was independent of obesity and body composition [21]. A meta-analysis demonstrated OSA progressed in terms of liver enzymes and histological alterations and demonstrated OSA was independently associated with NAFLD developmen [19]. This evidence is in agreement that the chronic hypoxic state induced by the sleep disorder of OSA may be a key component as the second-hit in the pathogenesis of NAFLD. If left untreated, this hypoxia mechanism could lead to the progression from NAFLD to NASH.
Sleep Insufficiency, Circadian Dysrhythmia, and NAFLD
The direct effect of isolated sleep insufficiency and NAFLD has only recently been explored and has remained largely inconclusive [27,28]. In a large study published in 2013 of 69,463 middle-age workers and their spouses, one group assessed sleep duration and quality using the Pittsburgh Sleep Quality Index (PSQI) and then determined the presence of fatty liver [26]. Results showed that after controlling for confounding factors such as age, alcohol intake, smoking, and sleep apnea, with an odds ratio for NAFLD decrease in sleep duration of 1.28 in men and 1.71 in women. This implies that in the middle-aged general population, a shorter sleep duration and poor sleep quality are significantly associated with an increased risk of NAFLD. Various follow-up studies have demonstrated conflicting conclusions [27,28]. One study of Japanese subjects showed that short sleep duration of < 6 hours was associated with reduced risk of NAFLD in men [27]. Another study of found no significant association with short sleep of < 7 hours per day but found a significantly increased risk for NAFLD in those sleeping > 9 hours per day [28]. The conflicting data on sleep duration and NAFLD, It is clear that work is needed to better understand the pathophysiologic mechanisms that may be involved regarding decreased sleep and NAFLD.
In addition to decrease in overall sleep time, alterations in sleep habits through circadian dysrhythmia can contribute to hepatic steatosis. One recent study evaluating the relationship between circadian misalignment and metabolic associated fatty liver disease (MAFLD) found prevalence of MAFLD to be 45% in the presence of circadian misalignment compared to 28% in the non-misaligned group [29]. The data also suggest that circadian misalignment is independently associated with MAFLD and fibrosis, while short sleep duration alone is not independently associated with this risk [29].
Microbiome Changes, Sleep, and NAFLD
The gut microbiome is an ecosystem within the human gut consisting of bacteria, fungi, and other microbes, which affect the host's physiology [30]. The microbiome is affected by the host's environmental factors such as diet, exercise, medications, circadian rhythm, and geographic location, and can also effect change in host physiology [30]. Environmental factors can lead to dysbiosis, a term used here to refer to a change in the composition of the microbiome that is associated with pathogenesis. The dysbiotic microbiome can alter activation of the immune system through direct interaction as well as indirectly through the production of metabolites that may trigger immune response locally or at other peripheral tissues through translocation. One such example would be through first-pass of these bacterial products to the liver through the portal system (gut-liver axis) [30-32]. Metabolic products such as phenols and ammonia along with proinflammatory bacterial components such as peptidoglycans and lipopolysaccharides (LPS) can trigger an inflammatory cascade that can lead to fibrosis [32,33].
Several studies done in both humans and animals have demonstrated a link between gut dysbiosis and NAFLD [34-37]. One study examining non-obese patients with and without NAFLD, found a 20% increase in the phylum Bacteroidetes and a 24% decrease in the phylum Firmicutes among those with NAFLD [35]. Notably, flora capable of producing short-chain fatty acids (SCFA) and 7α-dehydroxylation of bile acids were severely reduced [35]. Proteobacteria, another mainly gram negative phylum, have also been found to be elevated in patients with steatosis and NASH [36]. Another study evaluated stool samples of patients with biopsy-proven NAFLD using 16S ribosomal RNA gene sequencing, and found significant increase in Bacteroides spp. in patients with NASH and F ≥ 2 fibrosis [37]. Rumminococcus spp. were found to be increased within patients with severe fibrosis [37]. Changes in bacterial composition are linked to.
An important homeostatic mechanism would be the regulation on the amount and quality of the sleep the host is getting. As mentioned previously patients with NAFLD can have close associations with OSA and chronic intermittent hypoxia, which lead to dysbiosis, and a propensity to increase obligate anaerobes [38]. A one study on murine models, showed that a group receiving chronic intermittent hypoxia for 6 weeks, had a higher abundance of Firmicutes and a smaller abundance of Bacteroidetes and Proteobacteria phyla compared to the normoxic control [39]. Dysbiosis of the gut can lead to an increase in bacterial products such as reactive oxygen species or lipopolysaccharide which can ultimately circulate and cause increased inflammation within the liver.
Role of therapeutics
Lifestyle modification
Lifestyle modification including diet and exercise is the first line in managing patients with NAFLD. Primarily lifestyle modification is aimed at gradual weight loss by all main guidelines [2,40,41]. Various weight reduction targets have been proposed, including 3% - 5%, 5% - 7% and 7% - 10% weight loss for improvement of steatosis, inflammation, and NAFLD/NASH remission along with decrease in fibrosis, respectively [42]. One study of patients with histologically proven NASH evaluated 52 weeks of lifestyle modification for weight loss [43]. At the end of the 52 weeks, 25% of patients achieved resolution of steatohepatitis, 47% had reductions in NAFLD activity scores, and 19% had regression of fibrosis [43]. Patients with the highest amount of improvement had ≥ 10% overall weight loss [43]. While there is no specific diet currently recommended for NAFLD, the Mediterranean diet has shown improvement in other metabolic and cardiovascular diseases. Recently the ATTICA prospective observational study of healthy volunteers without any chronic diseases or diagnosis of NAFLD evaluated the role of a Mediterranean diet with routine follow-up in cardiovascular disease and metabolic disorders [44]. The study demonstrated that a Mediterranean diet was protective from diabetes mellitus and cardiovascular disease in patients with NAFLD [44]. Given the significant potential for benefit and low risk of harm, lifestyle modification through activity and dietary change remains a major recommendation for management of NAFLD.
Melatonin is a neurohormone that regulates the sleep-wake cycle. Its production in the pineal gland is inhibited by light perception-mediated input from the SCN [45]. In addition to pineal production, several peripheral tissues produce and bind melatonin [46,47]. In addition to its role in mediating sleep function, melatonin has several immunomodulatory effects. Melatonin increases proliferation of several immune cell lines, including lymphocytes (particularly T-helper 1 cells), natural killer cells, and neutrophils [48]. Additionally, it acts to suppress the systemic inflammatory response through inhibition of the NLRP3 inflammasome, decreased nuclear translocation of pro-inflammatory transcription factor NF-κB, anti-inflammatory transcription factor Nrf2, and decreased macrophage toll-like receptor 4 signaling when activated by bacterial LPS [49,50]. In addition, melatonin has an overall anti-oxidant effect through scavenging by its metabolites as well as through up-regulation of superoxide dismutase and down-regulation of NADPH oxidase [51,52]. One study of patients with NAFLD found that melatonin supplementation over three months decreased weight, waist size, blood pressure, transaminases, and C-reactive protein, compared to baseline, however this did not reach statistical significance when compared to a control group [53]. In animal models, melatonin has been demonstrated to reduce expression of Micro-RNA-34a-5p, and inhibitor of sirtuin 1 production [54]. Increased sirtuin 1 availability has been linked to decreased hepatic inflammation and fibrosis [54]. In combination, supplementation of melatonin has potential for benefit through improved sleep as well as decreased propagation of the inflammatory cascade.
Vitamin E is known to be a free radical scavenger, with use in patients with NASH without diabetes. In the pioglitazone, vitamin E or Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, usage of 800mg/day was found to be superior to placebo in patients without diabetes and cirrhosis for improvement of NASH histology 43% vs. 19% respectively [55]. Another study of longer term use of vitamin E (300 mg/day) over 3 years demonstrated improved NASH fibrosis [56]. Currently, 300-400 mg is being used rather than 800 mg to decrease adverse effects of vitamin E toxicity [57]. Increased doses of vitamin E have been observed with increased all-cause mortality, hemorrhagic stroke and risk for prostatic cancer in individuals with a family history of prostate cancer [58-60].
Thiazolidinediones
Thiazolidinediones are peroxisome proliferator activated receptor (PPAR)- γ ligands, which are used for type 2 diabetes mellitus (T2DM). Pioglitazone, a thiazolidinedione, has been shown in the past to significantly decrease steatosis and necroinflammation in patients with NASH and T2DM compared to placebos [61,62]. A meta-analysis showed improved steatosis, lobular inflammation, and ballooning on histology after usage of thiazolidinediones [63]. Thiazolidinediones have also been shown to improve fibrosis in NASH patients when compared to placebo, however it has not been seen in all studies to a significant extent [64-66]. A recent meta-analysis of 26 studies concluded that pioglitazone was associated with reductions in both AST and ALT and improved steatosis in both diabetic and non-diabetic NAFLD patients [67]. Pioglitazone is not without risk, it is well known to have a decently-sized side-effect profile ranging from weight gain, increased cardiovascular events, fluid retention, and increased risk for bone fractures in women [40,67,68]. While there is no finalized recommendation on dosing of pioglitazone, some groups recommend a safe starting dose of 15 mg per day titrating up to 30mg per day for histologic improvement [65,66,68]. Further research is still being done on this drug group, as it shows promise for improvement on the histologic level.
Fecal Microbiota transplantation
Gut microbiome dysbiosis and NAFLD have a close association, and direct manipulation through fecal microbiota transplantation as a potential therapy has been proposed and demonstrated in murine models [36,69]. Compared to mice that were fed only HFD, mice that underwent FMT and fed 8 weeks of HFD demonstrated correction of gut microbiota with increased abundance of Christensenella spp. and Lactobacillus spp., significant reduction in intrahepatic lipid accumulation and intrahepatic pro-inflammatory cytokines, and improvement in steatohepatitis [69]. Developing from murine models, a double-blinded randomized controlled trial involving 21 patients who underwent allogenic or autologous FMT demonstrated that allogenic FMT resulted in a relative decrease in small intestinal permeability [70]. The intestinal membrane dysfunction has been associated with NAFLD, and reduction in the permeability may reflect a therapeutic potential in NAFLD [71]. Current clinical investigation is underway to evaluate the efficacy of FMT in NASH (NCT02469272).
Fatty liver disease and its complications are believed to be the result of altered metabolism as well as an associated cascade of systemic inflammation. Sleep-related disorders, including obstructive sleep apnea, insufficient sleep duration, and circadian dysrhythmia, can all contribute to NAFLD pathogenesis. This can occur through direct effects on central and peripheral circadian regulators or through changes in the diurnal oscillation of gut microbial composition. Non-pharmacological therapies, including lifestyle modification through diet and exercise, have demonstrated efficacy. Pharmacological therapies, including melatonin, vitamin E, thiazolidinediones, and fecal microbiota transplant, are all promising options.
Johnson DA, Parekh PJ, D'Souza SM and Yoo BS contributed construction of project; all authors wrote and edited the manuscript.
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Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas N, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015; 149: 367-378.e5. PubMed: https://pubmed.ncbi.nlm.nih.gov/25865049/
Kouvari M, Boutari C, Chrysohoou C, Fragkopoulou E, Antonopoulou S, et al. Mediterranean diet is inversely associated with steatosis and fibrosis and decreases ten-year diabetes and cardiovascular risk in NAFLD subjects: Results from the ATTICA prospective cohort study. Clin Nutr. 2021; 40: 3314-3324. PubMed: https://pubmed.ncbi.nlm.nih.gov/33234342/
Borjigin J, Samantha Zhang L, Calinescu AA. Circadian regulation of pineal gland rhythmicity. Mol Cell Endocrinol. 2012; 349: 13-19. PubMed: https://pubmed.ncbi.nlm.nih.gov/21782887/
Gao J, Xu K, Liu H, Liu G, Bai M, et al. Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism. Front Cell Infect Microbiol. 2018; 8: 13. PubMed: https://pubmed.ncbi.nlm.nih.gov/29468141/
Thor PJ, Krolczyk G, Gil K, Zurowski D, Nowak L. Melatonin and serotonin effects on gastrointestinal motility. J Physiol Pharmacol An Off J Polish Physiol Soc. 2007; 58 Suppl 6: 97-103. PubMed: https://pubmed.ncbi.nlm.nih.gov/18212403/
Miller SC, Pandi PSR, Esquifino AI, Cardinali DP, Maestroni GJM. The role of melatonin in immuno-enhancement: Potential application in cancer. Int J Exp Pathol. 2006; 87: 81-87. PubMed: https://pubmed.ncbi.nlm.nih.gov/16623752/
Bonomini F, Dos Santos M, Veronese FV, Rezzani R. NLRP3 inflammasome modulation by melatonin supplementation in chronic pristane-induced lupus nephritis. Int J Mol Sci. 2019; 20: 3466. PubMed: https://pubmed.ncbi.nlm.nih.gov/31311094/
Tarocco A, Caroccia N, Morciano G, Wieckowski MR, Ancora G, et al. Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis. 2019; 10: 317. PubMed: https://pubmed.ncbi.nlm.nih.gov/30962427/
Galano A, Tan DX, Reiter RJ. Melatonin: A versatile protector against oxidative DNA damage. Molecules. 2018; 23: 530. PubMed: https://pubmed.ncbi.nlm.nih.gov/29495460/
Zhou J, Zhang S, Zhao X, Wei T. Melatonin impairs NADPH oxidase assembly and decreases superoxide anion production in microglia exposed to amyloid-β1-42. J Pineal Res. 2008; 45: 157-165. PubMed: https://pubmed.ncbi.nlm.nih.gov/18298462/
Pakravan H, Ahmadian M, Fani A, Aghaee D, Brumanad S, et al. The Effects of Melatonin in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial. Adv Biomed Res. 2017; 6: 40. PubMed: https://pubmed.ncbi.nlm.nih.gov/28503495/
Stacchiotti A, Grossi I, García-Gómez R, Patel GA, Salvi A, et al. Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy. Cells. 2019; 8: 1053. PubMed: https://pubmed.ncbi.nlm.nih.gov/31500354/
Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, et al. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med. 2010; 362: 1675-1685. PubMed: https://pubmed.ncbi.nlm.nih.gov/20427778/
Sumida Y, Naito Y, Tanaka S, Sakai K, Inada Y, et al. Long-term (≥2 yr) efficacy of vitamin E for non-alcoholic steatohepatitis. Hepatogastroenterology. 2013; 60: 1445-1450. PubMed: https://pubmed.ncbi.nlm.nih.gov/23933938/
Rinella ME, Sanyal AJ. Management of NAFLD: A stage-based approach. Nat Rev Gastroenterol Hepatol. 2016; 13: 196-205. PubMed: https://pubmed.ncbi.nlm.nih.gov/26907882/
Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005; 142: 37-46. PubMed: https://pubmed.ncbi.nlm.nih.gov/15537682/
Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: Meta-analysis of randomised controlled trials. BMJ. 2010; 341: c5702. PubMed: https://pubmed.ncbi.nlm.nih.gov/21051774/
Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: The selenium and vitamin E cancer prevention trial (SELECT). JAMA - J Am Med Assoc. 2009; 301: 39-51. PubMed: https://pubmed.ncbi.nlm.nih.gov/19066370/
Belfort R, Harrison SA, Brown K, Darland C, Finch J, et al. A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis. N Engl J Med. 2006; 355: 2297-2307. PubMed: https://pubmed.ncbi.nlm.nih.gov/17135584/
Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, et al. Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis. Gastroenterology. 2008; 135: 1176-1184. PubMed: https://pubmed.ncbi.nlm.nih.gov/18718471/
Singh S, Khera R, Allen AM, Murad MH, Loomba R. Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta-analysis. Hepatology. 2015; 62: 1417-1432. PubMed: https://pubmed.ncbi.nlm.nih.gov/26189925/
Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus a randomized trial. Ann Intern Med. 2016; 165: 305-315. PubMed: https://pubmed.ncbi.nlm.nih.gov/27322798/
Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, et al. Role of Vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: A randomized controlled trial. Diabetes Care. 2019; 42: 1481-1488. PubMed: https://pubmed.ncbi.nlm.nih.gov/31332029/
Budd J, Cusi K. Role of Agents for the Treatment of Diabetes in the Management of Nonalcoholic Fatty Liver Disease. Curr Diab Rep. 2020; 20: 59. PubMed: https://pubmed.ncbi.nlm.nih.gov/33015726/
Kumar J, Memon RS, Shahid I, Rizwan T, Zaman M, et al. Antidiabetic drugs and non-alcoholic fatty liver disease: A systematic review, meta-analysis and evidence map. Dig Liver Dis. 2021; 53: 44-51. PubMed: https://pubmed.ncbi.nlm.nih.gov/32912770/
Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol. 2018; 53: 362-376. PubMed: https://pubmed.ncbi.nlm.nih.gov/29247356/
Zhou D, Pan Q, Shen F, Cao HX, Ding WJ, et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep. 2017; 7: 1529. PubMed: https://pubmed.ncbi.nlm.nih.gov/28484247/
Craven L, Rahman A, Nair Parvathy S, Beaton M, Silverman J, et al. Allogenic Fecal Microbiota Transplantation in Patients with Nonalcoholic Fatty Liver Disease Improves Abnormal Small Intestinal Permeability: A Randomized Control Trial. Am J Gastroenterol. 2020; 115: 1055-1065. PubMed: https://pubmed.ncbi.nlm.nih.gov/32618656/
Citi S. Intestinal barriers protect against disease: Leaky cell-cell junctions contribute to inflammatory and autoimmune diseases. Science. 2018; 359: 1097-1098. PubMed: https://pubmed.ncbi.nlm.nih.gov/29590026/
Copyright © 2016 - 2023 | Open Access by Heighten Science Publications Inc. (HSPI) is licensed under a
Creative Commons Attribution 4.0 International License. Based on a work at www.hspioa.org.


