Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes.

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e., chassis) have difficulty in colonizing the hostile luminal environment. In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli bacteria isolated from the stool cultures of CR mice were modified to express functional genes. The reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E. coli can induce functional changes that affect physiology of and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to "knock in" specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts and enables LBT with curative intent.

Dynamics of Single-Cell Protein Covariation during Epithelial-Mesenchymal Transition.

Physiological processes, such as the epithelial-mesenchymal transition (EMT), are mediated by changes in protein interactions. These changes may be better reflected in protein covariation within a cellular cluster than in the temporal dynamics of cluster-average protein abundance. To explore this possibility, we quantified proteins in single human cells undergoing EMT. Covariation analysis of the data revealed that functionally coherent protein clusters dynamically changed their protein-protein correlations without concomitant changes in the cluster-average protein abundance. These dynamics of protein-protein correlations were monotonic in time and delineated protein modules functioning in actin cytoskeleton organization, energy metabolism, and protein transport. These protein modules are defined by protein covariation within the same time point and cluster and, thus, reflect biological regulation masked by the cluster-average protein dynamics. Thus, protein correlation dynamics across single cells offers a window into protein regulation during physiological transitions.

Open Access: Opening or Closing Doors for Junior Faculty?

The Open Access movement has transformed the landscape of medical publishing. Federal regulations regarding Open Access have expanded in the USA, and journals have adapted by offering a variety of Open Access models that range widely in cost and accessibility. For junior faculty with little to no funding, navigating this ever-changing landscape while simultaneously balancing the pressures of publication and promotion may present a particular challenge. Open Access provides the opportunity to amplify the reach and impact of scientific research, yet it often comes at a cost that may not be universally affordable. In this perspective, we discuss the impact of Open Access through the lens of junior faculty in general internal medicine. We describe the potential benefits and pitfalls of Open Access on junior faculty with a focus on research dissemination and cost. Finally, we propose sustainable solutions at the individual and systems-level to help navigate the world of Open Access to promote career growth and development.

Randomized trial of gastric and colorectal endoscopic submucosal dissection defect closure comparing a novel through-the-scope suturing system with an over-the-scope suturing system (with video).

BACKGROUND AND AIMS: Mucosal closure adds time but reduces adverse events associated with endoscopic submucosal dissection (ESD). We aimed to assess the closure time (CT), technical success, and cost-effectiveness between a novel through-the-scope helix tack suture system (TTSS) and the over-the-scope suturing system (OTSS). METHODS: In this single-center, prospective, randomized trial, all patients undergoing ESD with anticipated closure were randomized 1:1 to TTSS (study group) or OTSS (control group). Primary outcomes were CT and overall CT (OCT; CT + setup time). Secondary outcomes were rates of technical success, adverse events, and cost-effectiveness. RESULTS: Forty patients were randomized to OTSS (n = 20) or TTSS (n = 20). OTSS and TTSS groups were similar with respect to age, gender, proportion of colorectal polyps, proximal colon polyps, and mean size of the resected specimen (40.9 mm vs 40.4 mm). The mean CT was 18.4 minutes for OTSS and 23.3 minutes for TTSS (P = .36). The mean OCT was 32 minutes for OTSS and 39.5 minutes for TTSS (P = .36). Closure with a primary device was successful in 17 cases (85%) with OTSS and 18 cases (90%) with TTSS (P = .63). No closure-related intraprocedural adverse events or delayed perforations were noted. Mean cost of closure was significantly lower in the TTSS group for lesions <35 mm (P = .008). CONCLUSIONS: TTSS was not found to be superior to OTSS with respect to CT and technical and clinical success for closure of gastric and colorectal ESD defects. TTSS is more cost-effective for closure of lesions <35 mm. (Clinical trial registration number: NCT04925271.).

Health care resource utilization and costs associated with diagnosed medication overuse headache and potential acute medication overuse in individuals with migraine.

