Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: Gastrin-releasing peptide promotes suprachiasmatic nuclei cellular rhythmicity in the absence of vasoactive intestinal polypeptide-VPAC2 receptor signaling. J Neurosci. 2005;25:11155–64. [DOI] [PubMed] [PMC]212. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science. 2002;298:2213–6. [DOI] [PubMed] 213. Role of melanopsin in circadian responses to light. Science. 2002;298:2211–3. [DOI] [PubMed] 214. é C, Weihe E, Schäfer MK, et al. Cyclase-(PACAP)-Glutamate Co-transmission Phase-to by Suprachiasmatic Nucleus. Front Neurosci. 2019;13:1281. [DOI] [PubMed] [PMC]215. Changes in light-induced phase shift of circadian rhythm in mice lacking PACAP. Res Commun. 2003;310:169–75. [DOI] [PubMed] 216. The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms. Neuropharmacology. 2016;107:262–70. [DOI] [PubMed] 217. Ashton A, Jagannath A. in Schizophrenia and Signaling. Front Neurosci. 2020;14:636. [DOI] [PubMed] [PMC]218. . Mathematical insights into the role of dopamine signaling in circadian entrainment. Math Biosci. 2023;356:108956. [DOI] [PubMed] 219. üler AD, Steele AD. Dopamine systems and biological rhythms: Let's get a move on. Neurosci. 2022;16:957193. [DOI] [PubMed] [PMC]220. . Delayed circadian rhythm in adults with attention-deficit/hyperactivity disorder and chronic sleep-onset insomnia. Biol Psychiatry. 2010;67:1091–6. [DOI] [PubMed] 221. Retinal dopamine mediates multiple dimensions of light-adapted vision. J Neurosci. 2012;32:9359–68.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: English 简体中文 6Publishing-Submit a Manuscript F6Publishing-世界华人消化杂志在线投稿 is committed to discovery and dissemination of knowledge About the a All 10. 3748/wjg. v16. i4. 403] of This 4. 0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: Counts in Google of This 2010. doi: 10. 3748/wjg. v16. i4. 403 Probiotics and gut health: A special focus on liver diseases -of Nutrition and Health, University of 21 9of University of Kuopio, PO Box 1627, 70211 Kuopio, FinlandEl-Nezami, Food and Centre, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland; School of Biological Sciences, University of Hong Kong, S5-13 number: $[] Author contributions: Gratz SW, and El-Nezami HS wrote the 403. htm DOI: have been well defined and long used in human and animal health and nutrition. Many of the probiotic strains used today have been isolated from the human gut flora, and it is therefore more a reintroduction of organisms rather than a novel concept. The beneficial effects of probiotics and, especially, the clinical use of probiotics in the management of specific diarrhoeal diseases, including Rotavirus diarrhoea, Traveller’s diarrhoea and others are well accepted[1]. These effects are mainly based on colonisation resistance or the influence of probiotics on microflora balance. When discussing probiotics, it must be remembered that the intestinal microflora, resident in the large intestine, will always outnumber the probiotics that can be administered. Furthermore, probiotic processes will always be confounded by the diversity of the human microbiota and its variability in the face of varied human diets and genetic backgrounds[2]. Within the human gut, we have to separate processes occurring in the distal small intestine from those happening in the colon.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: CG: n=33; EG: n=64-67, missing n-values in the EG are due to the different number of meals for each participant. Detailed statistics in Tables S3. (E) Within group differences of body weight during the study. Body weight was collected at different time points, at the beginning of the study (T0), after the exploration phase (T1), after the intervention phase (T2), and after the follow-up phase (T3). During the follow-up phase, 34 EG participants voluntarily continued the intervention (continuing; black line and open circle) while 33 participants no longer followed the intervention (discontinuing; gray, dashed line and open circle). Only three control subjects continued their intervention in the follow-up phase, which is why a division into continuing and discontinuing was omitted in this group. Data are normalized so that all baseline data at T0 equals 0 to represent change. Differences of all CG and EG participants between T0, T1, and T2 were calculated with a 1-way ANOVA, as were differences between T2 and T3 of CG participants (Bonferroni post-hoc test, **** p ≤ 0. 0001). Differences between T2 and T3 of continuing and discontinuing EG participants were calculated with a paired t-test °° p ≤ 0. 01, °°°° p ≤ 0. 0001. Detailed statistics in Table S4. (F) Between group differences of BMI from T0-T3. Mixed-effect model with Bonferroni post-hoc test comparing CG and EG at different phases during the study, **** p ≤ 0. 0001. Detailed statistics in Table S5. (G) Significant correlation between body weight/BMI and MTVS. The more participants improved their regularity of meals (decreasing MTVS), the more weight/BMI they lost. Linear regression, CG: n=33; EG: n=67, ** p ≤ 0. 01. Detailed statistics in Tab. S6. (H) Significant correlation between body weight/BMI and MTVS of lunch and dinner. The more participants improved their regularity of lunch and dinner (decreasing MTVS), the more weight/BMI they lost. Linear regression, CG: n=33; EG: n=67, ** p ≤ 0. 01. Detailed statistics in Tab.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: 5-HT1B receptor-mediated presynaptic inhibition of GABA release in the suprachiasmatic nucleus. J Neurophysiol. 2005;93:3157–64. [DOI] [PubMed] 244. Cuesta M, Clesse D, Pévet P, Challet E. New light on the serotonergic paradox in the rat circadian system. J Neurochem. 2009;110:231–43. [DOI] [PubMed] 245. Cohen R, Kronfeld-. The substructure of the suprachiasmatic nucleus: Similarities between nocturnal and diurnal spiny mice. Evol. 2010;75:9–22. [DOI] [PubMed] [PMC]246. . Anticholinergic agents do not block light-induced circadian phase shifts. Brain Res. 1985;348:163–7. [DOI] [PubMed] 247. Modulation of photic resetting in rats by lesions of projections to the suprachiasmatic nuclei expressing p75 neurotrophin receptor. Neurosci. 2004;19:1773–88. [DOI] [PubMed] 248. The cholinergic forebrain arousal system acts directly on the circadian pacemaker. . 2016;113:13498–503. [DOI] [PubMed] [PMC]249. Signals from the brainstem sleep/wake centers regulate behavioral timing via the circadian clock. PLoS One. 2013;8:e70481. [DOI] [PubMed] [PMC]250. . Lack of M4 muscarinic receptors in the striatum, thalamus and intergeniculate leaflet alters the biological rhythm of locomotor activity in mice. Funct. 2020;225:1615–29. [DOI] [PubMed] [PMC]251. Aykan U, Güvel. Neuropharmacologic modulation of the melatonergic system. Explor Neurosci. 2023;2:287–306. 252. Whole-to the of the Suprachiasmatic Nucleus. Front Neurosci. 2018;12:807. [DOI] [PubMed] [PMC]253. -Hansen L.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: The small intestine harbours relatively low numbers of resident intestinal bacteria, but at the same time contains the major part of the gut associated lymphoid tissue (GALT), which samples intestinal microbes[3]. Hence modulation of systemic immune and allergic phenomena might be primarily mediated by the GALT of the small bowel. Supplementing qualitatively and quantitatively optimised microbes to this part of the gut might stimulate Treg cell development and consequent immunomodulation[1]. Within the large intestine, bacterial intervention might cause modulation of the microbial fermentation activity and direct action on the colonic epithelium to alter (suppress) innate immunity. These processes might explain the impact of probiotics on inflammatory and functional bowel disorders. The research field of probiotics is very heavily reviewed, using different clinical and microbiological angles to elucidate the topic. The aim of this review is to summarise the most recent trends in probiotic research, focusing on the clinical use of probiotics and their effects on the healthy and diseased gut and liver. The direct and indirect actions of probiotics on intestinal cells and their consequences on liver (summarised in Figure 1) will be discussed in this review. Open in 1 Potential mechanisms of action by which probiotics can promote GI health and the consequences for the liver. Probiotics and surface-layer proteins competitively exclude microbial pathogens from mucosal surfaces. Tight junction proteins, such as zona occludins-1 and claudin1, remain intact and thereby prevent both uptake of intact macromolecules and translocation of viable organisms (BT) to mesenteric lymph nodes, and ultimately to the liver. Through a cascade of signalling events, probiotics enhance production and secretion of anti-inflammatory cytokines, including interleukin-10 and transforming growth factor-β, by a subset of immune cells, referred to as T regulatory cells. Innate immune responses to probiotics include increased mucin and trefoil factor production by goblet cells and enhanced production of antibacterial defensins by Paneth cells and intestinal epithelia. Probiotics might alter the intestinal microbiota and hence limit intestinal bacteria overgrowth (IBO) and the production of lipopolysaccharides (LPS). and intestinal barrier functionThe intestinal barrier is seen as the first line of defence against pathogens and food allergens entering the intestinal tract, and probiotics have been intensely studied for their involvement in maintaining this barrier.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: S6. (I) Significant correlation between change in BMI, baseline BMI, and improvement in MTVS. Individuals with higher BMI benefit more from similar improvements in MTVS (shades of data points) than individuals with lower BMI in EG participants. Multiple regression, n=67, * p ≤ 0. 05, ** p ≤ 0. 01. Detailed statistics in Tab. S8. 2. 3. Weight changeDuring the exploration phase, when no instructions on eating times were given, CG and EG participants had a statistically non-significant average loss of 0. 17 kg (0. 06 kg/m²) and 0. 21 kg (0. 06 kg/m²), respectively (Figs. 1E, S2B-F, Tabs. S4, S5). However, during the intervention phase, when EG participants took their meals more regularly, they lost an average of about 2. 6 kg (95% CI [-2. 906, -1. 915]) and 0. 81 kg/m² (95% CI [-0. 9729, -0. 6420]) (Figs. 1E, S2B-E, Tabs. S4, S5), which translates to an average weight loss of 0. 40 kg (0. 145 kg/m²) per week during the intervention. The weight loss observed in this group is independent of the age of the participants and their sex (Fig. S2G, Tabs. S6, S2). In contrast, weight and BMI changes of -0. 39 kg (95% CI [-0. 9125, 0. 1307]) and -0. 14 kg/m² (95% CI [-0-3152, 0. 0304]), respectively, were not significant in the CG (Figs. 1E, S2B, C, F, Tabs. S4, S5), resulting in a significant difference in weight loss between groups at the end of the intervention (Figs. 1F, S2C, Tab. S5). The inclusion of the last available weight and BMI data of the drop-outs in an end-point analysis did not lead to any notable change in this result (Fig. S2H, Tab. S5). Four weeks after the intervention ended, all participants were contacted again for a follow-up assessment.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: Cholecystokinin (CCK)-expressing neurons in the suprachiasmatic nucleus: innervation, light responsiveness and entrainment in CCK-deficient mice. Neurosci. 2010;32:1006–17. [DOI] [PubMed] 254. Cholecystokinin neurons in mouse suprachiasmatic nucleus regulate the robustness of circadian clock. Neuron. 2023;111:2201–17. e4. [DOI] [PubMed] 255. MT1 and MT2 melatonin receptors are expressed in nonoverlapping neuronal populations. J Pineal Res. 2019;67:e12575. [DOI] [PubMed] 256. . The endogenous melatonin (MT) signal facilitates reentrainment of the circadian system to light-induced phase advances by acting upon MT2 receptors. Chronobiol Int. 2012;29:415–29. [DOI] [PubMed] 257. Hunt AE, Al-. Activation of MT2 melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Physiol. 2001;280:C110–8. [DOI] [PubMed] 258. Drunen RV, Eckel-Mahan K. of the Hypothalamus: to Physiology. Clocks Sleep. 2021;3:189–226. [DOI] [PubMed] [PMC]259. . Melatonin generates an outward potassium current in rat suprachiasmatic nucleus neurones in vitro independent of their circadian rhythm. Neuroscience. 2001;107:99–108. [DOI] [PubMed] 260. . Clock genes in calendar cells as the basis of annual timekeeping in mammals--a unifying hypothesis. J Endocrinol. 2003;179:1–13. [DOI] [PubMed] 261. . A novel human opsin in the inner retina. J Neurosci. 2000;20:600–5. [DOI] [PubMed] [PMC]262. . Melanopsin, ganglion-cell photoreceptors, and mammalian photoentrainment. J Biol Rhythms. 2003;18:227–34. [DOI] [PubMed] 263. .