Like anything else, shopping online has its advantages and disadvantages. However once you learn how to shop online, you will see that the pros outweigh the cons. The following tips will help you learn everything you need to know about Internet shopping.
When you are purchasing an item online, search for coupon codes. Lots of online retailers provide discounts and coupons, which can be found with a single search. Just type "promo code" along with the retailer's name, and see what pops up. This is a good way to save on online purchases.
Comparison shop every time you buy online. When you shop online, you have a better chance of landing a great deal. When shopping online, always look at the reputability of a site in addition to the price. Even if the price looks good, it will not matter if you do not wish to order from a site.
TIP! There is no reason not to shop for the best deal online. Shopping online is a simple way to find great prices on various items.
Update your antivirus protection before logging in to shop online. There are many websites that appear legitimate; however, they are not. Some people build stores with the goal to infect your computer with malware. Be very careful when shopping online, even with well-known and reputable sites.
You need to make sure the Internet connection you use is secure. Your home connection usually is if you are connected directly to your cable modem. Hackers gravitate toward public Wi-Fi connections when seeking out their new victims, so it is unwise to shop online in these venues.
Before you begin shopping online, be sure you have good anti-virus software. Online shopping attracts suspicious activities. They could just be there to give you malware. Even if you think a retailer is reputable, you should still take precautions.
TIP! Update your antivirus protection before logging in to shop online. Online shopping attracts suspicious activities.
Do you feel like you are spending too much money on expedited shipping services? If so, consider switching to standard shipping, and be patient. You might actually see that your products show up pretty fast with the standard shipping. You can use the money you've said from using standard shipping can be put to more online purchases.
If you are thinking about buying from a company that you have not done business with before, look up customer reviews online. Reviewing past customer feedback gives you a good idea what you can expect yourself. Anyone who has been rated lowly time and time again should be given a wide swerve.
Register with a site if you regularly shop there. That saves you time, but there are also benefits that save you money. Just make sure you check the option that lets you receive emails. It is usually an option during the registration process. It is easier to manage your account orders and returns if you register as well.
When purchasing clothing online, look for sizing charts. It can be hard to know if an item will fit properly when buying clothing online. Fortunately, you'll get some help determining the correct size for you from the sizing charts that most sites selling clothing provide. These can be extremely beneficial.
TIP! Use available sizing charts shown on online retailer's websites. One of the biggest challenges of buying clothes online is that you can't quite tell whether the piece will fit you.
Never pay the full retail price when you shop online. Retailers usually have schedules for when certain items are on sale. Make sure you wait to make your purchases during these times. By doing this, you can save up to 50% or more of the entire retail price. Patience can really help you save money.
You ought to understand that refurbished products may be the same as surplus. The description of the item should tell you whether it's been repaired or it was part of an overstock. A wonderful way to get great deals is to search for surplus and refurbished items.
Search discount and auction sites prior to making purchases from retail stores. More often that not, online retailers will have better discounts than regular stores. That can save you a ton with no loss in benefits. You should always look into the return policies. Each site has different policies.
TIP! Seek out online auctions and certain discount vendors before purchasing at a store. Places like Amazon and eBay often offer better prices than traditional retailers do.
With your new base of knowledge, you should be ready to get the ball rolling and realize big savings. Just utilize the excellent advice provided here to help you save money. You'll be so pleased that you read these tips when you have more money in your pocket.


