Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential ...targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4⁺Foxp3⁺ regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.
We evaluated the relationship between poor sleep quality and high body mass index (BMI) in a community-derived sample. In addition, we explored the premise that disordered eating (i.e. eating late at ...night and/or binge eating, which can occur at night) may partly explain the relationship.
An online survey asked 330 participants about their height and weight, recent sleep quality, and recent experiences of binge-eating and night-time eating.
Using multiple regression analyses, high BMI was shown to be related to shorter sleep duration, increased sleep latency, use of sleeping medications and worse binge-eating, whereas worse sleep quality was related to worse night-eating, after controlling for depression and demographics. Using mediational analyses, binge-eating was shown to partly mediate the relationship between worse sleep quality to higher BMI, whereas night-eating mediated the reverse association of high BMI to worse sleep quality.
The results suggest that night- and/or binge-eating may partly explain the observed relationship between worse sleep quality and overweight/obesity. Thus, the relationship may simply reflect that overweight people are more likely to binge-eat while they wait for sleep to come, and this may contribute to weight gain over time. In addition, the results may indicate that eating rather than weight gain or obesity may be responsible for causing the sleep deficits in overweight people.
•Eating behavior was tested as mediator between poor sleep and body mass index.•High BMI was linked to worse binge-eating.•Worse sleep quality was linked to worse night-eating.•Binge-eating partially mediated the worse sleep quality to high BMI relationship.•Night-eating partially mediated the high BMI to worse sleep quality relationship.
Objective
To investigate whether the slowing of bilateral postictal scalp electroencephalography (EEG) after focal impaired awareness seizures is associated with poor seizure outcomes after temporal ...lobe epilepsy (TLE) surgery.
Methods
This retrospective cohort study was conducted in the Department of Epileptology, Tohoku University Hospital from 2010 to 2020. The study included 42 patients with TLE who underwent a detailed presurgical evaluation and sequential resective surgery for the unilateral probable epileptogenic temporal lobe with 1 year or more of follow‐up. We reviewed the interictal epileptiform distribution and those of the ictal and postictal epochs of the first focal impaired awareness seizure recorded in presurgical scalp EEG. We classified patients either with postoperative seizure‐free status (Engel I) as group A or those with seizure persistence (Engel II‐IV) as group B.
Results
Of 42 patients, 29 (69%) were classified into group A. Compared with group B, group A had a lower number of bilateral postictal polymorphic delta activity (PPDA) (10.3%: 61.5%) and bilateral interictal epileptiform discharges (IEDs) (13.8%: 69.2%) (P = 0.003, P = 0.001, respectively). A combined analysis of bilateral PPDA and IEDs per individual patient showed significantly more frequent seizure persistence after surgery (P < 0.0001) than a single analysis of bilateral IEDs or PPDA alone (P = 0.001). The regression analysis revealed that bilaterally distributed PPDA or IEDs had 13.50 or 13.72 times higher odds of persisting seizures within 1 year of surgery (95% confidence interval: 1.90–95.88; 2.12–88.87, respectively) (P = 0.009, 0.006).
Significance
The results of this study revealed that the bilateral distribution of PPDA was associated with poor postoperative seizure outcomes in patients with TLE, as well as bilateral IEDs. Additionally, the concomitant bilateral distribution of interictal and postictal changes is a strong indicator of poor surgical outcomes.
Despite the robust immunogenicity of SARS-CoV-2 mRNA vaccines, emerging data have revealed enhanced neutralizing antibody and T cell cross-reactivity among individuals that previously experienced ...COVID-19, pointing to a hybrid immune advantage with infection-associated immune priming. Beyond neutralizing antibodies and T cell immunity, mounting data point to a potential role for additional antibody effector functions, including opsinophagocytic activity, in the resolution of symptomatic COVID-19. Whether hybrid immunity modifies the Fc-effector profile of the mRNA vaccine-induced immune response remains incompletely understood. Thus, here we profiled the SARS-CoV-2 specific humoral immune response in a group of individuals with and without prior COVID-19. As expected, hybrid Spike-specific antibody titers were enhanced following the primary dose of the mRNA vaccine but were similar to those achieved by naive vaccinees after the second mRNA vaccine dose. Conversely, Spike-specific vaccine-induced Fc-receptor binding antibody levels were higher after the primary immunization in individuals with prior COVID-19 and remained higher following the second dose compared to those in naive individuals, suggestive of a selective improvement in the quality, rather than the quantity, of the hybrid humoral immune response. Thus, while the magnitude of antibody titers alone may suggest that any two antigen exposures-either hybrid immunity or two doses of vaccine alone-represent a comparable prime/boost immunologic education, we find that hybrid immunity offers a qualitatively improved antibody response able to better leverage Fc-effector functions against conserved regions of the virus.
Recent data indicates improved immunity to SARS-CoV-2 in individuals who experience a combination of two mRNA vaccine doses and infection, "hybrid immunity," compared to individuals who receive vaccination or experience infection alone. While previous infection accelerates the vaccine-induced immune response following the first dose of mRNA vaccination, subsequent doses demonstrate negligible increases in antibody titers or T cell immunity. Here, using systems serology, we observed a unique antibody profile induced by hybrid immunity, marked by the unique induction of robust Fc-recruiting antibodies directed at the conserved region of the viral Spike antigen, the S2-domain, induced at lower levels in individuals who only received mRNA vaccination. Thus, hybrid immunity clearly redirects vaccine-induced immunodominance, resulting in the induction of a robust functional humoral immune response to the most highly conserved region of the SARS-CoV-2 Spike antigen, which may be key to protection against existing and emerging variants of concern. Thus, next-generation vaccines able to mimic hybrid immunity and drive a balanced response to conserved regions of the Spike antigen may confer enhanced protection against disease.
