The miR-181 family regulates colonic inflammation through its activity in the intestinal epithelium.

The intestinal epithelium is a key physical interface that integrates dietary and microbial signals to regulate nutrient uptake and mucosal immune cell function. The transcriptional programs that regulate intestinal epithelial cell (IEC) quiescence, proliferation, and differentiation have been well characterized. However, how gene expression networks critical for IECs are posttranscriptionally regulated during homeostasis or inflammatory disease remains poorly understood. Herein, we show that a conserved family of microRNAs, miR-181, is significantly downregulated in IECs from patients with inflammatory bowel disease and mice with chemical-induced colitis. Strikingly, we showed that miR-181 expression within IECs, but not the hematopoietic system, is required for protection against severe colonic inflammation in response to epithelial injury in mice. Mechanistically, we showed that miR-181 expression increases the proliferative capacity of IECs, likely through the regulation of Wnt signaling, independently of the gut microbiota composition. As epithelial reconstitution is crucial to restore intestinal homeostasis after injury, the miR-181 family represents a potential therapeutic target against severe intestinal inflammation.

Biodistribution and dosimetry of a single dose of albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC.

INTRODUCTION: PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties. METHODS: Ten patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120-160 µg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers. RESULTS: [177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased. CONCLUSION: Our data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer.

Salivary Gland Disorders in Children and Adolescents: A 15-year Experience

Abstract Introduction Diseases of the salivary glands are rare in children and adolescents, with the exception of viral-induced infections. Objective To determine the clinical course of the disease, the diagnostic procedures, the treatment and the outcome of all children and adolescents affected with salivary gland diseases at our clinic over a period of 15 years. Methods A retrospective chart review including a long-term follow-up was conducted among 146 children and adolescents treated for salivary gland disorders from 2002 to 2016. Results Diagnosing acute sialadenitis was easily managed by all doctors regardless of their specialty. The diagnosis of sialolithiasis was rapidly made only by otorhinolar- yngologists, whereas diagnosing juvenile recurrent parotitis imposed difficulties to doctors of all specialties - resulting in a significant delay between the first occurrence of symptoms and the correct diagnosis. The severity-adjusted treatment yielded improve- ments in all cases, and a full recovery of 75% of the cases of sialolithiasis, 73% of the cases of juvenile recurrent parotitis, and 100% of the cases of acute sialadenitis. Conclusions Due to their low prevalence and the lack of pathognomonic symptoms, salivary gland diseases in children and adolescents are often misdiagnosed, resulting in an unneces- sarily long period of suffering despite a favorable outcome following the correct treatment.

Salivary Gland Disorders in Children and Adolescents: A 15-year Experience.

Introduction Diseases of the salivary glands are rare in children and adolescents, with the exception of viral-induced infections. Objective To determine the clinical course of the disease, the diagnostic procedures, the treatment and the outcome of all children and adolescents affected with salivary gland diseases at our clinic over a period of 15 years. Methods A retrospective chart review including a long-term follow-up was conducted among 146 children and adolescents treated for salivary gland disorders from 2002 to 2016. Results Diagnosing acute sialadenitis was easily managed by all doctors regardless of their specialty. The diagnosis of sialolithiasis was rapidly made only by otorhinolaryngologists, whereas diagnosing juvenile recurrent parotitis imposed difficulties to doctors of all specialties - resulting in a significant delay between the first occurrence of symptoms and the correct diagnosis. The severity-adjusted treatment yielded improvements in all cases, and a full recovery of 75% of the cases of sialolithiasis, 73% of the cases of juvenile recurrent parotitis, and 100% of the cases of acute sialadenitis. Conclusions Due to their low prevalence and the lack of pathognomonic symptoms, salivary gland diseases in children and adolescents are often misdiagnosed, resulting in an unnecessarily long period of suffering despite a favorable outcome following the correct treatment.

Hopanoids, like sterols, modulate dynamics, compaction, phase segregation and permeability of membranes.

In recent years, hopanoids, a group of pentacyclic compounds found in bacterial membranes, are in the spotlight since it was proposed that they induce order in lipid membranes in a similar way cholesterol do in eukaryotes, despite their structural differences. We studied here whether diplopterol (an abundant hopanoid) promoted similar effects on model membranes as sterols do. We analyzed the compaction, dynamics, phase segregation, permeability and compressibility of model membranes containing diplopterol, and compared with those containing sterols from animals, plants and fungi. We also tested the effect that the incubation with diplopterol had on hopanoid-lacking bacteria. Our results show that diplopterol induces phase segregation, increases lipid compaction, and decreases permeability on phospholipid membranes, while retaining membrane fluidity and compressibility. Furthermore, the exposition to this hopanoid decreases the permeability of the opportunistic pathogen Pseudomonas aeruginosa and increases the resistance to antibiotics. All effects promoted by diplopterol were similar to those generated by the sterols. Our observations add information on the functional significance of hopanoids as molecules that play an important role in membrane organization and dynamics in model membranes and in a bacterial system.