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The most suitable clay to use is red terracotta clay, collected from a site free of weed seed. Often, digging deep will ensure that no unwanted seeds become part of the mix! The clay needs to be dried and ground finely to ensure a lump free mixture. Two bricks can serve as an effective grinder. Other clays, the blues and whites are not suitable for this process, as they contain minerals, which interfere with the growth of the seedlings.


Farhan Akhtar and Shibani Dandekar are new lovebirds in the town. The couple's dating rumours are doing the rounds on social media from the past few months, however, the two have neither accepted nor denied it.
Recently, the duo spotted on a dinner date. On Friday night they were spotted on a date night in Juhu, Mumbai.
For the evening, Shibani donned a black lacy top with a long jacket while Farhan opted for a casual look wearing a solid black t-shirt and blue trousers.
According to reports, the duo met on the sets of TV show I Can Do That where Farhan was hosting the show whereas Shibani participated in it along with Rithvik Dhanjani, Gauahar Khan and VJ Bani. It is being said that the duo have been dating for the past six months.
Farhan separated from wife Adhuna Bhabani after staying together for 16 long years. They have two daughters together—Shakya and Akira.
Previous articleअपनी शादी से 4 साल पहले ही दीपिका पादुकोण ने इस अभिनेता से कर चुकी थी सगाई!
Next articleरानी मुख़र्जी की बेटी हूबहू अपनी माँ जैसी दिखती है, तस्वीरे देखकर रहे जायेंगे हैरान!


text:
/*
 * PescaAlgorithm.java
 *
 * Created on 7 marzo 2007, 10.01
 *
 * To change this template, choose Tools | Template Manager
 * and open the template in the editor.
 */
/**
 *
 * @author scardoni
 */
package org.cytoscape.pesca.internal;

import java.util.*;
import java.util.concurrent.CompletableFuture;
import java.util.concurrent.ExecutionException;
import java.util.concurrent.ExecutorService;
import java.util.concurrent.Executors;
import java.util.function.Supplier;
import java.util.logging.Level;
import java.util.logging.Logger;
import javax.swing.*;

import org.cytoscape.model.CyNetwork;
import org.cytoscape.model.CyNode;
import org.cytoscape.model.CyTable;
import org.cytoscape.model.CyTableUtil;
import org.cytoscape.view.model.CyNetworkView;
//import giny.view.NodeView;
//import cytoscape.data.CyAttributes;
//import cytoscape.*;
//import cytoscape.view.cytopanels.*;
//import cytoscape.view.*;

//import cytoscape.view.CytoscapeDesktop;
public class PescaAlgorithm {

    private boolean directed = false;
    private boolean weighted = false;
    private boolean treeisOn = false;
    private boolean shortestPathisOn = false;
    private boolean spClusterisOn = false;
    private boolean spIsolatednodesisOn = false;
    private boolean spAllNodesIsOn = false;
    private String weightColumn = "";
    public CyNode source;
    static CyNetworkView vista;
    Vector vectorOfNodeAttributes = new Vector();
    Vector vectorOfNetworkAttributes = new Vector();
    //  public Vector<Centrality> VectorResults = new Vector();
    public boolean openResultPanel;
    public PescaCore pescacore;
    public PescaSPMap pescamap;
    public int totalnodecount;

    // multithread fields
    private final int THREADS_PER_CPU = 1;
    private ExecutorService executor;
    private boolean stop;

    /**
     * Creates a new instance of PescaAlgorithm
     */
    public PescaAlgorithm(PescaCore pescacore) {
        this.pescacore = pescacore;
    }

    public void ExecutePescaAlgorithm(CyNetwork currentnetwork, CyNetworkView currentview, JPanel c) {

        openResultPanel = false;
        PescaStartMenu menustart = (PescaStartMenu) c;
        // JOptionPane.showMessageDialog(view.getComponent(),
        //          "comincio1 = " );

