Notes

A good ADAR1-dependent RNA editing function in the cyclin-dependent kinase CDK13 promotes thyroid cancer malignancy blueprint.
This study points to the imminent danger of native ambrosia beetles spreading RL if the pathogen is introduced to Mexico's avocado orchards or natural areas given that these beetles are associated with Raffaelea species and that lateral transfer of RL among ambrosia beetles in Florida suggests that the likelihood of this phenomenon increases when partners are phylogenetically close. Therefore, this study provides important information about the potential vectors of RL in Mexico and other avocado producing regions. Confirming beetle-fungal identities in these areas is especially important given the serious threat laurel wilt disease represents to the avocado industry in Mexico.Cellulases are largely afflicted by inhibition from their reaction products, especially at high-substrate loading, which represents a major challenge for biomass processing. This challenge was overcome for endoglucanase 1 (E1) from Acidothermus cellulolyticus by identifying a large conformational change involving distal residues upon binding cellobiose. Having introduced alanine substitutions at each of these residues, we identified several mutations that reduced cellobiose inhibition of E1, including W212A, W213A, Q247A, W249A and F250A. One of the mutations (W212A) resulted in a 47-fold decrease in binding affinity of cellobiose as well as a 5-fold increase in the kcat. The mutation further increased E1 activity on Avicel and dilute-acid treated corn stover and enhanced its productivity at high-substrate loadings. These findings were corroborated by funnel metadynamics, which showed that the W212A substitution led to reduced affinity for cellobiose in the +1 and +2 binding sites due to rearrangement of key cellobiose-binding residues.
Hypophosphatasia (HPP) is a rare metabolic disorder caused by deficiency of alkaline phosphatase (ALP) enzyme activity, leading to defective mineralization, due to pathogenic variants of the ALPL gene, encoding the tissue non-specific alkaline phosphatase (TNSALP) enzyme. Inheritance can be autosomal recessive or autosomal dominant. An abnormal ALPL genetic test enables accurate diagnosis, avoiding the administration of contraindicated antiresorptive drugs that, in HPP patients, substantially increase the risk of atypical femur fractures (AFFs) and worsen fracture healing process that is usually already compromised in these patients.

Performing ALPL genetic testing to identify rare variants in suspected adult HPP patients. Comparing frequencies of ALPL common variants in individuals with biochemical and/or clinical signs suggestive of adult HPP and non-HPP controls, and among different clinical subgroups of patients with a clinical suspicion of adult HPP.

Patients with suspected adult HPP were retrospecer of risk for these fractures.
This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes.

A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken.

From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had β-human chorionic gonadotropin values < 50 mIU/mL. The 5/10-year overall survival (OS) and recurrence-free survival (RFS) rates was 97.2%/96.2% and 89.9%/86.9%, respectively. RFS was predicted by radiotherapy (RT) field, with focal RT having the worst outcome, whereas chemotherapy usage had no impact on survival. Among patients who received chemotherapy, response to chemotherapy did not predict survival outcomes. In M0 patients, primary basal ganglia tumors predicted a worse RFS. In patienmary tumor location, and extent of disease.Hereditary Spastic Paraplegia (HSP) is a disease in which dieback degeneration of corticospinal tracts, accompanied by axonal swellings, leads to gait deficiencies. SPG4-HSP, the most common form of the disease, results from mutations of SPAST, which is the gene that encodes spastin, a microtubule-severing protein. The lack of a vertebrate model that recapitulates both the etiology and symptoms of SPG4-HSP has stymied the development of effective therapies for the disease. hSPAST-C448Y mice, which express human mutant spastin at the ROSA26 locus, display corticospinal dieback and gait deficiencies, but not axonal swellings. On the other hand, Spast-knockout mice display axonal swellings but not corticospinal dieback or gait deficiencies. BIRB 796 order One possibility is that reduced spastin function, resulting in axonal swellings, is not the cause of the disease, but exacerbates the toxic effects of the mutant protein. To explore this idea, Spast-knockout and hSPAST-C448Y mice were crossbred, and the offspring were compared to the parental lines via histological and behavioral analyses. The crossbred animals displayed axonal swellings, as well as earlier onset, worsened gait deficiencies and corticospinal dieback compared to the hSPAST-C448Y mouse. These results, together with observations on changes in HDAC6 and tubulin modifications in the axon, indicate that each of these three transgenic mouse lines is valuable for investigating a different component of the disease pathology. Moreover, the crossbred mice are the best vertebrate model to date for testing potential therapies for SPG4-HSP.Meningiomas are common intracranial tumors with a female predominance. Their etiology is still poorly documented. The role of sexual hormones has long been evoked, and data have been conflicting across studies. However, a dose-dependent relationship between the incidence and growth of meningiomas and hormonal treatment with the progestin cyproterone acetate (CPA) has recently been established. CPA-associated meningiomas seem to be mainly located in the anterior and middle skull base, are more likely to be multiple, may harbor P1K3CA mutations in up to one-third of cases, and are more common with a longer duration of treatment. A similar but lower risk of meningiomas has been recently reported with the use of chlormadinone acetate and nomegestrol acetate as progestin treatments. Concerning hormonal replacement therapy (HRT) in menopausal patients, evidence from epidemiological studies seem to favor an increased risk of meningiomas in treated patients although a recent study failed to show an increased growth of meningiomas in HRT treated vs nontreated patients. Until larger studies are available, it seems wise to recommend avoiding HRT in patients with meningiomas. Evidence from published data does not seem to support an increased risk of meningiomas with oral contraceptive oral contraceptive (OR) use. Data are too scarce to conclude on fertility treatments. Based on studies demonstrating the expression of hormonal receptors in meningiomas, therapies targeting these receptors have been tried but have failed to show an overall favorable clinical outcome in meningioma treatment.
Patients with inflammatory bowel disease (IBD) frequently undergo multiple computed tomography (CT) examinations. With the widespread availability of magnetic resonance imaging (MRI), it is unclear whether the use of CTs in IBD has declined. We aimed to analyze the trends of CT and MRI use in a large cohort of IBD patients in a 10-year period.