OBJECTIVE: Estimate health care resource utilization and costs associated with medication overuse headache and potential acute medication overuse. METHODS: A retrospective analysis was conducted with Clinformatics Data Mart data (1 January 2019-31 December 2019) that included continuously enrolled commercially insured adults with migraine (International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] code G43.xxx). Medication overuse headache was defined as ≥1 inpatient or ≥2 outpatient claims with an ICD-10-CM code G44.41/40 (drug-induced headache). Potential acute medication overuse was defined as possessing sufficient medication for >10 mean treatment days/month for ergots, triptans, opioids, or combination analgesics or >15 mean cumulative days/month for simple prescription analgesics (e.g., acetaminophen, aspirin, other non-opioid analgesics) for >6 consecutive months. All-cause and migraine-related health care resource utilization and costs were compared after adjusting for demographic and clinical characteristics. RESULTS: Among 90,017 individuals with migraine, the frequency of medication overuse headache/potential acute medication overuse was 12.6% (diagnosed medication overuse headache: 0.6%; potential acute medication overuse: 12.1%). Adjusted all-cause total costs ($31,235 vs $21,486; difference: $9,749 [P < 0.001]) and adjusted migraine-related total costs ($9,770 vs $6,207; difference: $3,563 [P < 0.001]) were higher in the medication overuse headache/potential acute medication overuse group versus those without medication overuse headache/potential acute medication overuse. CONCLUSIONS: Individuals with diagnosed medication overuse headache/potential acute medication overuse had higher all-cause and migraine-related health care resource utilization and costs versus individuals without medication overuse headache/potential acute medication overuse, suggesting that improved migraine management is needed to reduce associated costs.

Ubrogepant users' real-world experience: Patients on ubrogepant, characteristics and outcomes (UNIVERSE) study.

OBJECTIVE: To assess the real-world effectiveness of ubrogepant by evaluating self-reported satisfaction with pain relief, ability to think clearly, and return to normal function in individuals who had used ubrogepant to treat a migraine episode within the preceding 14 days. BACKGROUND: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine in adults. Few studies have evaluated the real-world effectiveness of ubrogepant. METHODS: The UNIVERSE study was an observational, cross-sectional survey conducted between February 2021 and April 2021 in US adult Migraine Buddy application (app) users currently treated with ubrogepant. Individuals who were 18 years of age or older and reported at least one dose of ubrogepant in the previous 14 days completed a 30-question survey in the app. The survey assessed respondent demographics, migraine history, acute treatment patterns, and treatment satisfaction with ubrogepant. Respondents also reported prior acute medication use and reasons for switching to ubrogepant. RESULTS: Of the 1303 ubrogepant users contacted, 302 (23.2%; 50 mg, 120 participants; 100 mg, 182 participants) were included in this study. The mean (standard deviation) age was 41.9 (11.2) years, and 90.1% (272/302) were female. Satisfaction with migraine relief at 2, 4, and 24 h post-dose was reported by 75.8% (229/302), 83.4% (252/302), and 78.5% (237/302) of participants, respectively. Satisfaction with the ability to think clearly after taking ubrogepant was reported by 85.1% (257/302) of participants, and 83.8% (253/302) were satisfied with their ability to return to normal function. Furthermore, 90.7% (274/302) of participants reported that they were likely to continue using ubrogepant to treat their migraine. Most participants (n = 264 [87%]) reported switching to ubrogepant due to inadequate treatment response with their previous treatment. In this subgroup, comparable outcomes were observed with respect to satisfaction with migraine relief, ability to think clearly, and return to normal function. CONCLUSIONS: Ubrogepant demonstrated real-world effectiveness in the acute treatment of migraine, as evidenced by high levels of treatment satisfaction and a strong indication of their intent to continue using the medication.

A 3-Dimensional Evaluation of the Effects of Unilateral Vertical Mandibular Distraction Osteogenesis on Airway Volume Among Patients With Hemifacial Microsomia.

OBJECTIVE: The aim of this study was to evaluate the volumetric airway changes using three-dimensional images following unilateral vertical mandibular distraction osteogenesis (uVMD) among patients with hemifacial microsomia (HFM). DESIGN: This retrospective study analyzed cone-beam computed tomography (CBCT) scans of patients with HFM at three different timepoints; pretreatment (T0), posttreatment (T1), and at least 6 months post-distraction (T2). The individuals underwent uVMD between December 2018-Januaray 2021. The nasopharyngeal (NP) volume, oropharyngeal (OP) volume, and the area of maximum constriction (MC) were measured. Wilcoxon signed-rank test was used to compare the airway volumes between T0-T1, T1-T2, and T0-T2. RESULTS: Five patients met the inclusion criteria (mean age = 10.4 years; 1 female, 4 males). Intraclass correlation analysis showed excellent interrater reliability (r > .86, P < .001). Posttreatment, the OP airway volume exhibited a significant mean increase of 56% (P = .043) from T0 to T1, but decreased from T1-T2 by 13%. Likewise, the total airway volume presented with a significant mean increase of 48% between T0-T1 (P = .044), and a decrease of 7% from T1-T2. The changes in the NP airway volume and area of MC were not statistically significant (P > .05), but an increase in the mean values were observed. CONCLUSION: Surgical intervention with uVMD may significantly increase the OP airway volume and the total airway volume among patients with HFM immediately after distraction. However, the statistical significance diminished after six months post-consolidation, but the mean percent change may remain of clinical significance. The NP volume did not seem to show significant changes in response to uVMD.