        // System.out.println("execute algorithm view = " + view.getTitle() + "networkidentifier = " + network.getIdentifier());
        totalnodecount = currentnetwork.getNodeCount();

        //String networkidentifier = network.getIdentifier();
        int nodeworked = 0;
        Vector PescaMultiShortestPathVector = null;
        Vector SPdistributionVector;

        // Multithread initialization
        stop = false;

        // get the number of procesors available
        int numProc = Runtime.getRuntime().availableProcessors();
        System.out.println("Number of processors: " + numProc);

        // number of threads used
        int numThreads = numProc * THREADS_PER_CPU;
        System.out.println("Number of threads: " + numThreads + "\n");

        // construct threadpool
        // note: newCachedThreadPool may also be used
        executor = Executors.newFixedThreadPool(numThreads);

        //CyAttributes currentNetworkAttributes = Cytoscape.getNetworkAttributes();
        //CyAttributes currentNodeAttributes = Cytoscape.getNodeAttributes();
        List<CyNode> rootlist = CyTableUtil.getNodesInState(currentnetwork, "selected", true);

        //  pescaSPmap = new PescaSPMap();
        CyNode root = null;

        CyNode target = null;
        if (rootlist.size() >= 1) {
            root = (CyNode) rootlist.get(0);
        }

        //  System.out.println("nodo root è " + root.getSUID());
        //  System.out.println("current network è " + currentnetwork.getSUID());
        //  System.out.println("current networkview è " + currentview.getSUID());
        if (rootlist.size() == 2) {
            target = (CyNode) rootlist.get(1);

        }

        // Execute the multi shortest path algorithm for node root and put the results on the
        // vector called ShortestPathVector
        if (treeisOn) {

            openResultPanel = true;
            root = (CyNode) rootlist.get(0);
            PescaMultiShortestPathVector = new Vector();
            Vector tmpPescaMultiShortestPathVector = new Vector();

            tmpPescaMultiShortestPathVector = PescaMultiShortestPathTreeAlgorithm.ExecuteMultiShortestPathTreeAlgorithm(currentnetwork, root, directed, weighted, weightColumn);

            if (tmpPescaMultiShortestPathVector != null) {
                PescaMultiShortestPathVector = tmpPescaMultiShortestPathVector;
            }

            pescamap = shortestPathsDistribution(tmpPescaMultiShortestPathVector);
            // System.out.println(PescaMultiShortestPathVector.toString());
            //  pescacore.createPescaResultPanel(PescaMultiShortestPathVector);

        }

        if (spIsolatednodesisOn) {

            openResultPanel = true;
            PescaMultiShortestPathVector = new Vector();
            Vector SingleSPVector = new Vector();
            Vector tmpPescaMultiShortestPathVector = new Vector();
            SPdistributionVector = new Vector();

            // List<CyNode> rootlist2 = CyTableUtil.getNodesInState(currentnetwork, "selected", true);
            List<CyNode> rootlist2 = menustart.GiantComponent;
            source = menustart.NodestoConnect.get(0);
            System.out.println(rootlist2);

            List<SourceTarget> STPairs = new LinkedList<>();
            for (int i = 0; i < rootlist2.size(); i++) {
                System.out.println("i= " + i + "size = " + rootlist2.size());
                target = (CyNode) rootlist2.get(i);
                System.out.println("target = " + target.toString());
                if (target != source) {
                    STPairs.add(new SourceTarget(source, target));
                }
            }

            List<Vector> results;
            try {
                results = multithreadMultiSPSourceTargetExecute(currentnetwork, STPairs);
            } catch (InterruptedException ex) {
                System.out.println(ex);
                cancel();
                return;
            }

            int size = Integer.MAX_VALUE;

            for (Vector result : results) {
                if (result != null) {
                    PescaShortestPathList p = (PescaShortestPathList) result.firstElement();

                    if (p.size() == size) {
                        System.out.println("same");
                        SingleSPVector.add(result.firstElement());
                        PescaMultiShortestPathVector.addAll(result);
                        size = p.size();
                    } else if (p.size() < size) {
                        System.out.println("lesser");
                        SingleSPVector.removeAllElements();
                        PescaMultiShortestPathVector.removeAllElements();
                        SingleSPVector.add(result.firstElement());
                        PescaMultiShortestPathVector.addAll(result);
                        size = p.size();
                    }

                }
            }

            pescamap = shortestPathsDistribution(SingleSPVector);
        }

        // NOT USED
        if (shortestPathisOn) {
            openResultPanel = true;

            CyNode source = (CyNode) rootlist.get(0);
            target = (CyNode) rootlist.get(1);
            Vector tmpPescaMultiShortestPathVector = new Vector();

            PescaMultiShortestPathVector = new Vector();

            tmpPescaMultiShortestPathVector = PescaMultiShortestPathTreeAlgorithm.ExecuteMultiShortestPathSourceTargetAlgorithm(currentnetwork, source, target, directed, weighted, weightColumn);

            if (tmpPescaMultiShortestPathVector != null) {
                PescaMultiShortestPathVector = tmpPescaMultiShortestPathVector;
            }

            //  System.out.println(PescaMultiShortestPathVector.toString());
            //   pescacore.createPescaResultPanel(PescaMultiShortestPathVector);
            pescamap = shortestPathsDistribution(PescaMultiShortestPathVector);
        }
        // Calculate each properties

        if (spClusterisOn) {
            openResultPanel = true;
            PescaMultiShortestPathVector = new Vector();
            Vector SingleSPVector = new Vector();
            Vector tmpPescaMultiShortestPathVector = new Vector();
            SPdistributionVector = new Vector();

            List<SourceTarget> STPairs = new LinkedList<>();

            for (int i = 0; i < rootlist.size(); i++) {
                for (int j = 0; j < rootlist.size(); j++) {
                    if (i != j) {
                        STPairs.add(new SourceTarget(rootlist.get(i), rootlist.get(j)));
                    }
                }
            }

            List<Vector> results;
            try {
                results = multithreadMultiSPSourceTargetExecute(currentnetwork, STPairs);
            } catch (InterruptedException ex) {
                System.out.println(ex);
                cancel();
                return;
            }

            for (Vector result : results) {
                SingleSPVector.add(result.firstElement());
                PescaMultiShortestPathVector.addAll(result);
            }

            pescamap = shortestPathsDistribution(SingleSPVector);
            //  System.out.println("la pesca map dopo la chiamataaaa = " + pescamap.toString());
        }

        // NOT USED!
        /*
        if (spAllNodesIsOn) {
            openResultPanel = true;
            PescaMultiShortestPathVector = new Vector();
            Vector SingleSPVector = new Vector();
            Vector tmpPescaMultiShortestPathVector = new Vector();
            SPdistributionVector = new Vector();
            List<CyNode> allNodes = currentnetwork.getNodeList();

            // list of CompletableFutures - one per each root node
            List<CompletableFuture<Vector>> futureResults = new LinkedList<>();

            for (CyNode treeRoot : allNodes) {
                CompletableFuture<Vector> futureResult = CompletableFuture.supplyAsync(() -> {
                    try {
                        // execute
                        return PescaMultiShortestPathTreeAlgorithm.ExecuteMultiShortestPathTreeAlgorithm(currentnetwork, treeRoot, directed, weighted, weightColumn);
                    } catch (Exception e) {
                        System.out.println("Execution of SPTreeAlg interrupted");
                        return null;
                    }
                }, executor);
                futureResults.add(futureResult);
            }

            for (CompletableFuture<Vector> futureResult : futureResults) {
                if (stop || futureResult.isCompletedExceptionally()) {
                    cancel();
                    return;
                }
                try {
                    tmpPescaMultiShortestPathVector = futureResult.get(); // get the result of the computation
                    if (tmpPescaMultiShortestPathVector != null && tmpPescaMultiShortestPathVector.size() >= 1) {
                        SingleSPVector.addAll(tmpPescaMultiShortestPathVector);
                        PescaMultiShortestPathVector.addAll(tmpPescaMultiShortestPathVector);
                    }
                } catch (InterruptedException | ExecutionException ex) {
                    System.out.println(ex);
                    cancel();
                    return;
                }
            }

            pescamap = shortestPathsDistribution(SingleSPVector);
            //  System.out.println("la pesca map dopo la chiamataaaa = " + pescamap.toString());
        }
*/

        if (openResultPanel) {
            //  System.out.println(PescaMultiShortestPathVector.toString());
            String resulttype = null;