Conformational flexibility of DENV NS2B/NS3pro: from the inhibitor effect to the serotype influence.

The dengue virus (DENV) has four well-known serotypes, namely DENV1 to DENV4, which together cause 50-100 million infections worldwide each year. DENV NS2B/NS3pro is a protease recognized as a valid target for DENV antiviral drug discovery. However, NS2B/NS3pro conformational flexibility, involving in particular the NS2B region, is not yet completely understood and, hence, a big challenge for any virtual screening (VS) campaign. Molecular dynamics (MD) simulations were performed in this study to explore the DENV3 NS2B/NS3pro binding-site flexibility and obtain guidelines for further VS studies. MD simulations were done with and without the Bz-nKRR-H inhibitor, showing that the NS2B region stays close to the NS3pro core even in the ligand-free structure. Binding-site conformational states obtained from the simulations were clustered and further analysed using GRID/PCA, identifying four conformations of potential importance for VS studies. A virtual screening applied to a set of 31 peptide-based DENV NS2B/NS3pro inhibitors, taken from literature, illustrated that selective alternative pharmacophore models can be constructed based on conformations derived from MD simulations. For the first time, the NS2B/NS3pro binding-site flexibility was evaluated for all DENV serotypes using homology models followed by MD simulations. Interestingly, the number of NS2B/NS3pro conformational states differed depending on the serotype. Binding-site differences could be identified that may be crucial to subsequent VS studies.

Characterizing biofuel combustion with patterns of real-time emission data (PaRTED).

Emission properties and quantities from combustion sources can vary significantly during operation, and this characteristic variability is hidden in the traditional presentation of emission test averages. As a complement to the emission test averages, we introduce the notion of statistical pattern analysis to characterize temporal fluctuations in emissions, using cluster analysis and frequency plots. We demonstrate this approach by comparing emissions from traditional and improved wood-burning cookstoves under in-field conditions, and also to contrast laboratory and in-field cookstove performance. Compared with traditional cookstoves, improved cookstoves eliminate emissions that occur at low combustion efficiency. For cookstoves where the only improvement is an insulated combustion chamber, this change results in emission of more light-absorbing (black) particles. When a chimney is added, the stoves produce more black particles but also have reduced emission factors. Laboratory tests give different results than in-field tests, because they fail to reproduce a significant fraction of low-efficiency events, spikes in particulate matter (PM) emissions, and less-absorbing particles. These conditions should be isolated and replicated in future laboratory testing protocols to ensure that stove designs are relevant to in-use operation.

Emission factors and real-time optical properties of particles emitted from traditional wood burning cookstoves.

It is estimated that the combustion of biofuel generates 20% of all carbonaceous aerosols, yet these particles are studied less than those of other common sources. We designed and built a portable battery-operated emission-sampling cart to measure the real-time optical properties and other emission characteristics of biofuel cookstoves. In a field study in Honduras, we measured emission factors averaging 8.5 g/kg, higher than those found in previous laboratory studies. Strong flaming events emitted very dark particles with the optical properties of black particles. The elemental carbon to total carbon ratios ranged from 0.07 to 0.64, confirming that high elemental carbon fractions can be emitted from biofuel combustion and may not be used to distinguish fossil-fuel from biofuel sources when cooking is the dominant usage. Absorption Angstrom exponents, representing the dependence of absorption on wavelength, ranged from 1 (black) to 5 (yellow). Strongly absorbing particles with absorption inversely dependent on wavelength were emitted separately from particles with weak absorption and strong wavelength dependence; the latter probably contained conjugated aromatic compounds. Because combustion occurs in distinct phases, different types of carbonaceous aerosols from biofuel combustion are externally mixed at emission and may have different atmospheric fates.

Anti-inflammatory activity of two different extracts of Uncaria tomentosa (Rubiaceae).

We assessed in vivo the anti-inflammatory activity of two Cat's claw bark extracts, by comparing a spray-dried hydroalcoholic extract against an aqueous freeze-dried extract, to determine which extract was more effective. We used the carrageenan-induced paw edema model in mice. In addition, to assess the molecular mechanism of action, we determined the inhibition of NF-kappa B through the Electrophoretic Mobility Shift Assay (EMSA) and the effects on cycloxygenase-1 and -2. Results showed that the anti-inflammatory activity was significantly higher using the hydroalcoholic compared with the aqueous extract (P<0.05). The extracts also showed little inhibitory activity on cyclooxygenase-1 and -2. It cannot be excluded that the slight inhibitory activity on DNA binding of NF-kappa B is due to cytotoxic effects.