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: In colonic epithelia, probiotics are suggested to stimulate mucin production, and therefore enhance the self protecting properties of the intestinal epithelium[4]. Furthermore, tight junctional proteins, important for the physical tightness of the epithelial cell layer, are found to be enhanced by probiotics[5,6] and the disruption of tight junctions by pathogens can be counteracted[7]. Besides these effects on the physical barrier function, evidence is mounting that both commensal microflora and specific probiotic supplementations specifically enhance the immunological barrier function of the small intestinal mucosa[8]. For this cross talk between bacteria and the immune system, bacteria derived products including metabolites, cell wall components and DNA, can be sensed by enterocytes and immune competent cells[9]. Commensals, unlike pathogens, are efficiently killed by intestinal macrophages, therefore avoiding an inflammatory response in the mucosa[10]. At the same time, dendritic cells can sample commensals, incorporate them, and transport them to mensenteric lymph nodes. Here, commensal-loaded dendritic cells induce a local immune response with the activation of specific B-cells to produce secretory IgA against these commensals[8,10]. This appears to be a paradox, but this specific and local immune stimulation by commensals and probiotics can actually be considered non-inflammatory in the mucosal environment and the host systemics[8]. Therefore GALT, and specifically the mesenteric lymph nodes, can be considered another layer of intestinal barrier function[3,10]. Probiotics and inflammatory bowel diseases (IBD)The pathogenesis of IBD [ulcerative colitis (UC) and Crohn’s disease] remains unknown, but the intestinal microflora appears to play an important role. Changes in microflora composition have been observed in UC patients, with increased pro-inflammatory bacteria, including Enterobacteriaceae, increased Bacteroides fragilis within the mucosal microflora[11], and decreased protective bacteria, including lactobacilli and bifidobacteria[12]. Probiotic treatment has the potential to decrease the severity of symptoms in IBD via interaction with gut epithelium[13].

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: 34 of the 67 EG participants reported to have maintained the regularity of their meals and continued to lose body weight significantly, on average another 1. 12 kg (95% CI [-1. 479, -0. 7626]) and 0. 36 kg/m² (95% CI [-0. 4907, -0. 2457]), respectively (Figs. 1E, S2B, D, E, Tab. S4). In contrast, participants who reported to have resumed irregular eating gained a significant average of 0. 48 kg (95% CI [0. 1984, 0. 7616]) and 0. 17 kg/m² (95% CI [0. 07434, 0. 2603]), respectively (Fig. 1E, S2B, D, E, Tab. S4). 2. 4. Relation between weight change and improvement in the regularity of mealsTo examine the extent to which EG participants’ weight loss was effectively related to improvements in meal regularity, we correlated changes in body weight and BMI with individual MTVS changes. Consistent with our hypothesis, a significant relationship exists between weight loss and improvement in regularity in the EG (Fig. 1G, Tab. S6). A breakdown of meals shows that increasing the regularity of lunch and dinner has the greatest effects, with no significant relationship between increasing the regularity of breakfast and weight loss (Fig. 1H, Tab. S6). In contrast, in the CG, there were no or little improvements in regularity and, accordingly, no correlation with weight/BMI changes. Further analyses revealed that all MTVS up to 3, which corresponds to a time window for meals of up to ±45 min, resulted in comparably effective weight loss, whereas the efficiency of weight loss decreases significantly with an MTVS greater than 3 (Tab. 1). Table 1:Association of weekly MTVS with weekly weight loss. The table shows the weekly weight change of all participants during the exploration and the intervention phase while adhering to certain MTVSs in each week. 1-way ANOVA with Bonferroni post-hoc test comparing the mean of each row with the mean of the first row, * p ≤ 0. 05. 2. 5. Relation between weight change and baseline BMIA weight loss intervention which is particularly based on metabolic optimization is likely to be most effective for individuals with exceeded body weight.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: [DOI] [PubMed] [PMC]274. Orexin System: for a Healthy Life. Front Physiol. 2017;8:357. [DOI] [PubMed] [PMC]275. Acute suppressive and long-term phase modulation actions of orexin on the mammalian circadian clock. J Neurosci. 2014;34:3607–21. [DOI] [PubMed] [PMC]276. Flyer-Adams JG, Rivera-. Regulation of Memory by the Pigment-(PDF). J Neurosci. 2020;40:9066–77. [DOI] [PubMed] [PMC]277. Vaze KM, Helfrich-Förster C. for Delaying the Phase of Drosophila's. J Biol Rhythms. 2021;36:442–60. [DOI] [PubMed] [PMC]278. -Förster C, Martínez-Torres D. Pigment-dispersing factor is present in circadian clock neurons of pea aphids and may mediate photoperiodic signalling to insulin-producing cells. Open Biol. 2023;13:230090. [DOI] [PubMed] [PMC]279. . Endothelial and neuronal nitric oxide synthases are present in the suprachiasmatic nuclei of Syrian hamsters and rats. Neurosci. 2000;12:649–61. [DOI] [PubMed] 280. . Signaling in the mammalian circadian clock: the NO/cGMP pathway. Neurochem Int. 2004;45:929–36. [DOI] [PubMed] 281. . Circadian entrainment to light–dark cycles involves extracellular nitric oxide communication within the suprachiasmatic nuclei. Neurosci. 2010;31:876–82. [DOI] [PubMed] 282. . Circadian rhythm and sleep-wake systems share the dynamic extracellular synaptic milieu. Circadian Rhythms. 2018;5:15–36. [DOI] [PubMed] [PMC]283. Vinod C, Jagota A. Daily NO rhythms in peripheral clocks in aging male Wistar rats: protective effects of exogenous melatonin. Biogerontology.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: Proposed mechanisms include changes in short chain fatty acids (SCFA) production patterns, reduction in pro-inflammatory cytokine secretion, improving Th1/Th2 ratios, and eliminating pathogens. For example, the production of reuterin has been shown in vitro to reduce growth of pathogens, including Escherichia coli (E. coli), Salmonella enterica, Shigella sonnei, and Vibrio cholera. Adhesion of probiotics to enterocytes and enhancement of barrier function (secretion of B-defensins and mucus, TJ proteins) have also been shown for specific strains in vitro. However, it is unclear whether this strengthening of the intestinal barrier function would also occur in the large intestine, the area most affected by intestinal disease. Some evidence from a mouse model of colitis [interleukin (IL)-10 deficient mice] suggests that probiotic lactobacilli and the VSL#3 mix reduced bacterial translocation (BT) and intestinal permeability in the colon[14,15]. Mechanistic effects can also be observed with non-viable probiotics and culture supernatants in vitro and in animals, which might be a safer therapeutic for patients with impaired intestinal barrier and increased risk of sepsis. Bacteria-free culture supernatant from Lactobacillus plantarum was shown to inhibit inflammatory pathways important for intestinal inflammation, such as nuclear factor (NF)-κB binding activity and proteasome activity, in a young adult mouse colon cell line and in macrophages[16]. This might provide a novel and safe strategy for treatment of IBD, if results can be repeated in vivo. Probiotics and irritable bowel syndrome (IBS)IBS includes a range of symptoms, such as abdominal pain, altered bowel habits, bloating and flatulence in the absence of structural abnormalities in the intestine. As no curative treatment is available for IBS, therapy is palliative and supportive, targeting special symptoms, and is notoriously unsatisfactory. Studies have observed alterations in intestinal microflora in patients and increased symptoms following enteric infections, therefore probiotics might be a useful tool to improve symptoms. A meta analysis of probiotic treatment and IBS[17] included 20 trials with 23 probiotic treatments. This study showed that probiotics were associated with improved global IBS symptoms [risk ratio (RR) = 0.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: In fact, the higher the baseline BMI of EG participants at T1, the greater the weight loss (Fig. S2I, Tab. S6). Stratifying the subjects by baseline BMI, including the control group, additionally shows that in all strata the BMI of EG subjects decreased more than that of CG subjects, even if they had the same initial BMI (Fig. S2J, Tab. S7). Multiple regression shows that the reduction in MTVS and baseline BMI together predict the weight loss of the participants (Fig. 1I, Tab. S8). These data show that regularity in meal intake can lead to a significant loss of body weight and suggest that this effect is especially pronounced in individuals with a higher BMI. 2. 6. Relation between weight change and self-reported food quantity and compositionBy restricting meals to specific times and shortening the time window in which food is eaten, it is feasible that EG participants ate less or changed food composition during the intervention phase and therefore lost weight. However, on average, the reported food energy ingested by CG and EG participants did not substantially change during the study (Fig. 2A, S2K, L, Tab. S3, 6), apart from a minor average reduction of ∼350 kJ (95% CI [-627. 6, -67. 67]) per day in the EG (Fig. S2K, Tab. S3), and did not differ between CG and the EG. As they are rather small, these differences do not add up to a significant reduction in the total average energy consumed over the course of the study. Accordingly, the determined cumulative average energy intake during the intervention phase did not differ on any day from the estimated energy intake based on an extrapolation of the cumulative food consumption during the exploration phase, neither in the CG nor in the EC group (Fig. 2B). Nevertheless, there were some participants who reported having consumed fewer calories during the intervention phase, while some also reported having ingested more calories. However, consistent with our hypothesis that high regularity of mealtimes optimizes metabolism of similar amounts of food, there is no relationship between reported changes in average daily and cumulative energy intake and change in body weight/BMI of either CG or EG participants (Fig. 2C, D, Tab. S6).