            // network.unselectAllNodes();
            menustart.endcalculus(totalnodecount);
            //        VectorResults.clear();

            //      Visualizer visualizer = PescaCore.windows.getvisualizer();
            //      visualizer.setEnabled(VectorResults);
            //    CytoscapeDesktop desktop = Cytoscape.getDesktop();
            //    CytoPanel cytoPaneleast = desktop.getCytoPanel(SwingConstants.EAST);
            //cytoPaneleast.removeAll();
            //    int index = cytoPaneleast.indexOfComponent(visualizer);
            //    cytoPaneleast.setSelectedIndex(index);
            //  cytoPaneleast.add("Pesca Results", visualizer);
            if (treeisOn) {
                resulttype = root.getSUID() + " SPtree";

                // cytoPaneleast.add(root.getIdentifier() + " SPtree", prova);
                // openResultPanel = true;
            }

            if (spIsolatednodesisOn) {
                resulttype = root.getSUID() + " isolatednodes";
                // ResultPanel prova = new ResultPanel(PescaMultiShortestPathVector);
                //  prova.add(mainwindow);
                // resultframe prova2 = new resultframe();
                // prova2.add(prova);

                // cytoPaneleast.add(root.getIdentifier() + " isolatednodes", prova);
                // openResultPanel = true;
            }

            if (shortestPathisOn) {
                resulttype = root.getSUID() + "-" + target.getSUID() + " SP";
                //  ShortestPathResultPanel prova = new ShortestPathResultPanel();
                //  prova.changelist(PescaMultiShortestPathVector);
                //  cytoPaneleast.add(root.getIdentifier() + "-" + target.getIdentifier() + " SP", prova);
                // openResultPanel = true;
            }

            if (spClusterisOn) {
                // ShortestPathResultPanel prova = new ShortestPathResultPanel();
                resulttype = "SPCluster";
                //    ResultPanel prova = new ResultPanel(PescaMultiShortestPathVector);
                // prova.changelist(PescaMultiShortestPathVector);
                //   cytoPaneleast.add(" SPCluster", prova);
                // openResultPanel = true;
            }
            if (spAllNodesIsOn) {
                resulttype = "All Nodes SP";

                // cytoPaneleast.add(root.getIdentifier() + " SPtree", prova);
                // openResultPanel = true;
            }
            //  System.out.println("scrivo la pesca map 1" + pescamap.toString());
            pescacore.createPescaResultPanel(PescaMultiShortestPathVector, resulttype, pescamap);

            // shutdown all the threads from the pool
            executor.shutdown();
        }
    }

    public void endalgorithm() {
        cancel();
    }

    public void setChecked(boolean[] ison, boolean directed, boolean weighted) {
        String columnName = "";

        // Diameter = checkbox 0
        treeisOn = ison[0];
        //     DiameterisSelected = ison[0];
        // Average-Distance = checkbox 1
        shortestPathisOn = ison[1];
        // Degree = checkbox 2
        spClusterisOn = ison[2];
        spIsolatednodesisOn = ison[3];
        spAllNodesIsOn = ison[4];
        this.directed = directed;
        this.weighted = weighted;

        if (weighted) {

            columnName = JOptionPane.showInputDialog("Please input name of the Edge Table column for weights : ");
            this.weightColumn = columnName;
        }

        System.out.println(columnName);

    }

    public PescaSPMap shortestPathsDistribution(Vector PescaMultiShortestPathVector) {
        //  System.out.println("stampo risultati singolo vettore");
        PescaSPMap pescaspmap = new PescaSPMap();

        int paths = 0;
        if (spAllNodesIsOn) {
            paths = totalnodecount * (totalnodecount - 1);

        }

        if (treeisOn) {
            paths = totalnodecount - 1;

        }

        pescaspmap.setExpectedPaths(paths);
        for (Iterator i = PescaMultiShortestPathVector.iterator(); i.hasNext();) {
            PescaShortestPathList currentpath = (PescaShortestPathList) i.next();

            //     System.out.println("il currentpath = " + currentpath.toString());
            int currentsize = currentpath.size() - 1;

            pescaspmap.update(new Integer(currentsize), currentpath.getSourceDest());
        }
        System.out.println(" size |  number of sp \n" + pescaspmap.toString());
        //    CyTable networkTable = pescacore.network.getDefaultNetworkTable();
        //      networkTable.createColumn("SP-Distribution", Long.class, false);
        return pescaspmap;
    }

    private class SourceTarget {

        private CyNode source, target;

        public SourceTarget(CyNode source, CyNode target) {
            this.source = source;
            this.target = target;
        }

        public CyNode getSource() {
            return source;
        }

        public CyNode getTarget() {
            return target;
        }

    }

    private List<Vector> multithreadMultiSPSourceTargetExecute(CyNetwork currentNetwork, List<SourceTarget> STs) throws InterruptedException {

        // list of CompletableFutures - one per each source-target pair
        List<CompletableFuture<Vector>> futureResults = new LinkedList<>();

        // initiate and execute SP algorithms from each node
        for (SourceTarget st : STs) {
            CompletableFuture<Vector> futureResult = CompletableFuture.supplyAsync(new Supplier<Vector>() {
                @Override
                public Vector get() {
                    try {
                        // execute
                        return PescaMultiShortestPathTreeAlgorithm.ExecuteMultiShortestPathSourceTargetAlgorithm(currentNetwork, st.getSource(), st.getTarget(), directed, weighted, weightColumn);
                    } catch (Exception e) {
                        System.out.println("Execution of SP_ST_Alg interrupted");
                        return null;
                    }
                }
            }, executor);
            futureResults.add(futureResult);
        }

        List<Vector> results = new LinkedList<>();

        for (CompletableFuture<Vector> futureResult : futureResults) {
            if (stop || futureResult.isCompletedExceptionally()) {
                throw new InterruptedException();
            }
            try {
                Vector result = futureResult.get(); // get the result of the computation
                if (result != null) {
                    results.add(result);
                }
            } catch (InterruptedException | ExecutionException ex) {
                System.out.println(ex);
                throw new InterruptedException();
            }
        }

        return results;

    }

    private void cancel() {
        System.out.println("Canceling");
        stop = true;
        if (executor != null) {
            executor.shutdownNow();
        }
    }
}

redpajama_set_name: RedPajamaGithub


text:
Scientist Awarded AHA Grant to Develop Therapies for Rare Form of Childhood Muscular Dystrophy
Dr. Bijan K. Dey in his research laboratory at The RNA Institute (Photo by Mark Schmidt).
ALBANY, N.Y. (Aug. 7, 2017) – Scientist Bijan K. Dey could soon offer hope to young patients with a rare form of muscular dystrophy.
Dey, a faculty researcher at The RNA Institute at the University at Albany, has received the American Heart Association's (AHA) prestigious Scientist Development Grant to develop therapies for a deadly genetic childhood-muscle degenerative disease known as Duchenne Muscular Dystrophy (DMD).
DMD is a hereditary condition characterized by progressive muscle weaknesses and muscle degeneration. Among the nine types of muscular dystrophy, DMD is the most severe and life-threatening. It is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. As the disease progresses, it weakens the heart and respiratory muscles causing serious medical issues.
Symptoms typically begin in early childhood, usually between the ages of 3 and 5. Children with DMD are commonly restricted to wheelchairs within the first decade of their lives with an average life expectancy of 26. It primarily affects young boys.
"My team is exploring a novel approach for therapy that has not been previously investigated," Dey said. "Our goal is to gain a better understanding of the pathophysiology of DMD and DMD-associated heart dysfunctions in molecular detail. We are thankful for the American Heart Association's support."
Dey's research is focused on a class of small non-coding RNA molecules called microRNAs. During his postdoctoral training at the University of Virginia School of Medicine, he demonstrated that small non-coding RNA molecules regulate the stem cell population crucial to maintaining normal skeletal and cardiac muscle function – or normal human health.
Dey works with his laboratory scientist and students (Photo by Mark Schmidt).
His lab is investigating how microRNAs maintain normal muscle function and what goes wrong when children are diagnosed with DMD and associated heart dysfunctions.
Dey is optimistic that through the support of the AHA and The RNA Institute his team can develop a basic understanding of the disease, follow its progression, and provide an avenue for therapy-based treatment.
"Dey's innovative research program speaks to the vision of The RNA Institute to create translational therapies requiring both basic and applied research on non-coding RNA's role in muscle development and related human diseases," said Paul Agris, founding director of The RNA Institute and professor of biology at UAlbany. "Dr. Dey has the knowledge and experience to bring a whole new approach to muscular dystrophy research and take it to a new height."
Marlene Belfort, a distinguished professor at UAlbany and interim director of The RNA Institute, added that Dey has demonstrated his knowledge and expertise by earning highly competitive funding on the national stage. "At this funding climate, it is extremely challenging for a young investigator to be awarded an extramural grant early in their career," she said.
Dey's project is funded by the AHA through June 2020 for $231,000. It will not only support his research but also allow for mentor-based training of students and future scientists through The RNA Institute.
Students are encouraged to email Dey if interested in research opportunities in his lab: [email protected]

