ABSTRACT
Based on HARPS-N radial velocities (RVs) and TESS photometry, we present a full characterization of the planetary system orbiting the late G dwarf TOI-561. After the identification of three ...transiting candidates by TESS, we discovered two additional external planets from RV analysis. RVs cannot confirm the outer TESS transiting candidate, which would also make the system dynamically unstable. We demonstrate that the two transits initially associated with this candidate are instead due to single transits of the two planets discovered using RVs. The four planets orbiting TOI-561 include an ultra-short period (USP) super-Earth (TOI-561 b) with period Pb = 0.45 d, mass Mb = 1.59 ± 0.36 M⊕ and radius Rb = 1.42 ± 0.07 R⊕, and three mini-Neptunes: TOI-561 c, with Pc = 10.78 d, Mc = 5.40 ± 0.98 M⊕, Rc = 2.88 ± 0.09 R⊕; TOI-561 d, with Pd = 25.6 d, Md = 11.9 ± 1.3 M⊕, Rd = 2.53 ± 0.13 R⊕; and TOI-561 e, with Pe = 77.2 d, Me = 16.0 ± 2.3 M⊕, Re = 2.67 ± 0.11 R⊕. Having a density of 3.0 ± 0.8 g cm−3, TOI-561 b is the lowest density USP planet known to date. Our N-body simulations confirm the stability of the system and predict a strong, anti-correlated, long-term transit time variation signal between planets d and e. The unusual density of the inner super-Earth and the dynamical interactions between the outer planets make TOI-561 an interesting follow-up target.
Super-Earths belong to a class of planet not found in the Solar system, but which appear common in the Galaxy. Given that some super-Earths are rocky, while others retain substantial atmospheres, ...their study can provide clues as to the formation of both rocky and gaseous planets, and – in particular – they can help to constrain the role of photoevaporation in sculpting the exoplanet population. GJ 9827 is a system already known to host three super-Earths with orbital periods of 1.2, 3.6, and 6.2 d. Here, we use new HARPS-N radial velocity measurements, together with previously published radial velocities, to better constrain the properties of the GJ 9827 planets. Our analysis cannot place a strong constraint on the mass of GJ 9827 c, but does indicate that GJ 9827 b is rocky with a composition that is probably similar to that of the Earth, while GJ 9827 d almost certainly retains a volatile envelope. Therefore, GJ 9827 hosts planets on either side of the radius gap that appears to divide super-Earths into pre-dominantly rocky ones that have radii below ∼1.5Rꚛ, and ones that still retain a substantial atmosphere and/or volatile components, and have radii above ∼2Rꚛ. That the less heavily irradiated of the three planets still retains an atmosphere, may indicate that photoevaporation has played a key role in the evolution of the planets in this system.
Regulated removal of proteins and organelles by autophagy-lysosome system is critical for muscle homeostasis. Excessive activation of autophagy-dependent degradation contributes to muscle atrophy and ...cachexia. Conversely, inhibition of autophagy causes accumulation of protein aggregates and abnormal organelles, leading to myofiber degeneration and myopathy. Defects in lysosomal function result in severe muscle disorders such as Pompe (glycogen storage disease type II (GSDII)) disease, characterized by an accumulation of autophagosomes. However, whether autophagy is detrimental or not in muscle function of Pompe patients is unclear. We studied infantile and late-onset GSDII patients and correlated impairment of autophagy with muscle wasting. We also monitored autophagy in patients who received recombinant α-glucosidase. Our data show that infantile and late-onset patients have different levels of autophagic flux, accumulation of p62-positive protein aggregates and expression of atrophy-related genes. Although the infantile patients show impaired autophagic function, the late-onset patients display an interesting correlation among autophagy impairment, atrophy and disease progression. Moreover, reactivation of autophagy in vitro contributes to acid α-glucosidase maturation in both healthy and diseased myotubes. Together, our data suggest that autophagy protects myofibers from disease progression and atrophy in late-onset patients.
Macroautophagy is a lysosomal catabolic process that maintains the homeostasis of eukaryotic cells, tissues, and organisms. Macroautophagy plays important physiological roles during development and ...aging processes and also contributes to immune responses. The process of macroautophagy is compromised in diseases, such as cancer, neurodegenerative disorders, and diabetes. The autophagosome, the double-membrane-bound organelle that sequesters cytoplasmic material to initiate macroautophagy, is formed by the hierarchical recruitment of about 15 autophagy-related (ATG) proteins and associated proteins, such as DFCP1, AMBRA1, the class III phosphatidyl-inositol 3-kinase VPS34, and p150/VPS15. Evidence suggests that in addition to the canonical pathway, noncanonical pathways that do not require the entire repertoire of ATGs can also result in formation of autophagosomes. Here we will discuss recent discoveries concerning the molecular regulation of these noncanonical forms of macroautophagy and their potential roles in cellular responses to stressful situations.