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: 2016;17:859–71. [DOI] [PubMed] 284. . Is histamine the final neurotransmitter in the entrainment of circadian rhythms in mammals? Sci. 2000;21:293–8. [DOI] [PubMed] 285. Biello SM. Circadian clock resetting in the mouse changes with age. Age (Dordr). 2009;31:293–303. [DOI] [PubMed] [PMC]286. . Neurochemistry in Clinical Practice. In: Bollu PC, editor. Cham: Springer; 2022. 287. Histamine 1 receptor-Gβγ-cAMP/PKA-CFTR pathway mediates the histamine-induced resetting of the suprachiasmatic circadian clock. Mol Brain. 2016;9:49. [DOI] [PubMed] [PMC]288. Boudin H, Pélaprat D, Rostène W, Beaudet A. Cellular distribution of neurotensin receptors in rat brain: immunohistochemical study using an antipeptide antibody against the cloned high affinity receptor. J Comp Neurol. 1996;373:76–89. [DOI] [PubMed] 289. . Widespread expression in adult rat forebrain of mRNA encoding high-affinity neurotensin receptor. J Comp Neurol. 1998;402:475–500. [PubMed] 290. Meyer-. Neurotensin phase-shifts the firing rate rhythm of neurons in the rat suprachiasmatic nuclei in vitro. Neurosci. 2002;16:339–44. [DOI] [PubMed] 291. . Effects of neurotensin on discharge rates of rat suprachiasmatic nucleus neurons in vitro. Neuroscience. 2001;103:663–72. [DOI] [PubMed] 292. Jha PK, Bouâouda H, Kalsbeek A, Challet E. Distinct feedback actions of behavioural arousal to the master circadian clock in nocturnal and diurnal mammals. Rev. 2021;123:48–60. [DOI] [PubMed] 293. . Differential responses of circadian activity onset and offset following GABA-ergic and opioid receptor activation. J Biol Rhythms. 2003;18:297–306.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: 77] and with decreased abdominal pain (RR = 0. 78). Due to the large variety in probiotic strains used, no analysis on strain type was possible. Probiotics used included B. infantis, lactobacilli (L. acidophilus, L. plantarum, L. reuteri, L. rhamosus), Saccharomyces boulardii, Streptococcus faecium, VSL#3 (mix of eight), and other mixes. In a recent systematic review, Brenner et al[18] claimed that 16 randomized controlled human trials met their inclusion criteria, of which 11 had suboptimal study design. They concluded that only one study using a specific strain of B. infantis 35 624 efficiently improved IBS symptoms. Probiotics might offer a treatment possibility for IBS symptoms, but more controlled studies are needed to identify the ideal strain, dose, and duration of treatment. Probiotics after gut surgeryMorbidly obese patients can undergo Roux-en Y gastric bypass surgery (one type of bariatric surgery) for effective and enduring weight loss. This procedure uses restriction in stomach size and intestinal malabsorption as measures for achieving substantial weight loss. Problems that occur postoperationally are alteration of microflora with bacterial overgrowth (BO) in the blind sac of the intestine, intestinal pain, and possibly impaired vitamin B12 status (due to lack of intrinsic factor production from the stomach). This study[19] used probiotic treatment (6 mo, commercial product of unspecified lactobacilli) in 44 post operational patients. BO (measured with hydrogen breath test) improved only after 6 mo, but not earlier. Vitamin B12 status improved, gastrointestinal symptoms remained unchanged, but post operational weight loss was significantly increased in the probiotic group. The authors speculated that increased weight loss might be due to changes in microflora towards extracting fewer calories from the diet, although this was not studied. Probiotics/symbiotics have also been used to prevent postoperative infections in patients undergoing abdominal surgery (biliary cancer, liver transplantation, and pancreaticoduodenectomy). Major infections were pneumonia, urinary tract infection, wound infection, intra-abdominal abscess, and cholangitis. A recent meta analysis[20] found that probiotics reduced overall infections [odds ratio (OR) = 0.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: Likewise, the composition of the ingested foods did not change considerably in either group, and participants reported a normal distribution of the macronutrients of fat, carbohydrate, and protein in both phases of the study (Fig. 2E, S2M, Tab. S3). Also, there was no correlation between weight change and change in reported average daily and cumulative macronutrient intake (Fig. 2F, S2N, Tab. S6). Fig. 2:Changes in body weight/BMI are not related to changes in reported caloric intake and composition of macronutrients. Changes in reported daily caloric intake (A), cumulative caloric intake (B) and food composition (E) and their relationship to weight/BMI changes (C, D, and F). Data in (A) are normalized so that all baseline data of the exploration phase equal 1. To represent the x-fold change, data from the intervention phase are divided by data from the exploration phase of the corresponding participant. (A, E) 2-way repeated-measures ANOVA with Bonferroni post hoc test comparing CG and EG during the exploration or intervention phase and T0-T1 and T1-T2 within groups, * p ≤ 0. 05. Detailed statistics in Tables S3. (B) Mixed-effects model with Bonferroni post hoc test comparing determined and estimated cumulative energy intake. The estimated energy intake is formed as an assumed continuation of the average daily intake during the exploration phase. post hoc test showed no significant differences on any study day. (C, D, and F) Linear regression, CG: n=30; EG: n=67 (some participants were excluded subsequently from this analysis because of several erroneous diary entries about unrealistic amounts of food, e. g. , 30,000 g chicken for lunch). Detailed statistics in Tab. S6. 2. 7. Relation between weight change and other meal timing-related factorsBesides increasing regularity, restricting meals to certain times of the day can also shorten the daily window in which meals are eaten and shift meals to other times of the day. In fact, our intervention caused many EG participants to avoid occasional meals at extremely early or late times, limiting their meals to much shorter intervals of 11 h (95% CI [10. 468, 11. 520]) (Fig. 3A, B, Tab. S3), while those of the CG remained long with 13.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: [DOI] [PubMed] 294. The opioid fentanyl affects light input, electrical activity and Per gene expression in the hamster suprachiasmatic nuclei. Neurosci. 2005;21:2958–66. [DOI] [PubMed] 295. Hamada T, Shibata S. The role of GABAergic neuron on NMDA- and SP-induced phase delays in the suprachiasmatic nucleus neuronal activity rhythm in vitro. Neurosci Lett. 2010;468:344–7. [DOI] [PubMed] 296. . Investigating the role of substance P in photic responses of the circadian system: individual and combined actions with gastrin-releasing peptide. Neuropharmacology. 2010;58:277–85. [DOI] [PubMed] 297. The gut–brain peptide neuromedin U is involved in the mammalian circadian oscillator system. Res Commun. 2004;318:156–61. [DOI] [PubMed] 298. Identification of neuromedin S and its possible role in the mammalian circadian oscillator system. EMBO J. 2005;24:325–35. [DOI] [PubMed] [PMC]299. Expression of the vesicular GABA transporter within neuromedin S+ neurons sustains behavioral circadian rhythms. . 2023;120:e2314857120. [DOI] [PubMed] [PMC]300. Somatostatin regulates central clock function and circadian responses to light. . 2023;120:e2216820120. [DOI] [PubMed] [PMC]301. . Increase in somatostatin immunoreactivity in the suprachiasmatic nucleus of aged Wistar rats. Brain Res. 2002;958:463–7. [DOI] [PubMed] 302. . Aging selectively suppresses vasoactive intestinal peptide messenger RNA expression in the suprachiasmatic nucleus of the Syrian hamster. Res. 2001;87:196–203. [DOI] [PubMed] 303. . of Encoded by the Clock. J Biol Rhythms. 2020;35:353–67. [DOI] [PubMed] [PMC]304. Moore RY. in the Nucleus. J Biol Rhythms.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: 26], length of antibiotic treatment need (OR = -4. 01), reduced length of postoperative hospital stays (OR = -2. 7), but did not change overall mortality (OR = 0. 98). Overall the use of probiotics is very promising, although data are very variable (type of surgery, type of infection, and type of probiotic treatment). However, bacteremia might be a potential hazard in these vulnerable patients. The appropriate therapeutic route, length of therapy, time of administration, dosage, and kind of probiotic remain controversial and no uniform preventative strategy can be suggested on based of the current literature. is a longstanding practice of using lactulose in the treatment of hepatic encephalopathy, which suggests involvement of gut microflora in the management of chronic liver disease. Loguercio et al[21] use the phrase “gut liver axis” and suggest that the microflora might affect the liver and be cofactor in aetiology of chronic liver damage. This could happen via modulating chronic damage by ethanol or by contributing to complications such as encephalopathy (production of ammonia, ethanol, acetaldehyde, phenols, endotoxin, and benzodiazepines)[21]. Probiotic actions most relevant to liver disease are modification of intestinal barrier function and prevention of BT. Gram-negative BO, increased permeability, and impaired immunity all contribute to increased BT, and there is a strong correlation between the rate of BT and the severity of cirrhosis. Probiotics might alter gut flora towards protective organisms and increase barrier function[22]. Probiotics and non alcoholic fatty liver disease (NAFLD)NAFLD is the most common form of liver disease in the US; its incidence is rising together with rising problems of obesity and Type II diabetes. NAFLD includes a spectrum of pathologies. Steatosis (fatty liver), is clinically asymptomatic, but might predispose the liver to other insults, such as lipopolysaccharides (LPS) or hepatotoxins, that might lead to cirrhosis. Non-alcoholic steatohepatitis (NASH) is an intermediate state where lobular inflammation occurs. Cirrhosis is the most severe form, responsible for most liver specific morbidity and mortality[23]. Histopathological changes are very similar to alcoholic liver disease, and there might be a common pathway of development.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: 7 h (95% CI [12. 902, 14. 562]). Additionally, compared with before and with the CG, the EG intervention resulted in the first meal of the day being delayed to a later time for many subjects (EG: 09:21 (95% CI [08:58, 09:45]) vs. CG: 08:03 (95% CI [07:32, 08:33])) and the last meal of the day being advanced to an earlier time (EG: 20:17 (95% CI [19:59, 20:35]) vs. CG: 21:31 (95% CI [21:05, 21:57])) (Fig. 3C, D, Tab. S3). However, weight changes of participants do not correlate with these changes in eating characteristics (Fig. 3B-D, Tab. S6). Fig. 3:Influence of other changes in eating times and of personalization of meal schedules on weight loss. (A) 95th percentile of the time period during which food was ingested by 15 example participants during the exploration phase (yellow) and the intervention phase (purple). (B) Change in length of this period and its relation to weight/BMI changes. (C, D) Change in time of first (C) and last (D) caloric intake and their association with weight/BMI changes. (B-D) 2-way repeated-measures ANOVA with Bonferroni post hoc test comparing CG and EG during the exploration or intervention phase and T0-T1 and T1-T2 within groups, *** p ≤ 0. 001, **** p ≤ 0. 0001. Linear regression. EG: n=67, varying n-numbers result from incomplete entries in the diaries. Detailed statistics in Tables S3 and S6. (E) The relation between mid-Sleep phase and mid-Eat phase (brown) on the weekends of the exploration phase. The goodness of fit of this association improves during through EG intervention and affects both workdays and weekend days (purple). Linear regression, n=65, **** p ≤ 0. 0001. Detailed statistics in Table S6. (F) Relation of the mid-Sleep phase (mSP) and mid-Eat phase (mEP) during exploration and intervention phase.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: 2016;31:406–10. [DOI] [PubMed] 305. . Retinal innervation of calbindin-D28K cells in the hamster suprachiasmatic nucleus: ultrastructural characterization. J Biol Rhythms. 2000;15:103–11. [DOI] [PubMed] [PMC]306. . Potential pathways for intercellular communication within the calbindin subnucleus of the hamster suprachiasmatic nucleus. Neuroscience. 2004;123:87–99. [DOI] [PubMed] 307. Ikeda M, Allen CN. Developmental changes in calbindin-D28k and calretinin expression in the mouse suprachiasmatic nucleus. Neurosci. 2003;17:1111–8. [DOI] [PubMed] 308. öhr M, Hauptfleisch S, Lemmer B. Localization of components of the renin–angiotensin system in the suprachiasmatic nucleus of normotensive Sprague–Dawley rats: Part A. Angiotensin I/II, a light and electron microscopic study. Brain Res. 2004;1008:212–23. [DOI] [PubMed] 309. . Angiotensin II regulates the activity of mouse suprachiasmatic nuclei neurons. Neuroscience. 2008;154:839–47. [DOI] [PubMed] 310. Herichová I, Šoltésová D, Szántóová K, Mravec B, Neupauerová D, Veselá A, et al. Effect of angiotensin II on rhythmic per2 expression in the suprachiasmatic nucleus and heart and daily rhythm of activity in Wistar rats. Regul Pept. 2013;186:49–56. [DOI] [PubMed] 311. . Expression of the galanin receptor subtype Gal-R2 mRNA in the rat hypothalamus. J Chem Neuroanat. 1999;16:265–77. [DOI] [PubMed] 312. Mills EG, Izzi-. Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour. Endocrinol.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: Data suggest a “multi hit” hypothesis, where initial hits such as obesity and sub-clinical insulin resistance might promote the development of steatosis[23]. This enhances the fatty liver’s vulnerability to subsequent insult (e. g. ethanol and LPS) that increase the production of pro-inflammatory cytokines [e. g. tumor necrosis factor (TNF)-α]. This aggravates insulin resistance and leads to oxidative stress (increased production of reactive oxygen by hepatocytes and liver macrophages) and organelle dysfunctions, which kill hepatocytes and promote accumulation of inflammatory cells in the liver and the development of NASH[24]. Following years of chronic inflammation this might develop into fibrogenic response and cirrhosis. The contribution of microflora in the development of NAFLD is mainly based on increased hepatic oxidative stress by increased production of ethanol and LPS in the intestinal lumen, and subsequent release of inflammatory cytokines in intestinal epithelia and liver macrophages. Both processes then lead to injury of the intestinal epithelium and disrupted intestinal barrier function, which in turn increases hepatic exposure to intestine-derived toxins. This hypothesis is further supported by evidence that intestinal BO exacerbates fatty liver disease in rodents and humans, and that obese patients with NASH have increased prevalence of BO. Furthermore, obese subjects are known to have decreased intestinal motility and are therefore more prone to BO. A recent clinical trial confirms that patients with NASH have increased intestinal permeability and small intestinal BO[25]. From this data, an obvious way to control the development of NAFLD seems to be a manipulation of the gut microflora, mainly by the reduction of BO. This can be achieved by antibiotic treatment, which has been used successfully, but is controversial due to its unspecific impairment of all microflora and its severe side effects[23]. Probiotic therapy, on the other hand, has been suggested to counteract the development of NAFLD on various different levels. Competitive inhibition of pathogens by probiotics might alter their inflammatory effects in intestinal BO, which is associated with NAFLD. Furthermore, improved intestinal epithelium function and decreased BT and endotoxemia following probiotic treatment have been observed in experimental animals and humans[26].