redpajama_set_name: RedPajamaCommonCrawl


Mumbai, (IANS) Actor Salman Khan has heaped praise on Aamir Khan's latest release "Dangal", a biographical wrestling drama which hit the screens worldwide on Friday, calling it a much better film than his own release "Sultan".
In Ali Abbas Zaffar's "Sultan", which released earlier this year, Salman played a wrestling champion from Haryana whose successful career wreaks havoc in his personal life.
"My family saw 'Dangal' and thought it was a much better film than 'Sultan'. Love you personally Aamir but hate you professionally," wrote Salman on his Twitter page on Friday.
Directed by Nitesh Tiwari, and based on an incredible true story, "Dangal" chronicles the highly inspiring and empowering journey of a father who trains his daughters in wrestling.
In the film, Aamir plays Mahavir Singh Phogat, a former national champion who, much to the disapproval of his wife and his whole village, trained his daughters Geeta and Babita to wrestle.
"Dangal" has been dubbed in Tamil and Telugu.


Perspectives on the English Language is an innovative series of textbooks for the English language student, together forming a wide-ranging course for undergraduate students of English. The basis of the series is a 'core' of three books which together form a system of information about the English language to which any graduate in English (including those largely focusing on literature) should have access. Each book can be used flexibly, providing accessible and engaging starting-points, and building the foundations for further study.


text:
Het wereldkampioenschap superbike van Losail 2007 was de eerste ronde van het wereldkampioenschap superbike en het wereldkampioenschap Supersport 2007. De races werden verreden op 24 februari 2007 op het Losail International Circuit nabij Doha, Qatar.

Superbike

Race 1

Race 2

Supersport

Tussenstanden na wedstrijd

Superbike

Supersport

2007
Losail

redpajama_set_name: RedPajamaWikipedia


This qualification reflects the role of individuals who have senior or managerial responsibilities. They desire theknowledge and skills to provide strategic leadership. Competencies developed include manage organisational change, provide leadership across the organisation as well as develop and implement strategic plans for an organisation.
Pathways from the qualification:: After achieving this qualification, candidates may choose to undertake studies at higher education level.
Job Roles:Possible job titles relevant to this qualification include area manager, department manager, regional manager.


The Armed Forces worked out radar recon, penetration of the enemy air defense system, airstrikes on surface and sea targets, interception and destruction of air targets by fighter aircraft.
The Ukrainian Air Force has worked out strikes against enemy landing forces along the coasts of the Sea of Azov.
Fighter jets, bombers, and transport aviation of Ukraine's Air Force, as well as aviation of the Land Forces, anti-aircraft missile forces, e-warfare unit, and aerial reconnaissance were involved in the training spree, the press service of the Joint Forces Operation wrote on Facebook.
The Armed Forces worked out radar recon, penetration of the enemy air defense system, airstrikes on surface and sea targets, interception and destruction of air targets by fighter aircraft, as well as the destruction of enemy aircraft and missiles by anti-aircraft missile forces.
Ukraine's warcraft took off from the main and operational airfields in the Azov Sea area.
The JFO also reported on the readiness of e-warfare units and successful training sortees of assault and fighter aircraft that hit conditional enemy landing forces and vessels.
As UNIAN reported, Ukraine will strengthen its military presence in the Azov Sea. Measures will be taken "for the reliable protection of all borders and peaceful production activities in the water area of the Azov Sea."


Your Bower Products are covered by a limited product warranty (Limited Warranty) for the 1-year period following the original date of purchase (Warranty Period). If a substantial defect in material or workmanship arises with your Bower Product, and a valid warranty claim is received by Bower within the Warranty Period, you will be entitled to a replacement of the product purchased or a similar product (depending on availability).
This Limited Warranty is non-transferable and covers only the original end purchaser of the applicable Bower Product. Proof of purchase in the form of the original purchase receipt or packaging slip is required for warranty validation and service. Warranty claims must be made directly to Bower. Bower reserves the right to inspect the product and determine whether it is defective in materials or workmanship. If we find that the product is defective, we shall at no charge to you replace the product at our discretion, and return the product to you. You are responsible for shipping costs to Bower but there is no charge for the inspection or the return postage within the United States. This warranty does not cover damages resulting from accidental drops, misuse, abuse, tampering, modification, or breakage due to improper care.
Bower is not responsible for damages resulting from any breach of warranty including but not limited to loss of use, loss of revenue, and loss of anticipated profits. Merkury innovation's warranties do not cover any third party devices or the personal property of any consumer (includes cameras, lenses, smartphones, tablets & computers). Any alteration, change, modification, or repair (other than replacement of a replaceable component) made to the product by a party other than Bower will void this warranty.
BOWER WARRANTIES AND REMEDIES SET FORTH ABOVE ARE EXCLUSIVE AND IN LIEU OF ALL OTHER WARRANTIES, REMEDIES AND CONDITIONS, WHETHER ORAL OR WRITTEN, EXPRESS OR IMPLIED. BOWER SPECIFICALLY DISCLAIMS ANY AND ALL IMPLIED WARRANTIES, INCLUDING BUT NOT LIMITED TO WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE. IF THE LAW PROHIBITS BOWER FROM DISCLAIMING IMPLIED WARRANTIES OR WARRANTIES OF MERCHANTABILITY, ALL SUCH WARRANTIES ARE LIMITED TO THE DURATIONS REFERRED TO HITHERTO.
This Limited Warranty does not cover any Bower Product purchased through non-authorized dealers and/or online auction websites. Non-authorized dealer receipts and/or online sales auction confirmations are NOT accepted for warranty verification.
This Limited Warranty applies only to the Bower product to include any of the Bower licensed products in the Energizer, Everlast, US Army product line. The Limited Warranty does not extend to or otherwise apply to any non- Bower Product This Limited Warranty applies only to the normal use of the covered Bower Product, normal wear and tear excepted, in accordance with the written use instructions provided with the Bower Product. This Limited Warranty does not apply to damage to the Bower Product caused by accident, abuse, misuse, use for any purpose other than its intended purpose, acts of God, or any alteration or modification of the Bower Product.
To make a warranty claim please contact our customer support team at:support@bowerusa.com or from the returns page at www.bowerusa.com/returns.


text:
Michelin Plans 1.7 Million Square Foot Distribution Complex At RidgePort Logistics Center in Wilmington, Illinois
The Auto Industry: In Search of New Talent amid Changing Skills Requirements
What's Driving Today's Location Decisions in the Auto Industry?
Ridge Development, the industrial development arm of Transwestern Development Company, a diversified firm with an expertise in all commercial property, said Michelin has entered into a build-to-suit agreement in which the tire manufacturer will lease 1.7 million square feet of distribution space to be constructed at the RidgePort Logistics Center in Wilmington, Illinois, approximately 40 miles southwest of Chicago.
RidgePort, a 1,500-acre, rail-served intermodal park has room for 14 million square feet of industrial, warehousing and logistics buildings. It is strategically located three miles south of the Interstate 55 Arsenal Road exit that leads to the BNSF Logistics Park-Chicago in Elwood and Union Pacific-Joliet Intermodal Terminal in Joliet. RidgePort is flanked by more than two miles of BNSF mainline frontage to the west and Interstate 55 to the east.
"We are excited to break ground on the Michelin project," said Jim Martell, President of Ridge Development. "As one of the largest U.S. distribution complexes when fully built out, this project should boost RidgePort to one of the most significant logistics parks in the country."
"The Michelin project substantiates RidgePort as a compelling player in the freight movement and logistics sector in Will County," said John Greuling, President/CEO of the Will County Center for Economic Development. "This project confirms the county as one of the more significant logistics centers in the Midwest as far as attractiveness and transportation options."
The park would serve as the western terminus of the proposed Illiana Expressway, a toll road that would connect I-55 and I-65 in northern Illinois and Indiana. Located in the Will County Inland Port region, the largest inland container port in North America, RidgePort provides economic incentive packages to qualified companies, has an Enterprise Zone designation and qualifies for a Foreign Trade Zone designation.
"Since the annexation of RidgePort into the city of Wilmington, the relationship has been both positive and progressive in getting to the end result of having a signature intermodal center," said Marty Orr, Mayor of Wilmington. "We are excited to have Michelin become a part of that and welcome them to the neighborhood."
"The Michelin distribution center will be a showpiece for RidgePort Logistics Center and the city of Wilmington," said Tony Graff, Wilmington City Administrator. "The project is already benefitting the city, bringing with it both temporary construction and permanent jobs, a high standard of employee safety and exceptional community relations."