Mucormycosis infection associated with global COVID-19 pandemic - an institutional histopathological study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) in the recent times have instilled signs of immunosuppression globally which has further precipitated increasing range of opportunistic infections. Mucormycosis is a distressing opportunistic fungal infection with a high incidence and is the third commonest acute invasive infection following candidiasis and aspergillosis. The aim of the present observational study is to delineate the enigmatic histopathological profile between mucormycosis cases seen prior to pandemic (PPM) and pandemic associated mucormycosis (PAM). MATERIAL AND METHODS: Tissue archives of 105 histopathologically diagnosed cases of mucormycosis were included and analysed for demographical details and histopathological parameters like fungal load and localization, granuloma formation, necrosis, inflammatory infiltrate and tissue invasion. RESULTS: 0ut of 105 included cases, 11/105 (10.48%) were reported PPM and 94/105 (89.52%) PAM. Among 94 cases of PAM, 51/94 (54%) cases also showed COVID-19 positivity, while 43/94 (46%) did not. Of all the histological variables, increased fungal load and necrosis were observed in PAM relative to PPM cases. CONCLUSIONS: The histopathological variables like fungal load, necrosis, granuloma formation and tissue invasion, could help the clinician in assessing the clinical status at the time of tissue diagnosis and improve the treatment accordingly.

Correction: JMJD5 links CRY1 function and proteasomal degradation.

[This corrects the article DOI: 10.1371/journal.pbio.2006145.].

Lead extractions: dissecting adhesions up to the lead-tip of the right ventricle: safety and success-rates.

AIMS: Goal of Transvenous Lead Extraction (TLE) is complete removal of all targeted leads, without complications. Despite counter traction manoeuvres, efficacy rates are often hampered by broken right ventricle lead (RV-lead) tips. Mechanically powered lead extraction (Evolution sheath) is effective, however safety of dissection up to the lead tip is unclear. Therefore, we examined the feasibility and safety of RV-lead extraction requiring dissection up to the myocardium. METHODS AND RESULTS: From 2009 to 2018, all TLE in the Isala Heart Centre (Zwolle, The Netherlands) requiring the hand-powered mechanical Evolution system to extract RV-leads (n = 185) were examined from a prospective registry. We assessed 4 groups: TLE with the first generation Evolution (n = 43) with (A1,n = 18) and without (A2,n = 25) adhesions up to the myocardium and TLE with the Novel R/L type (n = 142) of sheath with (B1, n = 59) and without (B2, n = 83) adhesions up to the myocardium. Complete success rate in Group B was significantly higher than group A (96.5 vs 76.7%, p = 0.0354). When comparing the patients with adhesions up to the myocardium, total complete success is higher in the R/L group (61.1% vs 90.5%, p = 0.0067). There were no deaths. Overall major complication rates were low (2/185; 1.1%) and there was no statistically significant difference in major and minor complications between the two groups. CONCLUSION: Extraction strategy with the bidirectional Evolution R/L sheath for right ventricular leads with adhesions up to the myocardium is safe and feasible.

Peripheral cannulation and endoaortic balloon occlusion for management of porcelain aorta during cardiac surgery.

Porcelain aorta with extensive calcification of the ascending aorta complicates cardiac surgery and increases perioperative risk. Aortic cannulation and cross-clamping in these patients increase the risk of serious complications including perioperative embolic stroke. Although different techniques have been proposed, surgery in these patients remains a challenge. We present the clinical implications of the porcelain aorta and surgical strategies involving axillary arterial cannulation and endoaortic balloon to allow for the institution of cardiopulmonary bypass and cardioplegic arrest during surgery. The surgery included a redo sternotomy with bioprosthetic mitral valve replacement, tricuspid valve repair with an annuloplasty, and closure of the left atrial appendage. In appropriately selected patients, endoaortic balloon occlusion was a valuable tool to facilitate the safe conduct of an operation. Careful preoperative evaluation and planning by a multidisciplinary team are essential in these cases.