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: Values close to 1 (blue) or -1 (red) indicate high intertwining of the data, values close to 0 (white) indicate independence or orthogonality of the data. The assignment of the coefficients to the independent variables is the same as in (K). 2. 8. Effect of meal schedule personalization on weight lossA key part of our hypothesis involves the personalization of meal schedules. Consistent with the concept of social jet lag (the discrepancy between socially imposed and biological times), our data show that during the exploration phase, eating times on workdays differ from those on work-free days. Because social constraints usually matter less on non-working days, we expect eating times on these days to correspond more closely to individual circadian characteristics, such as the chronotype. The MCTQ questionnaire measures the chronotype based on the mid-sleep phase (mSP), i. e. , the midpoint between sleep onset and waking up [25]. Corresponding to the mSP, we determined the mid-eat phase (mEP), which we define as the midpoint between the first and the last meal of the day. Indeed, our data show that the later the mSP of participants, the later their mEP on weekends (Fig. 3E, Tab. S6), with the mSP and mEP being almost antiphasic on average, i. e. 12 hours apart (Fig. 3F, Tab. S9). The EG intervention maintains most of this relationship. However, the residuals of the regression become smaller, resulting in a model fitting the data better (Fig. 3E, Tab. S6). Interestingly, the closer the intervention brings an observed value to the predicted value, i. e. , the smaller the residual becomes, the more weight the participant loses (Fig. 3G, Tab. S6). This indicates that the personalized adjustment of eating times to the individual chronotype, i. e. , the establishment of a highly accurate phase relation between mEP and mSP, leads to a particularly effective reduction of excess weight. Another part of the hypothesis is that the adaptation of eating times to the times of hunger presumably determined by the circadian system contributes to weight loss. The calculation of individual eating times was based on the frequency of the hours at which meals were eaten on all days of the exploration phase. These days typically included more workdays than non-workdays (Fig. 3H).

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: Skip to main content Intended for healthcare professionals Search this journalSearch all journalsEnter search terms. . . Searchsearch Enter search terms. . . Searchsearch Search Access/ProfileAccessView access optionsView profileCreate profile Cart 0 by discipline Select discipline: All disciplines All disciplines Life & & Sciences & HumanitiesSelect subject: All subjects All subjects Cardiology & Medicine & Endocrinology & -legal & Orthopaedics & Medicine & & & & Methods & & & & & Criminology & Economics & & & Management & Marketing & & & & & & & & PlanningBrowse journals Sage publishes a diverse portfolio of fully journals in a variety of disciplines. you can explore our Disciplines Hubs, including: Journal portfolios in each of our subject areas. Links to Books and content from across Sage. for/ Reviewers SocietiesFrequently asked questions In this journal : 3. 5 5-Factor: 5. 7 email alertsYou are adding the following journal to your email alertsNew contentThe NeuroscientistCreate email alert Restricted accessReview 10. 1177/10738584031262149ContentsAbstract1999. Orphanin-FQ/nociceptin (OFQ/N) modulates the activity of suprachiasmatic nucleus neurons. J Neurosci 19:2152–2160. 1997. Functional identification of the mouse circadian clockgene by transgenic BAC rescue. Cell 89:655–667. 2001. A neural circuit for circadian regulation of arousal. 4:732–738. 1995. Nucleoplasmin-targeted aequorin provides evidence for nucleus calcium barrier. Res 216:236–243. 2002. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295:1070–1073. 1989. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. 86:9030–9033. 1990. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. 87:682–685. 1994. Nuclear targeting of aequorin. A new approach for measuring nuclear Ca2+ concentration in intact cells. 16:259–268. 1993. Nuclear Ca2+ concentration measured with specifically targeted recombinant aequorin. EMBO J 12:4813–4819. 1994.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: In a series of feeding studies in mice, Cani et al[27] claimed that high-fat feeding changes the intestinal microflora composition (less bifidobacteria), which led to increased LPS levels in plasma, pro-inflammatory cytokines and increased intestinal permeability. All these effects could be counteracted by prebiotic treatment and increasing bifidobacteria species (summarized in[27]). This would indicate a direct effect of intestinal bacteria on low-grade inflammation, insulin insensitivity, and fat deposition in the liver. Other research suggests a direct decrease in pro-inflammatory cytokines e. g. TNF-αvia downregulation of NF-κB activity by probiotic treatments[14,28-30]. In a study in ob/ob mice, probiotics (VSL#3) and TNF-α antibodies were used to treat NAFLD. Both treatments improved liver function, reduced hepatic fatty acid content, and both interfered with NF-κB signalling and reduced hepatic fatty acid β-oxidation close to levels in lean mice. The authors suggest that this effect might result from improved hepatic insulin resistance[28]. Another study, using the same probiotic in normal mice, measured hepatic natural killer T (NKT)-cell depletion in high-fat fed animals[31]. NKT are unconventional T cells that express both T cell and Killer cell receptors. They regulate hepatic inflammatory process by balancing production of pro- and anti-inflammatory cytokines. Alterations of NKT function might lead to overproduction of TNF-α, causing inflammation in insulin resistance. High-fat diet induced the depletion of NKT from the liver, leading to insulin resistance and steatosis. Probiotics significantly improved all these symptoms and the effect resulted from TNF-α signalling and led to improved insulin signalling[31]. There is some suggestive evidence that probiotics might have efficacy in NAFLD in humans, but more controlled trials are needed[30]. Probiotics and alcoholic liver diseaseIn alcoholic liver disease, bowel liver interactions are well described, and relationships include increased gut permeability, endotoxemia, and TNF-α production[32]. In rats, Lactobacillus GG has been shown to reduce alcohol induced gut leakiness and steatohepatitis[33].