Storm Racing's Menno Klont will not be on the grid of the upcoming WTF1 Superleague round in Austria. He is invited by Dutch national broadcaster Ziggo to compete in a F1 2017 Final.
"I went to a shopping centre to set some laps in Monaco in Codemaster's F1 2017 simulator," Klont explains. "My time proved to be among the fastest ten nationwide, therefore I'm invited to go to a television studio for a Top 10 showdown. I had a good talk with my team, and they gave me the green light to attend the event. I am looking forward to compete in this final and wish Bart the best of luck in Austria."
Bart de Vos will jump in the #9 Storm Racing car again after he had been driving it at the French Grand Prix, finishing in ninth position.


The twin cities of Islamabad and Rawalpindi play home to thousands of employees from other cities who reside in both the towns either temporarily or permanently. With each year, the number of people from other cities, who get employed here and need residence in Rawalpindi-Islamabad, increases. To accommodate these employees, government and various private sectors launch housing schemes from time to time. But because Islamabad and Rawalpindi are known to host some of the highest valued properties in Pakistan, not everyone can afford to buy property there.
For that reason, many people are forced to live on rents in Islamabad and the sister city, Rawalpindi, under adverse conditions. The announcement regarding the launch of Model Housing Scheme in Rawalpindi has come as a breath of fresh air for such people who would now be in position to consider better options for their work place as well as residence. Availability of better accommodation will also reduce their travelling distance and they might end up saving some money which otherwise is spent on high rents and ever inflated petrol.
Cantonment, be it in any city, is widely regarded as a posh area in terms of property prices and the standard of living. Not just that, but the fact that the MHS of Rawalpindi will also host all facilities such as schools, parks, masajid and community centres has brought good news for all kinds of people. It would be premature to comment on the prices of properties in this particular project but Zameen, the best B2B portal for Pakistan real estate reckons that the rental value for houses in this scheme might not be as high as the rents in Islamabad.


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text:
< What I did last summerSilliman envy >
By Mark Alden Branch '86 | 9:52am September 09 2019
There's still a bit of work to be done on the new Yale Science Building, which took the place of Gibbs Laboratories. But the redesigned courtyard of Science Hill is open for inspection.
Filed under Science Hill, Yale Science Building
SAT/ACT & ISEE TUTOR: Robert Kohen, Ph.D.,
Harvard and Columbia grad, provides individualized tutoring for the SAT/ACT and ISEE. (212) 658-0834;
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702-623-6362. https://www.lvcriminaldefense.com.
Beautiful renovated Paris one bedroom apartment in the Marais. It is available now through April and August. Please contact for more info. ladyo26@aol.com
Copyright 2015 Yale University. All rights reserved. As of July 1, 2015, the Yale Alumni Magazine operates as a department of Yale University. Earlier print and digital content of the Yale Alumni Magazine was published and copyrighted by Yale Alumni Publications, Inc., and is used under license.


text:
Q: What does ACPI NMI LINT mean? and Why it changes across kernel version? I'd like to understand what the following lines mean
[    0.000000] ACPI: LAPIC_NMI (acpi_id[0x01] dfl dfl lint[0x0])
[    0.000000] ACPI: NMI not connected to LINT 1!
[    0.000000] ACPI: LAPIC_NMI (acpi_id[0x02] dfl dfl lint[0x0])
[    0.000000] ACPI: NMI not connected to LINT 1!
[    0.000000] ACPI: LAPIC_NMI (acpi_id[0x03] dfl dfl lint[0x0])
[    0.000000] ACPI: NMI not connected to LINT 1!
[    0.000000] ACPI: LAPIC_NMI (acpi_id[0x04] dfl res lint[0x6f])
[    0.000000] ACPI: NMI not connected to LINT 1!

And why the value of the second to last line changes across the kernel version?
e.g.:
with kernel 4.9.3 it's [0x6f]
with kernel 4.7.8 it's [0x1f]
and so on

A: Since you haven't gotten a proper answer, I'll try and provide an incomplete one. ACPI is an interface for discovery and configuration of hardware devices. They can provide Linux with information about critical events using non maskable interrupts (NMI). Each NMI is then connected to a Linux interrupt.
So LAPIC_NMI means Local Advanced Programmable Interrupt Controller Non-Maskable Interrupt. acpi_id[0x01] is the id of that device. I believe 0x01..0x04 corresponds to your computers processor cores.
Then for some reason I don't understand the Linux acpi implementation wants the NMI to be connected to the first Linux interrupt. In your case it isn't and it could mean that if a processor core generates an NMI, it is not trapped correctly by Linux.
In practice I don't think it matters (but don't quote me on that) because the interrupts the mechanism is supposed to trap are exceedingly rare.

redpajama_set_name: RedPajamaStackExchange


Pours an opaque golden to light orange color with a white head that dissipates fairly quickly. Some lacing is left on the glass. Very yeasty aroma with some hints of spice and fruit. Some banana, apple, and a hint of citrus smoothly mixed with clove and spice. Huge character of sweet citrus and herbal hops. Alcohol sets in mid-palate to finish and leaves a mild bready yeast after note. Strong carbonation and huge body, a large personality in this brew.