We retrospectively analyzed adults ≥18 years of age using a de-identified database, IBM Explorys. Patients with ≥1 CT of the abdomen (± pelvis) or MRI of the abdomen (± pelvis) at least 30 days after the diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were included. We examined the factors associated with patients undergoing multiple CTs (≥5 CTs of the abdomen) and performed a trend analysis from 2010 to 2019.

Among 176 110 CD and 143 460 UC patients, those with ≥1 CT of the abdomen annually increased from 2010 to 2019 with mean annual percentage change of +3.6% for CD and +4.9% for UC. Similarly, annual percentage change for patients with ≥1 MRI (CD +15.6%; UC +22.8%) showed a rising trend. There was a 3.8% increase in CD patients receiving ≥5 CTs of the abdomen annually compared with a 2.4% increase among UC patients in the 10-year period. Age ≥50 years, men, African Americans, public insurance payors, body mass index ≥30kg/m2, and smoking history were associated with ≥5 CTs.

There is a considerable increase in the number of CT scans performed in IBD patients. Further studies can explore factors influencing the use of CT and MRI of the abdomen in IBD patients.
There is a considerable increase in the number of CT scans performed in IBD patients. Further studies can explore factors influencing the use of CT and MRI of the abdomen in IBD patients.
Subcutaneous (SC) vedolizumab presents the opportunity for inflammatory bowel disease (IBD) patients to manage their treatment at home. There is currently no data on the process of transitioning patients established on intravenous (IV) to SC as part of routine clinical care. The aim of this programme is to evaluate the clinical and biochemical outcomes of switching a cohort of IBD patients established on IV vedolizumab to SC 12 weeks following the transition.

178 adult patients were offered the opportunity to transition to SC vedolizumab. Patients who agreed were reviewed prior to switching and at week 12 (W12) after their first SC dose. Evaluation outcomes included disease activity scores, the IBD-Control patient-reported outcome measures (PROMs) and faecal calprotectin (FCP). Reasons for patients declining or accepting transitioning, pharmacokinetics, adverse drug reactions and risk factors for a poor outcome in SARS-CoV-2 infection were also assessed.

124 patients agreed to transition, of which 106 patients had been on IV vedolizumab for at least 4 months. There were no statistically significant differences in disease activity scores or IBD-Control PROMs between baseline and W12. A statistically significant increase in FCP was observed (31µg/g vs. 47µg/g; p=0.008), although this was unlikely to be clinically relevant. The most common adverse drug reaction reported was injection site reactions (15%). Based on this cohort of patients, an expected reduction of £572,000 per annum is likely to be achieved.

Transitioning patients established on IV vedolizumab to SC appears to be safe and effective, with high patient satisfaction and multiple benefits for the health service.
Transitioning patients established on IV vedolizumab to SC appears to be safe and effective, with high patient satisfaction and multiple benefits for the health service.
Gastric bypass (GB) increases postprandial glucose excursion, which in turn can predispose to the late complication of hypoglycemia. Diagnosis remains challenging and requires documentation of symptoms associated with low glucose, and relief of symptom when glucose is normalized (Whipple's triad).

To compare the yield of mixed meal test (MMT) and continuous glucose monitoring system (CGMS) in detecting hypoglycemia after gastric bypass surgery (GB).

The study was conducted at General Clinical Research Unit, Cincinnati Children's Hospital (Cincinnati, OH, United States).

Glucose profiles were evaluated in 15 patients with documented recurrent clinical hypoglycemia after GB, 8 matched asymptomatic GB subjects, and 9 healthy weight-matched non-operated controls using MMT in a control setting and CGMS under free-living conditions.

Patients with prior GB had larger glucose variability during both MMT and CGMS when compared to non-surgical controls regardless of their hypoglycemic status. Sensitivity (71 vs.
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