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: Consequently, for some subjects, the EG intervention created a discrepancy between what may have been physiologically optimal eating times, presumably reflected better by data from non-workdays, and the calculated eating times. As the EG participants were instructed to adhere to the calculated eating times even on non-working days, their usual eating times at the weekend were sometimes greatly shifted (Fig. 3I, Tab. S2). However, the magnitude of these shifts does not correlate with weight changes (Fig. S2O, Tab. S6). On the contrary, if the calculated eating times resulted in large shifts of the weekend meals, this also means that previously particularly large "meal jet lags" between working and non-working days were eliminated. Indeed, the more the calculated eating times led to a shift of late weekend breakfasts to earlier times and early weekend dinners to later times, the more the participants lost weight (Fig. 3J, Tab. S6). The independent variables used above for simple regressions may influence each other and therefore their influence on BMI may be confounded. Therefore, a multiple regression with the most important and least multicollinear variables (ΔMTVS, ΔkJ, Δcalorie intake interval, ΔmSp-mEP relation, Δweekend breakfast, Δweekend dinner) was done to study their individual influences on the BMI of EG participants while keeping the other variables constant. According to this analysis, only the change in MTVS and also the resulting elimination of "dinner jet lags" have significant influence on the BMI (Fig. 3K, Tab. S8). The elimination of "breakfast jet lags" and the improvement of the mSP-mEP ratio did not reach significance but showed a strong tendency to influence BMI. In contrast, changes in caloric intake or the time interval during which food is consumed had no effect on the BMI. A concurrent analysis of covariance shows that MTVS is most strongly intertwined with BMI, while other variables play a role to a much lesser extent (Fig. 3L). 2. 9. General well-being outcomesSince stable circadian rhythms are generally associated with many aspects of health, regular entrainment of a variety of peripheral and brain clocks by the Zeitgeber food may enhance overall well-being.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: Indem man beide Teile unter der Kontrolle verschiedener, aber überlappender Promotoren exprimiert, kann man ein deutlich spezifischeres Cre-Expressionsmuster erreichen, als es bisher möglich war. Ziel ist es, die funktionelle Anatomie des SCNs zu untersuchen, indem man die sogenannte „Core“-Region des SCN genetisch läsioniert. Es wird sehr interessant sein, die Effekte einer solchen genetischen SCN-Core Läsion auf das zirkadiane System zu untersuchen. wird dazu beitragen, die funktionelle Anatomie dieses komplexen Nukleus besser zu verstehen. Der vierte Teil dieser Arbeit beschäftigt sich mit der Rolle der zirkadianen Uhr als Vermittler zwischen verschiedenen physiologischen Systemen. Es ist bekannt, dass die zirkadiane Uhr und die metabolische Regulation eng miteinander verknüpft sind. Außerdem ist eine kürzere Schlafdauer mit metabolischen Dysfunktionen assoziiert, wie zum Beispiel einer erhöhten Wahrscheinlichkeit von Fettleibigkeit. Eine Möglichkeit ist, dass die metabolischen Effekte von Schlafentzug durch die zirkadiane Uhr vermittelt werden. Daher war die Hypothese dieser Studie, dass in Abwesenheit einer funktionellen zirkadianen Uhr die metabolischen Auswirkungen von Schlafentzug reduziert sind. Um dies zu testen, wurden transgene Mäuse untersucht, die keine funktionelle Uhr besitzen (Per1/2-Doppelmutanten).

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: The same group also found that the mucosa associated microflora were altered in rats on a high alcohol feed, and this dysbiosis could be counteracted by Lactobacillus GG or oat supplementation[34]. Furthermore, alcoholics have altered microflora with decreased numbers of bifidobacteria and lactobacilli. A recent pilot study[32] compared control subjects with alcoholics in a clinic, either on standard treatment for alcoholic disease (Vitamin B1 & B6 supplements and diazepam, n = 34) or on standard treatment + probiotics (0. 9 × 10e8 CFU B. bifidum and 0. 9 × 10e9 CFU L. plantarum, n = 32) for five consecutive days. No placebo was included in the control group. They found that lactobacilli, bifidobacteria, and enterococci were reduced in alcoholics and the numbers were restored in the probiotic treatment group. E. coli levels were not altered. Liver function parameters [alanine aminotransferase (ALT) and aspartate aminotransferase] were significantly improved by probiotics compared to standard treatment, but remained below levels found in healthy controls. Other liver enzymes (GGT and LDH) were not significantly altered. In the subgroup of alcoholics with well-defined hepatitis, standard treatment only altered total bilirubin, but probiotics improved all the liver parameters mentioned above. The authors concluded that bifidobacteria seemed to play an important role in steatohepatitis of alcoholic and non alcoholic causes, including obesity[35]. In a double blind placebo controlled (sucrose capsule) intervention Lata et al[36] studied the effect of probiotic E. coli Nissle in cirrhotic patients (n = 39, 34 with alcoholic cirrhosis). They found an improvement of intestinal colonization in faeces, and a restoration of “physiological microflora” in faeces (more patients with normal microflora containing lactobacilli and bifidobacteria, less patients with potentially pathogenic bacteria). They also showed trends towards a reduced endotoxin level in blood (P = 0. 07) and a reduced Child-Pugh score (P = 0. 07), which is a measure for severity of overall liver disease.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: Previously published data show that increased regularity of breakfast in particular, and not so much that of dinner, was identified as a predictor of weight loss [26]. In contrast, in our study, an increase in the regularity of lunch, and somewhat more strongly that of dinner, is related to weight loss. Although the diary entries of some participants show that they changed their energy intake and also the food composition of fat, carbohydrates, and proteins during the study, the observed weight loss is not related to these changes. Related results have already been shown in mice, although here with a restriction to the entire active phase rather than specific eating times. Not surprisingly, mice gain weight and develop diabetes-like states under a high-fat diet [17]. It is surprising, however, that the negative physiological consequences of the high-fat diet can be almost completely prevented if the mice consume the equivalent amounts of high-fat food exclusively during their activity phase and do not receive any food during their sleep phase [17, 27]. There are also similar studies with humans in which the time window of food intake is limited to a certain length. This is, for example, 16:8 intermitted fasting or TRE/TRF, in which meals are taken only during specific time window, yet at unspecified times during that period. The effects of these protocols is mixed and often less pronounced than in our study, as less weight is lost [19–23, 28] or a longer period is required to achieve similar results [29] than in our study - with the caveat that participants with more overweight and older participants participated in these studies than in ours. Besides increased regularity, our intervention has similar effects on eating behavior, such as shortening the hours in which food is eaten. Interestingly, in our study these parameters are not related to the observed weight loss. However, other studies have also explored the effect of restricting individual meals to specific times. In mice, restricting the same amount of high-fat chow to two times per day reduces the development of obesity [30]. And in humans, restricting meals to three fixed, uniform times leads to similar weight loss like we observed in our study - but in combination with calorie reduction and standardized food [31]. The fact that our participants lost weight to a similar extent despite free choice of meals might be due to the individual tailoring of meal schedules.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: It is likely that the functioning of the clock may depend on the presence of a particular neurotransmitter on a mechanism in which co-localized neurotransmitters interact in a functionally significant manner. With more information available on the role of neurotransmitters in the working of the clock, which is involved in so many functions of the body, better opportunity for neurotransmitter-based manipulation of the clock has also been reported. Problems of shift-work insomnia and ill effects of jet lag are among the clock-related functions for which much attention has been given in recent years. Melatonin has been in use with some success in reducing the above effects. However, search for other chronobiotic agents is continuing and it is likely that there may be some new dimensions given to the problem and its solution in future. A report of a close relationship between circadian clock and cell proliferation makes things even more interesting. Investigations into the role of neurotransmitters in the SCN as well as in the afferent and efferent inputs have come a long way with the advent of newer techniques of positron emission transaxial tomography (PET) scan and polymerase chain reaction (PCR). In both plants and animals, circannual rhythms are widely distributed. Endogenous circannual rhythms form the basis for many seasonal rhythms. A number of neuroendocrine mechanisms have been implicated in the regulation of seasonal changes in the physiology and behaviour of animals. Some of these neuroendocrine pathways are necessary for the regulation of particular overt seasonal responses, though they may not be directly linked to the circadian time-keeping system. Photoperiodic input and circannual function may have profound influence on many of the functions of body. Naturally, neurotransmitters are involved not only in circadian function but also in seasonal processes. It has been postulated that heterogeneity of the clocks which are seen within the SCN may be one of the factors that form the basis of seasonal adaptations [23]. A typical example of the close linkage between seasonal rhythms and affective disorders can be seen in a seasonal form of mood disorder, seasonal affective disorder (SAD). Treatment for SAD based on circadian principles includes not only light therapy but also the use of certain drugs, again based on circadian principles involving neurotransmitters. The SCN has been subdivided into a dorsomedial shell and a ventrolateral core.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: Improved liver function by probiotics has already been published[5], but the mechanism remains unclear. They assume that microflora reduce the toxic load of liver, e. g. reduced endotoxin, which stimulates pro-inflammatory cytokines (TNF-α, IL-1, 6)[22]. Probiotics to cure/alleviate cirrhosis? In cirrhosis there are many conditions that alter microflora and the function of the intestinal epithelium, as recently reviewed in detail[37]. BT is caused by BO, increased permeability, and altered host defence. BT and microflora imbalance are strongly correlated with the severity of cirrhosis[38]. In a rat model of acute liver injury (using either D-galactosamine or endotoxin), probiotic lactobacilli and bifidobacteria attenuated liver injury (ALT and bilirubin), reduced BT, and normalized hepatic TNF-α and glutathione levels compared to liver injury controls[39,40]. Lactobacilli might counteract BT by (1) promoting growth of anaerobes and Gram-positive bacteria while inhibiting gram-negative bacteria, or (2) increasing SCFA while decreasing pH, inducing growth factors and proliferation of microflora, and inhibiting adherence and invasion of pathogens. Patients with liver cirrhosis have imbalanced intestinal microflora with increased aerobes (enterobacter and enterococci) and anaerobes (clostridia), and decreased bifidobacteria counts in stool. In a probiotic intervention trial in cirrhotic patients[38] (mainly caused by hepatitis virus B and C; HBV and HCV) patients received two different probiotic capsules [bifidobacteria + L. acidophilus + Enterococcus or Bacillus subtilis (B. subtilis) + Enterococcus faecium (E. faecium)], two capsules per day for 14 d. In both probiotic groups, bifidobacteria counts increased with treatment, while faecal pH and ammonia levels in faeces and blood decreased. Additionally, B. subtilis + E. faecium decreased clostridia counts and endotoxin levels in the blood of cirrhotic patients.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: It is true that our data show that scheduling single meals to supposedly circadian optimal eating times of the participants is not essential for successful weight loss. Circadian clocks can adjust flexibly to Zeitgebers and it is apparently more important to choose times for meals when people (have to) eat particularly frequently than the time that is probably genetically determined. That is, if the intervention leads to eating at times that are far from those normally chosen on non-working days, this has no negative impact on weight loss efficiency. Our data suggest that the regularity of eating times seems to be more important than the times themselves. However, our pilot data still show that personalization of meal schedules is nevertheless useful. First, depending on the individual chronotype of the participants, their mealtime windows were earlier or later in the day. And those for whom the intervention optimized this relationship were particularly effective at losing excess weight. Second, weight loss is more successful if the eating time schedule is such that an individual who usually eats dinner at an early time on non-working days, but has dinner later on working days, consistently eats at the later time. This also tends to apply to breakfast if an individual eats breakfast earlier on working days than on non-working days and the meal plan is aligned with the early time of the working days. Since food serves as a Zeitgeber for a large number of tissues, including several brain regions, it can be hypothesized that regular eating not only has a positive effect on body weight, but also on other aspects of well-being. A previous study by Panda et al. [18] has already shown that shortening the eating interval to 10-12 hours per day has a positive effect on the general well-being of the participants. Similarly, in our study, we also found significant improvements in different aspects of subjective well-being over the course of the study, specifically in physical and mental health, sleep quality, and self-efficacy. This shows that adhering to daily structured mealtimes can improve not only metabolic but also other physical and also psychological levels of health. There are several explanatory approaches for why increased meal regularity can lead to weight loss despite equal caloric intake. For example, circadian clocks influence the composition of the microbiome, which regulates metabolic balance and body weight [32–37]. Additionally, circadian clocks help to anticipate mealtimes and provide the necessary digestive components in advance of food intake in advance [38–41].