Background
Laparoscopic lavage was proposed in the 1990s to treat purulent peritonitis in patients with perforated acute diverticulitis. Prospective randomized trials had mixed results. The aim of ...this study was to determine the success rate of laparoscopic lavage in sepsis control and to identify a group of patients that could potentially benefit from this treatment.
Methods
This retrospective multicentre international study included consecutive patients from 24 centres who underwent laparoscopic lavage from 2005 to 2015.
Results
A total of 404 patients were included, 231 of whom had Hinchey III acute diverticulitis. Sepsis control was achieved in 172 patients (74·5 per cent), and was associated with lower Mannheim Peritonitis Index score and ASA grade, no evidence of free perforation, absence of extensive adhesiolysis and previous episodes of diverticulitis. The operation was immediately converted to open surgery in 19 patients. Among 212 patients who underwent laparoscopic lavage, the morbidity rate was 33·0 per cent; the reoperation rate was 13·7 per cent and the 30‐day mortality rate 1·9 per cent. Twenty‐one patients required readmission for early complications, of whom 11 underwent further surgery and one died. Of the 172 patients discharged uneventfully after laparoscopic lavage, a recurrent episode of acute diverticulitis was registered in 46 (26·7 per cent), at a mean of 11 (range 2–108) months. Relapse was associated with younger age, female sex and previous episodes of acute diverticulitis.
Conclusion
Laparoscopic lavage showed a high rate of successful sepsis control in selected patients with perforated Hinchey III acute diverticulitis affected by peritonitis, with low rates of operative mortality, reoperation and stoma formation.
Successful in the majority
The frequency of various limb-girdle muscular dystrophy (LGMD) molecular diagnoses has previously been investigated only in cohorts of patients presenting LGMD phenotype.
A total of 550 muscle ...biopsies underwent multiple protein screening (including calpain-3 functional assay) and extensive gene mutation analysis to examine the frequency of LGMD subtypes in patients with distinct clinical phenotypes (severe childhood-onset LGMD, adult-onset LGMD, distoproximal myopathy, and asymptomatic hyperCKemia).
The percentage of molecularly ascertained cases directly relates with the degree of clinical involvement: 60% of total LGMD (77% of childhood-onset, 46% of adult-onset, 66% of distoproximal myopathy) and 14% of hyperCKemia. The higher number of molecular diagnoses in severe phenotypes might suggest that genes selected for our screening are those more frequently associated with severe LGMD, and that the hyperCKemia group includes heterogeneous diagnoses. The probability of obtaining a molecular diagnosis increases when a protein defect is found in a muscle biopsy: in such cases, we diagnosed 87% of LGMD and 76% of hyperCKemia.
Diagnosing 77% of childhood-onset limb-girdle muscular dystrophy (LGMD) and 60% of total LGMD is an important result. The missing identification of gene mutations in about 40% of patients with typical LGMD phenotype suggests that unknown genetic or nongenetic etiologies are still to be recognized. Dysferlin, caveolin-3, and emerin protein defects invariably corresponded to primary disorders (100%), whereas a lower correlation was found for sarcoglycans (77%) and calpain-3 (84%). The different efficiency of genetic diagnosis after the identification of a protein defect in the various disorders is possibly due to different pathogenetic effects of mutations.
Danon disease, an X-linked dominant disorder, results from mutations in the lysosome-associated membrane protein-2 (
LAMP2) gene and presents with hypertrophic cardiomyopathy, skeletal myopathy, and ...mental retardation. To investigate the effects of
LAMP2 gene mutations on protein expression in different tissues, we screened
LAMP2 gene mutations and LAMP-2 protein deficiency in the skeletal muscle of nine unrelated patients with hypertrophic cardiomyopathy and vacuolar myopathy. We identified three novel families (including one affected mother) with unreported
LAMP2 gene null mutations and LAMP-2 protein deficiency in skeletal and myocardial muscle, leukocytes, and fibroblasts. LAMP-2 protein deficiency was detectable in various tissues, including leukocytes, explaining the multisystem clinical involvement. Skeletal muscle immunopathology showed that mutant protein was not localized in the Golgi complex, vacuolar membranes expressed sarcolemmal-specific proteins, and the degree of muscle fiber vacuolization correlated with clinical muscle involvement. In our female patient, muscle histopathology and LAMP-2 protein analysis was inconclusive, indicating that diagnosis in females requires mutation identification. The random X-chromosome inactivation found in muscle and leukocytes excluded the possibility that selective involvement of some tissues in females is due to skewed X-chromosome inactivation. Therefore, biochemical analysis of leukocytes might be used for screening in male patients, but genetic screening is required in females.