Summary
Herpetic epithelial and stromal keratitis is a sight‐threatening ocular infection. To study the role of the epithelium in the innate response to herpes simplex virus 1 (HSV‐1) infection of ...the cornea, we used a telomerase‐immortalized human corneal epithelial cell (HCEC) line, HUCL, and primary HCECs as a model and infected the cells with HSV‐1 (KOS strain). HSV‐1 infection of HCECs resulted in a two‐phase activation of nuclear factor‐kappaB (NF‐κB), JNK and p38, with the first peak at 1–4 hr and a second peak at 8 hr. Concomitant with the first peak of activation, transcriptional expression of interleukin (IL)‐6, IL‐8, tumour necrosis factor (TNF)‐α and interferon (IFN)‐β was rapidly induced in HSV‐1‐infected cells. HSV‐1 infection also induced the production of IL‐6, IL‐8, and TNF‐α in both HUCL cells and primary HCECs. Coincident with the second phase of NF‐κB activation in HSV‐1‐infected HCECs, the expression of Toll‐like receptor 7 (TLR7) was induced, whereas the level of TLR3 was greatly down‐regulated. Thus, in response to HSV‐1 infection, HCECs produce proinflammatory cytokines, leading to infiltration, and IFNs to enhance the antiviral activity in the cornea, probably through sequential activation of TLRs.
Summary Background Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is ...increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. Methods We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11 009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42 938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. Findings We identified five genome-wide significant loci (binomial test p≤5·0×10−8 ) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 95% CI 1·08–1·16; p=7·24×10−11 ), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3 . Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2 , chromosome 6 between FILIP1 and SENP6 , chromosome 12 close to KLHDC5 and PTHLH , and in another region of chromosome 12 close to CHST11 . One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight—a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.
Changing composition of the gut microbiome is an important component of the gut adaptation to various environments, which have been implicated in various metabolic diseases including obesity and type ...2 diabetes, but the mechanisms by which the microbiota influence host physiology remain contentious. Here we find that both diets high in the fermentable fiber inulin and vertical sleeve gastrectomy increase intestinal expression and circulating levels of the anti-microbial peptide Reg3g. Moreover, a number of beneficial effects of these manipulations on gut function, energy balance, and glucose regulation are absent in Reg3g knockout mice. Peripheral administration of various preparations of Reg3g improves glucose tolerance, and this effect is dependent on the putative receptor Extl3 in the pancreas. These data suggest Reg3g acts both within the lumen and as a gut hormone to link the intestinal microbiome to various aspects of host physiology that may be leveraged for novel treatment strategies.
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•Reg3g is required for metabolic benefits of surgical or dietary interventions•Surgical or dietary intervention improves gut function in a Reg3g-dependent manner•Alteration of microbiome composition can provoke Reg3g in the system•Pharmacological application of Reg3g improves glucose tolerance in DIO mice
Shin et al. find that both surgical and dietary gut manipulations increase the gut peptide Reg3g and require Reg3g for their beneficial effects on body weight, glucose levels, and gut function. Reg3g may also act as a gut hormone since systemic administration improves glucose regulation via actions on the pancreas.
Lactate is abundant in rapidly dividing cells owing to the requirement for elevated glucose catabolism to support proliferation
. However, it is not known whether accumulated lactate affects the ...proliferative state. Here we use a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we identify a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodelling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We find that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. This mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient-replete growth phase to stimulate timed opening of APC/C, cell division and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodelling and can overcome anti-mitotic pharmacology via mitotic slippage. In sum, we define a biochemical mechanism through which lactate directly regulates protein function to control the cell cycle and proliferation.
To investigate the antimicrobial resistance and assess the molecular characteristics of β-lactamases (ESBLs, AmpC β-lactamases and carbapenemases) among Enterobacteriaceae isolates that caused ...intra-abdominal infections (IAIs) in patients hospitalized in the Asia-Pacific region during 2008-14.
Multiplex PCR was used to detect the specific types of β-lactamase in 2893 isolates with MICs of ertapenem >0.5 mg/L. In-hospital acquisition times for most isolates were also delineated.
Among 2728 (94.3%) isolates proven with β-lactamase production, the rates of non-susceptibility to imipenem were low (average = 7.9%) among IAI Enterobacteriaceae isolates from all Asia-Pacific countries except Vietnam (17.7%) and the Philippines (10.2%). A stepwise and significant increase in annual rates of carbapenemase production among these isolates was noted. CTX-M-15 and CTX-M-14 were the dominant ESBL variants in most IAI Enterobacteriaceae species. The most abundant AmpC β-lactamase variants were bla
among isolates of Escherichia coli and bla
among isolates of Klebsiella pneumoniae. In addition, the IAI Enterobacteriaceae isolates harbouring a bla
or bla
allele were associated with high community-acquired rates (38.0% and 42.6%, respectively). AmpC ACT and MIR variants were mostly detected in Enterobacter species. The bla
-harbouring isolates of E. coli, K. pneumoniae and Enterobacter cloacae were most commonly identified among IAI isolates from Vietnam and the Philippines. Also of note, bla
-harbouring IAI Enterobacteriaceae isolates were detected exclusively in Vietnam.
The high resistance burden in Vietnam and the Philippines warrants aggressive control policies to combat the worsening trend in antimicrobial resistance among Enterobacteriaceae species causing IAIs.
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