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: In terms of the functional impact of NO in the working of the SCN, blocking of NO production disrupts light transmission to the SCN [63], thus indicating the possibility of the role of NO in the light-input pathway. NO synthesis is required for phase changes of electrical activity [64]. Intracerebroventricular application of L-NAME (a drug that blocks NOS in hamsters) produces attenuation of light-induced phase-advances of activity rhythms [65]. Reports also indicate interruption in the light-triggered cascade of glutamate release from retinal terminals in the SCN by blockade of NO action in intact animals, which leads to subsequent interruption of NMDA receptor activation [66,67]. Interruption of intracellular increase of calcium, activation of nNOS, augmented production of cyclic guanosine monophosphate (cGMP), activation of protein kinase C, and phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), as well as interruption of the expression of immediate early genes, are other effects of blockade of NO action. Starkey and co-workers [68] provided evidence for the presence of functional type II NOS within the SCN of guinea pig. All isotypes of NO synthase have also been identified in the normal adult mammalian SCN. Contribution by more than one NOS isotype to the regulation of circadian rhythms cannot be ruled out. In this context, it is interesting to note the demonstration by Kriegfeld and co-workers [69] that mice lacking the gene for type I NOS experience no change in the ability to phase-shift or entrain circadian rhythm of locomotor activity. Yet another study, also by Kreigfeld and co-workers [70], has suggested that endothelial isoform of NOS among the three known isoforms may not be necessary for photic entrainment in mice. However, considering the three different forms of NOS identified, until the isoforms of NOS involved in regulating the clock phase by modulating inputs are completely established it is difficult to speculate the exact role of NO. There has been much speculation as to the photopigment mediating light information to the SCN. However, this is not yet known with certainty [71].

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: Flora imbalance in cirrhotics might be caused by decreased gut motility, diminished excretion of sectretory IgA, lysozyme, mucus, acids, increased pH, shortage of bile acids, and excessive alcohol intake. Elevated blood ammonia is a crucial factor in hepatic encephalopathy aetiology. Loguercio et al[21] conducted a pilot study in patients suffering from hepatitis of various causes (HCV, alcoholism, and NASH). The patients received a probiotic mix (Lactobacillus acidophilus, L. bifidus, L. rhamnosus, L. plantarum, L. salivarius, L. bulgaricus, L. lactis, L. casei, L. breve + fructo-oligosaccharides + vitamins). Interestingly, the authors reported no effect of probiotics in HCV patients. In NASH patients some liver function parameters (ALT and γ-glutamyltransferase) improved, TNF-α decreased and plasma malondialdehyde decreased in some patients with probiotic treatment. The strongest effect of protiotics was seen in patients with alcoholic liver cirrhosis, where all parameters of liver function improved, as did TNF-α and malondialdehyde. From these studies in humans, it appears that the microflora is an important cofactor in the aetiology of chronic liver disease, and that probiotics might have a therapeutic role. Probiotics to bind toxins and carcinogensSome experimental evidence suggests that probiotics could be used to bind and immobilise toxic compounds within the gut lumen. Through this process, the negative effects of dietary toxins could be reduced and gut and liver health improved. In vitro, L. rhamnosus GG is able to bind mycotoxins known to interfere with intestinal mucosal barrier. In Caco-2 cells, the negative effects of mycotoxins on cell differentiation and intestinal integrity can be attenuated with L. rhamnosus GG[41,42]. In rats, genotoxic effects of food carcinogens, such as heterocyclic amines, on the colonocytes and hepatocytes were counteracted by the use of different probiotics[43,44].