text:
De Lairessestraat 165
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post@tettero.net
Art Architecture The Temporary Centre Quarterly Report
Email , Facebook , Twitter
1Q2017 Travails of an art advisor
The year got off to a wonderful start when the British designer and stylist Victoria Bartlett and I attended one of New York's best-loved New Year's traditions: the Annual New Year's Day Marathon Benefit Reading, organised by the Poetry Project in the beautifully conserved St. Marks Church on East 10th St. This year was the 43rd edition with contributions from more than 200 poets and musicians.
We went, together with artist Ugo Rondinone, to support his husband, the poet and artist John Giorno. Not that he needed support. Giorno is known, among other things, for his solo performance in Andy Warhol's five-hour-long film Sleep (1963), in which, as the title suggests, we see five hours of footage of him sleeping. Giorno was one of the stars of the 23-hour-long poetry marathon. A lifelong Buddhist, he recited his beautiful, reflective poem 'Everyone Gets Lighter', in which he reflects upon old age.This wonderful evening spawned a visit to Rondinone's studio in the heart of Haarlem, where he has carried out a beautifully minimal conversion of a large Neo-Romanesque church. Rondinone has recently made an imposing installation consisting of seven towers of brightly coloured rocks rising more than seven metres high in the Ivanpah Valley in Nevada's Mojave Desert. Entitled Seven Magic Mountains, the artwork can be seen until the summer of 2018. His studio was still full of preparatory studies and several new pieces he is still working on.
Ugo Rodinone
Later in the month I attended the third annual Verbier Art Summit, which took place in the mountain village in Switzerland from 19 to 21 January. Initiated in 2014 by Anneliek Sijbrandij, the summit brings together artists, experts and aficionados in private houses for a series of lectures and debates that cast a critical eye on today's art world. I have been a board member since 2015 and was enormously happy with the large attendance and the great enthusiasm for this year's theme: Does Size Matter? Presented by guest director Beatrix Ruff and the Stedelijk Museum Amsterdam, the invited speakers included Rem Koolhaas and artist Tino Sehgal. A report on this successful summit will be published later this year, designed by Irma Boom. Next year's guest director will be Daniel Birnbaum of the Moderna Museet in Stockholm, who will concentrate on digital culture in art. Congratulations Anneliek on this enormous success.
A beautiful major renovation of a private residence kept me in Amsterdam for most of February. It is a wonderful honour and challenge to develop an art collection in parallel with shaping the space in which it will be seen. A unique opportunity. I hope to publish the result in a future newsletter.
Art Verbier Beatrix Ruff
Towards the end of February I saw At the Center of the World, a unique exhibition at the Hammer Museum in Los Angeles of work by Jimmie Durham, one of America's most enigmatic artists. In his research into the formal language of American culture, the artist, who is descended from Cherokee Indians from Colorado, has developed a powerful critique of the concept of history. As a Native American, he sees 'official' history as highly subjective. He strives to lighten the gravitas of history by showing its absurdity through humour and playfulness. His work is of course strongly influenced by his background but also shows how the whole of American history has been influenced by the Indians and their culture.
At the end of February, I attended the first Desert X, an exhibition spread across almost twenty locations in the Coachella Valley around Palm Springs, some 100 miles outside Los Angeles. Palm Springs has a beautiful modern art museum, a wealth of modern architecture and a rich design history. Desert X is attempting to place this small city on the international cultural map. The most imposing piece was the installation by Doug Aitken entitled Mirage (2017), a simple timber frame house covered in mirrored cladding that reflects the surrounding raw desert landscape.
In March I was in Maastricht for the 30th edition of the world's most famous art fair, the TEFAF. The organisers of the fair were already eagerly looking forward to their new adventure, the opening in May of the first modern and contemporary TEFAF in the Park Avenue Armory in New York. Together with the Old Masters/Decorative Art fair in the autumn, this new fair will give a new élan to the TEFAF formula, which was originally established by a group of Dutch art dealers. In Maastricht my eye was caught by the brilliant 1948 work Elle Danse by Francis Picabia and a Design for a Recreation Room in the Kharkov Palace of Pioneers and Octobrists from 1934 by the lesser-known Ukrainian artist Vasily Ermilov (1894-1968).
This was followed immediately by the fifth Art Basel | Hong Kong, which is slowly but surely beginning to develop its own character. The fair had a balanced mix of Asian and Western contemporary art, such as Stars Art Group members Huang Rui and Ai Weiwei alongside Italian artists Piero Dorazio and Lucio Fontana. The fair is now of essential importance for the development and support of a growing art market in Hong Kong and the Asian region. Many of the larger galleries now have a branch in Hong Kong and the construction of the M+ Museum in Kowloon to house the collection of Swiss businessman and diplomat Uli Sigg will give a further impulse to the establishment of HK as an art centre in China. The opening is planned for the summer of 2019.
That's it for the first quarter. Stay tuned… More soon on the busiest art year in two decades!
Vasiliy Ermilov


Rumenn is a Design Studio in Singapore. Passion is what drives them into creating designs that hope to bring a little fascination and fun to life.
Having past experiences in designing for medical, consumer and industrial products mainly serving the electronic industries, they hope to extend these experiences to the aspects of everyday lifestyle products to further enhance its user value experience for all to enjoy.
All Rumenn products are designed in-house and manufactured by their trusted vendors.


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'Cause I know what's pain.
If I die tonight would you regret it?
Without your touch, touch, touch.


text:
Parambrata Chatterjee on the past, present, future and 'Aranyak'
Written By: Subhash K Jha
New Delhi Published: Dec 24, 2021, 07:38 PM(IST)
Parambrata Chatterjee in 'Aranyak' Photograph:( Others )
One of Bengali cinema's most prolific and promising actors Parambrata Chatterjee is back in 'Aranyak' this time teaming up with Raveena Tandon to solve gruesome serial killings.
One of Bengali cinema's most prolific and promising actors Parambrata Chatterjee is back in 'Aranyak' this time teaming up with Raveena Tandon to solve gruesome serial killings. Parambrata feels the OTT has blurred the lines between regional and national cinema. "I think it is everything in one box so you can just choose what to watch and I have myself witnessed this during the last few years how perceptions have changed, how people appreciate good work over boundaries of language these days."
Parambrata feels the OTT and the big screen will co-exist. "It's nice, so yes it is opening up the possibilities for access of content in general and it is here to stay alongside the big screen. The big screen will never fade but yes, OTT is creating opportunities for foreign subjects which never found their way here and it is also providing opportunities to people who would want to experiment with telling stories on the screen … it's becoming a little more widespread the whole filmmaking process is more democratic."
Parambrata says there were several reasons why he agreed to be in Netflix's Aranyak. "First of all, this was for Netflix one of the most prestigious platform that we have. Someone like Raveena Tandon was my co-star. All of these mattered and then when I heard the story and eventually the script I think it made complete sense, so yeah. This is something that came my way and there was no question of not stepping into it."
He enjoyed working with Raveena. "You know I'm the 90s' boy and no matter what kind of cinema I've done, later on, I've watched all the right kinds of cinema while growing up, so yes I've watched a lot of Raveena Tandon movies.So it was very strange to end up working for such a long time and so many days and so closely with somebody whom I've kind of been a bit of a fanboy in my teens and I also said that to her on the first day of the shoot. But yeah after about the first 4-5 days it became really easy.We became great friends and it was very easy very chilled out and very nice.We developed a great friendship."
Explaining why he is not seen more often in Hindi cinema, Parambrata says, "After 'Kahaani' people expected that I would just immediately move to Mumbai and start doing Hindi films. I didn't want that.I got very busy in Bengal. I learned direction myself and I was doing a lot of stuff.I don't regret it at all. I made some wrong choices in Hindi. I'm a little careful about that now and almost as a part of my answer to your previous question about what to do I think the advent of OTT has given me and many others like me a lot of good work."
More than twenty years as an actor and director in Bengali cinema...how does Parambrata assess these two decades? "I started so young that it is been two decades almost …yeah it's been fascinating and in very many ways it's been very very fascinating. When I look back at it I just sometimes feel that I've had many lives. There's a film in English called The Many Lives Of Pippa Lee. It's beautiful. I think my journey and many such as the journeys of many of the people remind me of that film because I really feel that we live many lives in one lifetime .So what I'd done back in 2001-2 seems like a different life, it feels like a different person that was living that life."
Looking ahead the actor has many projects lined up. "I think I need to get much wiser than what I am now. I still am quite impulsive about certain things.I think all the experiences have made me mature, they have also managed to keep the hunger alive. You know, deciding to quit television was a big turning point for me. Doing the films of Sandip Ray and then The Bong Connection was a turning point. It made me a film actor. Then leaving for the UK to study was a turning point although that was something that people thought was absolute madness. But I am glad I did it. I'd think of turning producer and director is a big turning point. And I would say recently the pandemic has been a turning point."
He feels the Bengali film industry has reached a turning point. "I think any industry when mainstream films and commercial films stop working …I think that's a bad sign for the industry because you know I think mainstream and parallel cinema keep each other in check. I think mainstream cinema in Bengali has completely stopped working and that is not a good sign and I think the people who are making that kind of cinema have become a little complacent. It stopped exploring more rooted subjects, well-grounded subjects and that's a problem. Having said that, there is a lot of interesting work happening and the people who have probably got complacent are also trying out new things and there's no stopping that, and then the next one or two years will be very crucial. After the pandemic, we thought the whole Bengali cinema industry will probably just collapse but that didn't happen thankfully. On the contrary a lot of new films are being made. It would be very very interesting to see how it goes and I think that there will be a little bit of churning, so let's see how it goes. We as a production company are producing 3 films next year, midsize Bengali films. And in the OTT space I am doing a series for Prime Video called The Girl, and then another series for Lionsgate Play. I am also doing a film being produced by Applause Entertainment. I'm currently shooting for a sports film.So it's a jampacked schedule for me."
Parambrata has also directed several film. His last directorial Abhijan chronicled the life and career of the legendary Soumitra Chatterjee. What drew him to this project? "Abhijan came my way. The producers were a dear friend of Soumitrada so they came to me and said they would like to make this. I did think about it and then came to the conclusion that yes I would like to make this. I don't know ….when the film releases some people might not like it some people might like it very much. But I think for me it's been a very unique experience interacting with Soumitrada spending so much time with him They gave me a lot of insight into the person's mind and existence and that is what I've tried to reflect on the screen."