Precise endoballoon positioning for High-Risk sternal re-entry in an ascending aortic pseudoaneurysm with patent coronary grafts.

Redo cardiac surgery can present a unique set of challenges even to the experienced surgeon. Although outcomes have steadily improved in the modern era; if an intraoperative adverse event occurs, there is a 5% incidence of mortality and 19% incidence of myocardial infarction, stroke or death. Overall, the modern incidence of mortality at reoperation varies but be segregated into low and higher risk cohorts depending on the planning computed tomography imaging and risk to substernal structures on re-entry. Patients with ascending aortic or root pseudoaneurysms represent a particularly difficult subset of high-risk patients requiring reoperative cardiac surgery due to the danger of exsanguination and air embolization. The gold standard for management of such cases remains the use of deep hypothermic circulatory arrest (DHCA) to achieve safe re-entry in such cases however this can result in unpredictable DHCA duration depending on the degree of pericardial adhesions. We report a case of aortic pseudoaneurysm in a patient with patent coronary grafts managed using an endoballoon precisely positioned relative to the proximal anastomoses resulting in a safe surgical re-entry and shorter DHCA time.

Corneal Neurotization: A Meta-analysis of Outcomes and Patient Selection Factors.

BACKGROUND: Corneal neurotization describes reinnervation of the anesthetic or severely hypoesthetic cornea with a healthy local nerve or graft. Preliminary evidence has shown corneal neurotization to improve corneal sensation, visual acuity, and ocular surface health. Factors that improve patient selection and lead to better neurotization outcomes have yet to be elucidated, limiting ability to optimize perioperative decision-making guidelines. METHODS: A systematic review with meta-analysis was performed of the MEDLINE and Embase databases using variations of "corneal," "nerve transfer," "neurotization," and "neurotization." The primary outcomes of interest were corrected visual acuity, NK Mackie stage, and central corneal sensation. Regression analyses were performed to identify the effects of surgical technique, duration of denervation, patient age, and etiology of corneal pathology on neurotization outcomes. RESULTS: Seventeen studies were included. Corneal neurotization resulted in significant improvement in NK Mackie stage (0.84 vs 2.46, P < 0.001), visual acuity (logarithm of minimum angle of resolution scale: 0.98 vs 1.36, P < 0.001), and corneal sensation (44.5 vs 0.7, P < 0.001). Nerve grafting was associated with greater corneal sensation improvement than nerve transfer (47.7 ± 16.0 vs 35.4 ± 18.76, P = 0.03). Denervation duration was predictive of preneurotization visual acuity (logarithm of minimum angle of resolution scale; R2 = 0.25, P = 0.001), and older age (ß = 0.30, P = 0.03) and acquired etiology (ß = 0.30, P = 0.03) were predictive of improved visual acuity. CONCLUSIONS: Corneal neurotization provides significant clinical improvement in visual acuity, NK Mackie staging, and corneal sensation in patients who experience NK. Both nerve grafting and nerve transfer are likely to yield similar levels of benefit and ideally should be performed early to limit denervation time.

Novel indolo [3,2-c]isoquinoline-5-one-6-yl [1,2,4]triazolo [3,4-b] [1,3,4]thiadiazole analogues: Design, synthesis, anticancer activity, docking with SARS-CoV-2 Omicron protease and MESP/TD-DFT approaches.

Indoloisoquinoline derivatives are associated with varieties of biological and pharmacological properties. Therefore, we herein reported the synthesis of novel series of indolo [3,2-c]isoquinoline incorporated with [1,2,4]triazolo [3,4-b] [1,3,4]thiadiazole moieties. Spectroscopic methods were used to determine the chemical structures of these molecules. Whereas, the B3LYP functional with the def2-SVP basis set were used to improve TD-DFT geometries and solvent effects. Investigations, which are directly connected to the optical spectra (absorption and emission) of molecules. These findings reveals that the compound 3d-f with a strong electron acceptor NO2 exhibited UV-visible spectra peaks to near infrared (NIR) range in solvents. Compound 3e exhibited a lowest ∆E of 2.28 eV in MeCN. Further, among the newly synthesized compounds 3d and 3g exhibits highest activity against four cell lines with strongest potent cytotoxicity, as contrasted to the control drug (Doxorubicin). Docking experiments revealed that compounds in contrast to 3a and 3d had strong interactions with Asn322, Met323, Ala387,Ala386, Gln506 and Gly326 with a greater binding affinity which are important amino acid residues that play a key role in SARS-CoV-2 Omicron main protease (Mpro) through hydrophobic, hydrogen bonding, Pi-sigma, Pi-sulfur and van der Waals interactions.