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: This could lead to less successful weight loss. In addition, after exclusion and drop-out of some participants, in the remaining evaluable 100 participants, there was a significant difference in baseline body weight and BMI between CG and EG. However, even if CG participants had been heavier from the start, it cannot be assumed that the applied sham treatment with an eating window of 18 hours during wake time would have had a stronger effect. Second, those subjects in the EG group whose baseline BMI was similar to those of the CG subjects lost significant weight during the intervention, while CG participants did not. Taking these two arguments into account, it cannot be assumed that a floor effect, in which the CG participants cannot lose any more weight due to a lower baseline weight, is the reason for the lack of weight loss in the CG. Lasty, studies show that even much larger baseline BMI differences do hardly affect the success of weight loss programs [45, 46], so we assume that this also applies to our study. During the course of the study, there were some drop-outs in both groups. Importantly, these did not differ in baseline weight from the completers, which is why it can be ruled out that the intervention was not effective in a particular BMI group. Rather, the subjects who dropped out were those who either could not continue due to illness or did not adhere to the meal plan. However, the inclusion of drop-outs in the analysis of weight progression does not fundamentally change the results. 3. 2. ConclusionThe present study can be regarded as a pilot study, the results of which we believe justify a continuation with adjustment of the above-mentioned limitations. In summary, our data show that the increase of regularity of meals to a period of 90 min for each meal promotes a significant reduction of body weight and a significant increase of well-being within short time. Importantly, the successes achieved do not seem to be related to a reduction in calories, a change in food composition, or other eating behaviors. Additionally, we believe that this intervention poses hardly any health risks since it is most likely solely based on the optimization of metabolic processes. On the contrary, the strong increase in general well-being during the study rather indicates an improvement in health on many different levels. 4. Methods4. 1. Experimental approachThe study was a randomized controlled intervention trial with repeated measures investigating the effect of regularity of mealtimes on body weight and parameters related to overall well-being.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: A novel opsin, melanopsin, was identified [72] and found to be exclusively expressed in the ganglion cells of RHT [20,73,74]. Melanopsin-containing RHT ganglion cells also use PACAP, another well known neurotransmitter of the RHT [20]. Melanopsin, however may not be the only circadian photoreceptor since melanopsin knock-out mice showed typical, although reduced, light responses such as entrainment and phase shifting. Possibilities of other neuroactive substances serving as neurotransmitters in the RHT in addition to glutamate and PACAP, which are the most important candidates, have been indicated. Projections of substance P (SP)-containing ganglion cells to the ventrolateral part of the SCN have been demonstrated in lesion experiments in the rat [75]. Electrophysiological investigations also further support the role of substance P as an excitatory neuromodulator [76] responsible for the expression of both NMDA and non-NMDA receptor-mediated components of RHT transmission. Moreover, it is also reported that SP and glutamate work as agonists upstream of glutamate [77]. substantial evidence [17,78,79] suggesting a role for histamine as a neurotransmitter in circadian entrainment [17,78,79], its role has been underplayed. With more information available and even a suggestion that histamine may be acting as a final neurotransmitter on which photic and non-photic entrainment converge [80], there has been more attention in this direction. Histamine can induce phase shifts in circadian rhythms in a manner similar to that of light pulses. Intracerebroventricular injection of histamine is also found to alter circadian function [81]. Direct effects of histamine on SCN neurons have been shown in vitro either as inhibitory or excitatory depending on experimental conditions [82,83]. It is also reported that at the level of the SCN the direct excitatory effects of histamine on neuronal firing is mediated via H1 receptors and the inhibitory effects via H2 receptors [82,83]. However, in vivo studies, it has been shown that the effects of histamine on circadian rhythms may be mediated through receptors other than histamine receptors [84,85]. The foregoing discussion supports the view that histamine may exert modifying effects on circadian rhythmicity as well as neuronal excitability.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: Salminen et al[51] investigated the severity and outcome of lactobacillus bacteraemia in 89 patients, and report mortality of 26% 1 mo after illness onset, but only in patients with severe underlying comorbidities. Future of probiotic researchMost recent developments in probiotic and prebiotic research use a new systems biology approach to assess the complex relationship between the microflora, probiotic modulations, and the impact on host metabolism in multiple compartments. A major finding is the impact of microflora modulation on host energy metabolism, especially lipid metabolism in the liver where marked decreases in plasma lipoproteins and hepatic glutamine and glycogen levels are observed[52]. This group uses a germ free mouse model colonized with human baby flora, to study the effects of a probiotic intervention (L. paracasei or L. rhamnosus) on gut flora composition, SCFA in caecal content, plasma, urine, faecal and liver metabolomics, and bile acids in ileal flushes. The integration of multicompartment metabolic data using hierarchical principal component analysis showed that probiotic lactobacilli induce changes in hepatic influx and efflux of fatty acids, increased enterohepatic recycling of bile acids and dietary fats, lowered plasma LP, and stimulated glycolysis. Probiotic intervention also changed the proteolytic activity and bacterial metabolism of AA and SCFA in the gut[53]. In a mouse model of high-fat feeding and NAFLD, an association was shown between the metabolism of choline by microbiota and the host. The author suggested a contribution of microflora to the development of the NAFLD phenotype[54]. This complex analytical and statistical methodology allows investigation of the impact of microflora and probiotics on various body compartments simultaneously and might, in the future, lead to a better understanding of the influence of probiotics on the host. Similarly, the complex metabolic relationships between the microflora and the host have also been studied in human cohorts and this approach might be used to gain further understanding of the relation between changes in the microflora (dysbiosis) and disease[55]. appears that specific clinical applications of probiotics are safe, effective, and can clearly be recommended.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: 2-way repeated-measure ANOVA with Bonferroni post-hoc test, CG: n=30; EG: n=67, * p ≤ 0. 05, (detailed statistics in Tab. S3). (L) Correlation between reported ingested energy during the exploration phase vs. the intervention phase. Linear regression, CG: n=30; EG: n=67 (some participants were excluded from this analysis because of several erroneous diary entries about unrealistic amounts of food), (detailed statistics in Tab. S6). (M) Determined and estimated cumulative intake of fat, carbohydrates, and proteins during the study. Mixed-effects model with Bonferroni post hoc test comparing determined and estimated cumulative energy intake. The estimated macronutrient intake is formed as an assumed continuation of the average daily intake during the exploration phase. post hoc test showed no significant differences on any study day. (N) No significant correlation between body weight/BMI and changes of cumulative macronutrient intake. Linear regression, CG: n=30; EG: n=67, (detailed statistics in Tab. S6). (K, L, M, N) Some participants were excluded from this analysis because of several erroneous diary entries about unrealistic amounts of food. (O) The absolute deviation between the times of weekend meals and the times of food intake calculated for the EG intervention did not affect the subjects’ BMI change. Linear regression, n=67 (detailed statistics in Tab. S6). Table S1:Baseline characteristics of final 100 participants. Table S2:Statistical data on the difference between two groups. Missing n-numbers in 3I are due to incomplete diary entries on weekends during the exploratory phase or because participants usually did not have a particular meal. The data in the table refers to the data shown in Fig. S2A, S2G, and 3I. Table S3:Statistical data from all Two-way-analyzing time, group, as well as interaction effects between time x group. In data for Figure 1, missing p-values in the and EG are due to the different number of meals for each participant. In the data for Figure 2, some participants were excluded from this analysis because of several probably erroneous diary entries about unrealistic amounts of food. In data for Figure 3, varying n-numbers result from incomplete entries in the diaries.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: There is a clear circadian rhythm in the histaminergic activity, with high levels during the active period and low levels during the sleep period. Maintenance of circadian rhythmicity of sleep-wakefulness cycles, food intake, motility and adrenocortical hormone release seems to depend on histaminergic activity. Thus, although evidence is accumulating for a role of histamine in circadian function, it is difficult to assign it a specific role in circadian activity at this time. Neurotensin (NT) Cell bodies of the rat SCN contain the neuropeptide neurotensin (NT) and two NT receptor types, namely NTS1 and NTS 2 [86 - 88]. In humans there is a larger population of NT neurons as compared to monkeys and other animals. Although involved in many physiological processes, the role of NT in circadian rhythm is not completely known at present. Meyer-Spasche and co-workers [89] reported that NT can phase shift the firing rate rhythm of SCN neurons. They also provided evidence that NT may play a role in regulating the circadian pacemaker through NTS1 and NTS2 receptors. NT-binding sites found in the ventral region of the SCN, which receives photic and non-photic information, is indicative of the involvement of NT in the synchronization of clock to these environmental stimuli [90]. Studies using NTS1 and NTS2 agonists, neurotransmitter receptor antagonists, as well as the exogenous application of NT, have yielded some valuable results. An increase in discharge rate of SCN neurons was observed on NT application [90]. NT-mediated effects on SCN neurons seem to result from activation of NTS1 and NTS2 receptors rather than involve glutamate or GABA receptors or modulation of the synaptic release of glutamate or GABA [90]. NPY, which is an established neurotransmitter of the geniculohypothalamic tract (GHT), was found to regulate SCN neuronal activity [91 - 93] and to produce long lasting suppression of firing rate of SCN neurons. When co-applied with NPY, NT was found to damp the profound inhibitory effect of NPY [90,92,93]. This is interesting since there are studies showing that NPY immunoreactive terminals overlap with NT-binding sites in the ventral part of the SCN. This was considered as evidence of an interaction of NPY and NT to regulate neural activity.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: Lactobacillus rhamnosus strain GG prevents enterohemorrhagic Escherichia coli O157:H7-induced changes in epithelial barrier function. Infect Immun. 2008;76:1340-1348. [PubMed] [DOI] [Cited in This 8. Isolauri E, Salminen S. Probiotics, gut inflammation and barrier function. North Am. 2005;34:437-450, viii. [PubMed] [DOI] [Cited in This 9. Corthésy. Cross-talk between probiotic bacteria and the host immune system. J Nutr. 2007;137:781S-790S. [PubMed] [DOI] [Cited in This 10. Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science. 2004;303:1662-1665. [PubMed] [DOI] [Cited in This 11. Wang M, Molin G, Ahrné S, Adawi D, Jeppsson B. High proportions of proinflammatory bacteria on the colonic mucosa in a young patient with ulcerative colitis as revealed by cloning and sequencing of 16S rRNA genes. Sci. 2007;52:620-627. [PubMed] [DOI] [Cited in This 12. . Intestinal bacteria and ulcerative colitis. Intest Microbiol. 2003;4:9-20. [PubMed] [DOI] [Cited in This 13. . Probiotics and their derivatives as treatments for inflammatory bowel disease. Dis. 2009;15:1906-1914. [PubMed] [DOI] [Cited in This 14. . Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology. 2001;121:580-591. [PubMed] [DOI] [Cited in This 15. . Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology. 1999;116:1107-1114. [PubMed] [DOI] [Cited in This 16. .