Aims
The peculiar clinical features and the pathogenic mechanism related to calpain‐3 deficiency (impaired sarcomere remodelling) suggest that the ubiquitin‐proteasome degradation pathway may have a ...crucial role in Limb Girdle Muscular Dystrophy 2A (LGMD2A). We therefore investigated muscle atrophy and the role of the ubiquitin‐proteasome and lysosomal‐autophagic degradation pathways.
Methods
We selected 25 adult male LGMD2A patients (and seven controls), classified them using clinical severity score, analysed muscle fibre size by morphometry and protein and/or transcriptional expression levels of the most important atrophy‐ and autophagy‐related genes (MuRF1, atrogin1, LC3, p62, Bnip3).
Results
Muscle fibre size was significantly lower in LGMD2A than in controls and it was significantly correlated with patients' clinical disability score recorded at the time of biopsy, suggesting that functional and structural muscle impairment are dependent. The large majority of atrophic fibres originate from a mechanism different from regeneration, as assessed by neonatal myosin immunolabelling. As compared with controls, LGMD2A muscles have higher MuRF1 (but not atrogin1) protein and MuRF1 gene expression levels, and MuRF1 protein levels significantly correlated with both muscle fibre size and clinical disability score. LGMD2A muscles have slightly increased levels of LC3‐II and p62 proteins and a significant up‐regulation of p62 and Bnip3 gene expression.
Conclusions
In LGMD2A muscles the activation of the atrophy programme appeared to depend mainly upon induction of the ubiquitin‐proteasome system and, to a lesser extent, the autophagic‐lysosomal degradation pathway.
Background: The limb girdle muscular dystrophies (LGMD) are a heterogeneous group of Mendelian disorders highlighted by weakness of the pelvic and shoulder girdle muscles. Seventeen autosomal loci ...have been so far identified and genetic tests are mandatory to distinguish among the forms. Mutations at the calpain 3 locus (CAPN3) cause LGMD type 2A. Objective: To obtain unbiased information on the consequences of CAPN3 mutations. Patients: 530 subjects with different grades of symptoms and 300 controls. Methods: High throughput denaturing HPLC analysis of DNA pools. Results: 141 LGMD2A cases were identified, carrying 82 different CAPN3 mutations (45 novel), along with 18 novel polymorphisms/variants. Females had a more favourable course than males. In 94% of the more severely affected patient group, the defect was also discovered in the second allele. This proves the sensitivity of the approach. CAPN3 mutations were found in 35.1% of classical LGMD phenotypes. Mutations were also found in 18.4% of atypical patients and in 12.6% of subjects with high serum creatine kinase levels. Conclusions: A non-invasive and cost–effective strategy, based on the high throughput denaturing HPLC analysis of DNA pools, was used to obtain unbiased information on the consequences of CAPN3 mutations in the largest genetic study ever undertaken. This broadens the spectrum of LGMD2A phenotypes and sets the carrier frequency at 1:103.
Aliment Pharmacol Ther 2011; 34: 92–99
Summary
Background There is recent evidence that mast cells may play important roles in the gut, especially concerning visceral hypersensitivity and motor ...activity. However, most data are only available for clinical conditions characterised by diarrhoea, where MC have chiefly investigated in the mucosal layer of the colon and there is almost no information concerning constipation.
Aim To investigate mast cells distribution in all colonic layers in controls and severely constipated patients.
Methods Full‐thickness specimens from colons of patients undergoing surgery for slow transit constipation (n = 29), compared with controls, were obtained and the number of mast cells (evaluated by specific monoclonal antibodies) counted as a whole and in single colonic segments (caecum, ascending, transverse, descending and sigmoid).
Results Compared with controls, constipated patients revealed significantly higher number of mast cells, both as overall number and in single colonic segments. The distribution of mast cells resulted fairly homogeneous in the various segment of the large bowel, in both controls and patients, and no significant difference in the percentage of degranulated cells was found between groups.
Conclusions Colonic mast cells display a homogeneous distribution within the viscus. This cell population is shown to increase in severely constipated patients, which might represent a mechanism trying to compensate for the impaired propulsive activity of these patients.