An age-related algorithm for management of micro-orbitism from anophthalmia: a systematic review with supplemental case reports.

Management of pediatric anophthalmia and resultant micro-orbitism is challenging. The efficacy and safety of treatment methods vary with age as bony changes grow recalcitrant to implants in those at skeletal maturity and osteotomies become technically challenging following frontal sinus pneumatization. This study aims to review methods for managing micro-orbitism and develop an age-based treatment approach. A systematic literature review was conducted. Data were screened and extracted by two investigators and relevant English-language primary-literature was analyzed. Information on sample-size, number of orbits, intervention, age, complications, and prosthetic retention was obtained. Representative case reports are presented, in addition. Nineteen studies met inclusion: 294 orbits in 266 patients were treated. Two studies reported distraction-osteogenesis. Two studies utilized bone grafting. Osteotomies were performed in 41 patients from three studies. Use of solid implants was detailed in two studies. Three studies described osmotic implant. Four studies described inflatable implants. Other techniques were described by three of the included studies, two of which utilized dermis-fat grafting. All but one study were observational case reports or case series. Across all studies regardless of surgical technique, risk of bias and heterogeneity was high due to attrition bias and selective outcomes-reporting. Selection of therapy should be tailored to skeletal-age to optimize outcomes; those 0-4 yrs are managed with dermis-fat grafts, 5-7 yrs managed with implants, and 8+ yrs managed with osteotomies. For those 8+ yrs with aerated frontal sinuses or insufficient bone stock, we propose onlay camouflage prosthetics which improve projection, increase orbital volume, and avoid risk for frontal sinus injury.

Functionality, satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: a post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials.

BACKGROUND: Triptans are the first-line option for the acute treatment of migraine attacks; however, triptans are contraindicated in people with certain underlying cardiovascular risk factors and are associated with inadequate efficacy or poor tolerability in some individuals. Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. METHODS: This post hoc analysis of the phase 3 ACHIEVE trials examined the impact of ubrogepant on the Functional Disability Scale (FDS), satisfaction with medication, and Patient Global Impression of Change (PGIC) in participants who were self-reported triptan insufficient responders (TIRs), defined as those who are unable to take triptans due to contraindications, tolerability issues, or insufficient efficacy. Responder definitions for the FDS, satisfaction measures, and PGIC were based on qualitative interpretation of the respective response options for the pooled ubrogepant 50 mg and placebo groups. RESULTS: In the pooled analysis population (n = 1799), 451 (25%) participants were TIRs, with most (80%) reporting insufficient efficacy with triptan use. A significantly higher proportion of TIRs treated with ubrogepant vs placebo reported being able to function normally from 2 to 8 h post dose (P < 0.05). Notably, significance was demonstrated at the time of the primary outcome assessments (2 h post dose), where rates of normal function were 38% for ubrogepant vs 29% for placebo (P = 0.048). A greater proportion of TIRs in the ubrogepant arm vs the placebo arm were satisfied with treatment at 2 (33% vs 21%, P = 0.006) and 24 h (58% vs 28%, P < 0.001) and indicated that their migraine improved at 2 h vs placebo (30% vs 18%, P = 0.006). Results were generally similar in the insufficient efficacy subpopulation of TIRs as in the overall TIRs group. Ubrogepant was safe and well tolerated in TIRs, with no new safety signals identified. CONCLUSIONS: In people with migraine who are TIRs, individuals treated with ubrogepant had favorable 2-h outcomes, as measured by the FDS, satisfaction with medication, and PGIC, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02828020 (ACHIEVE I), registered July 11, 2016; NCT02867709 (ACHIEVE II), registered August 16, 2016.

Vasculo-toxic and pro-inflammatory action of unbound haemoglobin, haem and iron in transfusion-dependent patients with haemolytic anaemias.