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: AbstractObjectiveMany weight loss strategies are based on the restriction of calories or certain foods. Here, we tested a weight loss intervention based solely on increasing the regularity of meals to allow the circadian system to optimally prepare food metabolism for these times. Participants & MethodsIn a two-group, single center randomized-controlled single-blind study (pre-registration DRKS00021419) with participants aged 18-65 years and BMI ≥ 22 kg/m², we used a smartphone application to identify the times at which each participant eats particularly frequently and asked participants of the experimental group to restrict their meals to only these times for six weeks. Control participants received sham treatment. Primary outcome was self-reported body weight/BMI and secondary outcome the well-being of participants. ResultsOf 148 participants entering the study, 121 were randomized and of these 100 (control: 33, experimental: 67) finished the study. Our results show that the more regular the meals of participants of the experimental group became, the more weight/BMI they lost, averaging 2. 62 kg (0. 87 kg/m²); p < 0. 0001 (BMI: p < 0. 0001) compared to an insignificant weight loss of 0. 56 kg (0. 20 kg/m²) in the control group; p = 0. 0918 (BMI: p = 0. 0658). Strikingly, weight loss was not related to changes in self-reported calories, food composition, and other food-related factors. Additionally, physical and mental well-being improved significantly. ConclusionIn summary, increasing the regularity of meals causes participants to lose excess body weight and improves overall well-being. HighlightsIndividual optimal times for meals are determined via an app-based meal diary. Generation of a structure plan for mealtimes are adjusted to individual circadian clocks. Following this plan, participants lost an average body weight of 2. 6 kg over six weeks. Weight loss is achieved without changes in self-reported food quantity or composition. Regular mealtimes contribute to the improvement of the general well-being. 1. IntroductionCircadian clocks induce endogenous 24-hour rhythms in the expression of more than half of all genes across all tissues [1, 2], allowing the body to anticipate daily changes between day and night and to prepare and harmonize physiological processes accordingly.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: From a developmental point of view, NT-expressing neurons developed earlier than the other 3 types of peptidergic neurons, and AVP [94]. It remains to be seen whether NT-expressing neurons contribute significantly to the generation of circadian rhythms in early human life. (NMS) A recent addition to the ever increasing list of neurotransmitters of the SCN is neuromedin S (NMS), a 36 amino acid neuropeptide. It is a potent brain-gut neuropeptide whose presence in the SCN was reported by Nakahara and co-workers [95] as a neurotransmitter of the circadian oscillator system. NMS expression is found to be restricted to the core part of the SCN and has a diurnal peak under light-dark cycle [96]. Intracerebroventricular administration of neuromedin S in rats activates SCN neurons and has the capability to induce non-photic type of phase shifts in the circadian rhythm of locomotor activity. It is also possible that NMS along with VIP may have a role in maintenance of circadian rhythmicity. Recently, it has been shown that neuromedin M (NMU) is regulated in a circadian manner with peak expression in the light phase of LD cycle [97]. Further studies are required to understand the specific role of NMS in the SCN. At present, it is implicated in the regulation of circadian rhythms through autocrine andor paracrine actions through its receptors [96]. Gastrin releasing peptide (GRP) Gastrin releasing peptide (GRP) has also been identified as a neurotransmitter in the SCN. Although GRP and its receptor BB2 are found to be synthesized by rodent SCN neurons [98 - 100], the role of GRP in circadian rhythm regulation is not well known. Evidence points towards a role for GRP in photic entrainment [101,102], in spite of a number of studies favouring glutamate as the main neurotransmitter [36,37,103]. McArthur and co-workers [104] studied the role of GRP in photic entrainment by using the resetting actions of GRP application on electrical activity rhythms during subjective day, early subjective night, and late subjective night in vitro in rats and hamsters.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: Bacteria-free solution derived from Lactobacillus plantarum inhibits multiple NF-kappaB pathways and inhibits proteasome function. Dis. 2009;15:1537-1547. [PubMed] [DOI] [Cited in This 17. . Meta-analysis of probiotics for the treatment of irritable bowel syndrome. Gastroenterol. 2008;14:2650-2661. [PubMed] [DOI] [Cited in This 18. . The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gastroenterol. 2009;104:1033-1049; quiz 1050. [PubMed] [DOI] [Cited in This 19. -Boussard T, Morton JM. Probiotics improve outcomes after Roux-en-Y gastric bypass surgery: a prospective randomized trial. J Gastrointest Surg. 2009;13:1198-1204. [PubMed] [DOI] [Cited in This 20. . Does the use of probiotics/synbiotics prevent postoperative infections in patients undergoing abdominal surgery? A meta-analysis of randomized controlled trials. Clin Pharmacol. 2009;65:561-570. [PubMed] [DOI] [Cited in This 21. ì M. Gut-liver axis: a new point of attack to treat chronic liver damage? Gastroenterol. 2002;97:2144-2146. [PubMed] [DOI] [Cited in This 22. Sheth AA, Garcia-Tsao G. Probiotics and liver disease. J Clin Gastroenterol. 2008;42 Suppl 2:S80-S84. [PubMed] [DOI] [Cited in This 23. . Non-alcoholic fatty liver disease: lumen-liver interactions and possible role for probiotics. J Hepatol. 2003;38:681-687. [PubMed] [DOI] [Cited in This 24. Medina J, Fernández-Salazar LI, García-Buey L, Moreno-Otero R. Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis. Diabetes Care. 2004;27:2057-2066.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: (H) Significant correlation between change in BMI, baseline BMI, and improvement in MTVS. Individuals with higher BMI benefit more from similar improvements in MTVS (shades of data points) than individuals with lower BMI in EG participants. Multiple regression, n=67, * p ≤ 0. 05, ** p ≤ 0. 01. Detailed statistics in Tab. S9. 2. 3. Weight changeDuring the exploration phase, when no instructions on eating times were given, CG and EG participants had a statistically non-significant average loss of 0. 17 kg (0. 06 kg/m²) and 0. 21 kg (0. 06 kg/m²), respectively (Figs. 1E, S2B-F, Tabs. S4, 5). However, during the intervention phase, when EG participants took their meals more regularly, they lost an average of about 2. 6 kg (95% CI [-2. 906, -1. 915]) and 0. 81 kg/m² (95% CI [-0. 9729, -0. 6420]) (Figs. 1E, S2B-E, Tabs. S4, 5), which translates to an average weight loss of 0. 40 kg (0. 145 kg/m²) per week during the intervention. In contrast, weight and BMI changes of -0. 39 kg (95% CI [-0. 9125, 0. 1307]) and -0. 14 kg/m² (95% CI [-0-3152, 0. 0304]), respectively, were not significant in the CG (Figs. 1E, S2B, C, F, Tabs. S4, 5), resulting in a significant difference in weight loss between groups at the end of the intervention (Figs. 1F, S2C, Tab. S5). The inclusion of the last available weight and BMI data of the drop-outs in an end-point analysis did not lead to any notable change in this result (Fig. S2G, Tab. S5). Four weeks after the intervention ended, all participants were contacted again for a follow-up assessment. 34 of the 67 EG participants reported to have maintained the regularity of their meals and continued to lose body weight significantly, on average another 1. 12 kg (95% CI [-1. 479, -0. 7626]) and 0.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: This belief is further strengthened by the observation that dysfunction of serotonergic pathways play a role in affective disorders and that these disorders are frequently treated with agents that alter serotonergic neurotransmission. Further studies about this pathway are likely to give more information about the link between disruptions of circadian function and affective disorders. GABA It is now widely accepted that gamma amino butyric acid (GABA) is an important neurotransmitter of the SCN for regulating SCN function. Most SCN neurons express the neurotransmitter GABA and are thus GABAergic [12]. GABA receptors and receptor subunits have been described by Castel and Morris [139], Naun and co-workers [140], van den Pol [141], Gao and co-workers [142], and O'Hara and co-workers [143]. In most of the brain regions, GABA primarily acts through interaction with GABAA and GABAB receptors and produces neuronal inhibition through membrane hyperpolarization and increased membrane conductance. Glutamic acid decarboxylase (GAD) is the enzyme required for synthesizing GABA and is found in nearly all neurons of the SCN [116]. Additional support for an inhibitory role of GABA in the rat SCN has come from the studies of Gribkoff and co-workers [144,145]. However, recent investigations have shown that GABA has dual effects on the SCN neurons, excitatory during day and inhibitory at night [146], and this has been attributed to changes in [Cl-]I during the circadian cycle. This dual inhibitory [147] and excitatory [148] action of GABA has been thought of as the probable reason for the synchronization of spiking in the SCN neurons. Under some circumstances, such as in early development, GABA can also be depolarizing and potentially excitatory [126,149 - 151]. The excitatory effect of GABA on SCN neurons in the night seems to be complex. While the action of GABA in the day on SCN neurons is uniformly inhibitory, the effects of GABA during the night are heterogeneous due to both depolarizing and hyperpolarizing effects. The GABA-mediated depolarizing effect seen at night is restricted to a subset of SCN neurons.

Output: pass


Input: Claim: Probiotics can support gut health by improving the balance of bacteria. [SEP] Text: [PubMed] [DOI] [Cited in This 25. à. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877-1887. [PubMed] [DOI] [Cited in This 26. -Arenzana JM, Aldazabal P. Probiotic supplementation reduces the risk of bacterial translocation in experimental short bowel syndrome. J Pediatr Surg. 2002;37:699-702. [PubMed] [DOI] [Cited in This 27. . The role of the gut microbiota in energy metabolism and metabolic disease. Des. 2009;15:1546-1558. [PubMed] [DOI] [Cited in This 28. . Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37:343-350. [PubMed] [DOI] [Cited in This 29. . Probiotics reduce the inflammatory response induced by a high-fat diet in the liver of young rats. J Nutr. 2009;139:905-911. [PubMed] [DOI] [Cited in This 30. . Probiotics for non-alcoholic fatty liver disease and/or steatohepatitis. Syst Rev. 2007;CD005165. [PubMed] [DOI] [Cited in This 31. . Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol. 2008;49:821-830. [PubMed] [DOI] [Cited in This 32. . Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol. 2008;42:675-682. [PubMed] [DOI] [Cited in This 33. . Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. Alcohol. 2009;43:163-172. [PubMed] [DOI] [Cited in This 34. . Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats.

Output: corroborate


Input: Claim: Eating carbohydrates always leads to weight gain. [SEP] Text: 36 kg/m² (95% CI [-0. 4907, -0. 2457]), respectively (Figs. 1E, S2B, D, E, Tabs. S4, 5). In contrast, participants who reported to have resumed irregular eating gained a significant average of 0. 48 kg (95% CI [0. 1984, 0. 7616]) and 0. 17 kg/m² (95% CI [0. 07434, 0. 2603]), respectively (Fig. 1E, S2B, D, E, Tab. S4). 2. 4. Relation between weight change and improvement in the regularity of mealsTo examine the extent to which EG participants’ weight loss was effectively related to improvements in meal regularity, we correlated changes in body weight and BMI with individual MTVS changes. Consistent with our hypothesis, a significant relationship exists between weight loss and improvement in regularity in the EG (Fig. 1G, Tab. S6). A breakdown of meals shows that increasing the regularity of lunch and dinner has the greatest effects, with no significant relationship between increasing the regularity of breakfast and weight loss (Fig. S2H, Tab. S6). In contrast, in the CG, there were no or little improvements in regularity and, accordingly, no correlation with weight/BMI changes. Further analyses revealed that all MTVS up to 3, which corresponds to a time window for meals of up to ±45 min, resulted in comparably effective weight loss, whereas the efficiency of weight loss decreases significantly with an MTVS greater than 3 (Tab. S7). 2. 5. Relation between weight change and baseline BMIA weight loss intervention which is particularly based on metabolic optimization is likely to be most effective for individuals with exceeded body weight. In fact, the higher the baseline BMI of EG participants at T1, the greater the weight loss (Fig. S2I, Tab. S6). Stratifying the subjects by baseline BMI, including the control group, confirms this result, but also shows that in all strata the BMI of EG subjects decreased more than that of CG subjects, even if they had the same initial BMI (Fig. S2J, Tab. S8). Multiple regression shows that the reduction in MTVS and baseline BMI together predict the weight loss of the participants (Fig. 1H, Tab. S9).

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: SCN transplants lacking CalB cells failed to restore rhythmicity [247]. CalB cells are found to co-localize with other peptides such as GRP, SP, and VIP. Interconnections of CalB cells with and VIP have been reported [246], and the pattern of interconnection of CalB cells appear specialized in the sense that some are bilateral, while others are not [248]. The strength of linkage between interconnections also varies. Intra-SCN connections are influenced to a great extent by the projections of CalB cells. The connections are direct in some cases and indirect in others. However, indirect communication as is the case with CalB to AVP is equally effective. In addition to intra SCN communication, CalB cells may also project to extra SCN regions [248]. CalB cells appear to be non rhythmic. They, however, receive photic input from the RHT and GHT, and rapid transmission of light information to CalB neurons may facilitate circadian output [226]. Light exposure always increases firing rates of SCN neurons. However, cells in the core of the SCN oscillate in their responsiveness to photic input [5]. Light also induces clock gene expression in the SCN but only during the night [8,249]. This gene expression pattern seems to be mirrored by changes in subcellular localization of CalB, the cellular nucleus being devoid of CalB during the night [249]. Behavioural and molecular responses to nocturnal light pulses also disappeared on decreasing CalB levels [249]. Thus, CalB cells in the SCN function as gates to relay photic signals when open and to block the signals when closed, which suggests a central role for CalB neurons in gating photic input. Further investigation seems essential to elucidate the relation between functional connectivity and a single coherent output from the SCN. Calretinin (CALR) Calretinin (CALR) is another variety of neurons found in the SCN (in the core ventral part) that appears to be co-localized with VIP neurons. CALR cells are small to medium sized. Optic tracts also show heavy immunoreactivity for CALR. Like calbindin (CalB), CALR is a calcium binding protein.

Output: pass