Increasing evidence suggests that free haem and iron exert vasculo-toxic and pro-inflammatory effects by activating endothelial and immune cells. In the present retrospective study, we compared serum samples from transfusion-dependent patients with ß-thalassaemia major and intermedia, hereditary spherocytosis and sickle cell disease (SCD). Haemolysis, transfusions and ineffective erythropoiesis contribute to haem and iron overload in haemolytic patients. In all cohorts we observed increased systemic haem and iron levels associated with scavenger depletion and toxic 'free' species formation. Endothelial dysfunction, oxidative stress and inflammation markers were significantly increased compared to healthy donors. In multivariable logistic regression analysis, oxidative stress markers remained significantly associated with both haem- and iron-related parameters, while soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble endothelial selectin (sE-selectin) and tumour necrosis factor α (TNFα) showed the strongest association with haem-related parameters and soluble intercellular adhesion molecule 1 (sICAM-1), sVCAM-1, interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) with iron-related parameters. While hereditary spherocytosis was associated with the highest IL-6 and TNFα levels, ß-thalassaemia major showed limited inflammation compared to SCD. The sVCAM1 increase was significantly lower in patients with SCD receiving exchange compared to simple transfusions. The present results support the involvement of free haem/iron species in the pathogenesis of vascular dysfunction and sterile inflammation in haemolytic diseases, irrespective of the underlying haemolytic mechanism, and highlight the potential therapeutic benefit of iron/haem scavenging therapies in these conditions.

Prevalence and Tolerance of Prognostic Uncertainty Among Thoracic Oncologists.

We undertook a cross-sectional survey of a random sample of thoracic oncologists from the American Society of Clinical Oncology clinical directory to characterize whether prognostic uncertainty has increased and if tolerance of uncertainty is associated with prognostic discussion practices. We also assessed the Physicians' Reactions to Uncertainty Scale and presented a vignette about an incurable patient with uncertain life expectancy. One hundred and ninety-two of 438 surveys (43.8%) were received. Of the respondents, 52.1% agreed "there is more prognostic uncertainty in the management of lung cancer now than 10 years ago," and 37.4% noted difficulty "staying up-to-date." In multivariable analyses, physician-reported anxiety about uncertainty (p = .05) and reluctance to disclose uncertainty (p = .04) were inversely associated with reporting having prognostic discussions with most patients. For the vignette, 92.1% reported they would discuss incurability, but only 76.3% said they would discuss the patient's life expectancy. Our data suggest prognostic uncertainty has increased in thoracic oncology and oncologists' tolerance of uncertainty may affect discussion practices.

Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease.

Circadian clock proteins are endogenous timing mechanisms that control the transcription of hundreds of genes. Their integral role in coordinating metabolism has led to their scrutiny in a number of diseases, including nonalcoholic fatty liver disease (NAFLD). Discoordination between central and peripheral circadian rhythms is a core feature of nearly every genetic, dietary, or environmental model of metabolic syndrome and NAFLD. Restricting feeding to a defined daily interval (time-restricted feeding) can synchronize the central and peripheral circadian rhythms, which in turn can prevent or even treat the metabolic syndrome and hepatic steatosis. Importantly, a number of proteins currently under study as drug targets in NAFLD (sterol regulatory element-binding protein [SREBP], acetyl-CoA carboxylase [ACC], peroxisome proliferator-activator receptors [PPARs], and incretins) are modulated by circadian proteins. Thus, the clock can be used to maximize the benefits and minimize the adverse effects of pharmaceutical agents for NAFLD. The circadian clock itself has the potential for use as a target for the treatment of NAFLD.

JMJD5 links CRY1 function and proteasomal degradation.

The circadian oscillator is a molecular feedback circuit whose orchestration involves posttranslational control of the activity and protein levels of its components. Although controlled proteolysis of circadian proteins is critical for oscillator function, our understanding of the underlying mechanisms remains incomplete. Here, we report that JmjC domain-containing protein 5 (JMJD5) interacts with CRYPTOCHROME 1 (CRY1) in an F-box/leucine-rich repeat protein 3 (FBXL3)-dependent manner and facilitates targeting of CRY1 to the proteasome. Genetic deletion of JMJD5 results in greater CRY1 stability, reduced CRY1 association with the proteasome, and disruption of circadian gene expression. We also report that in the absence of JMJD5, AMP-regulated protein kinase (AMPK)-induced CRY1 degradation is impaired, establishing JMJD5 as a key player in this mechanism. JMJD5 cooperates with CRY1 to repress circadian locomotor output cycles protein kaput (CLOCK)-brain and muscle ARNT-like protein 1 (BMAL1), thus linking CRY1 destabilization to repressive function. Finally, we find that ablation of JMJD5 impacts FBXL3- and CRY1-related functions beyond the oscillator.