Bioengineering bacterial encapsulin nanocompartments as targeted drug delivery system

The development of Drug Delivery Systems (DDS) has led to increasingly efficient therapies for the treatment and detection of various diseases. DDS use a range of nanoscale delivery platforms produced from polymeric of inorganic materials, such as micelles, and metal and polymeric nanoparticles, but their variant chemical composition make alterations to their size, shape, or structures inherently complex. Genetically encoded protein nanocages are highly promising DDS candidates because of their modular composition, ease of recombinant production in a range of hosts, control over assembly and loading of cargo molecules and biodegradability. One example of naturally occurring nanocompartments are encapsulins, recently discovered bacterial organelles that have been shown to be reprogrammable as nanobioreactors and vaccine candidates. Here we report the design and application of a targeted DDS platform based on the Thermotoga maritima encapsulin reprogrammed to display an antibody mimic protein called Designed Ankyrin repeat protein (DARPin) on the outer surface and to encapsulate a cytotoxic payload. The DARPin9.29 chosen in this study specifically binds to human epidermal growth factor receptor 2 (HER2) on breast cancer cells, as demonstrated in an in vitro cell culture model. The encapsulin-based DDS is assembled in one step in vivo by co-expressing the encapsulin-DARPin9.29 fusion protein with an engineered flavin-binding protein mini-singlet oxygen generator (MiniSOG), from a single plasmid in Escherichia coli. Purified encapsulin-DARPin_miniSOG nanocompartments bind specifically to HER2 positive breast cancer cells and trigger apoptosis, indicating that the system is functional and specific. The DDS is modular and has the potential to form the basis of a multi-receptor targeted system by utilising the DARPin screening libraries, allowing use of new DARPins of known specificities, and through the proven flexibility of the encapsulin cargo loading mechanism, allowing selection of cargo proteins of choice

Postnatal dexamethasone, respiratory and neurodevelopmental outcomes at two years in babies born extremely preterm.

IMPORTANCE: Postnatal dexamethasone is associated with reduction in bronchopulmonary dysplasia. There remains, however, concern that its short-term benefits are accompanied by long-term adverse effects e.g. poorer neurodevelopmental outcomes. OBJECTIVE: Our aim was to determine the effects of administration of postnatal dexamethasone on respiratory and neurodevelopmental outcome at two years of age after adjusting for neonatal and infant risk factors. MATERIALS AND METHODS: The study included 412 infants born at 23-28 weeks of gestation, 29% had received postnatal dexamethasone. Two outcomes were examined, respiratory hospital admissions in the past 12 months and neurodevelopmental impairment. Logistic regression, adjusted for sex, birthweight z-score, gestation, maternal smoking, oxygen dependency at 36 weeks, airleak, patent ductus arteriosus, pulmonary haemorrhage, major ultrasound abnormality, mode of ventilation and age at assessment, was undertaken. RESULTS: After adjustment, postnatal dexamethasone was associated with significantly increased proportions of both respiratory hospital readmission: (0.35 vs 0.15, difference = 0.20; 95% CI: 0.08, 0.31) and neurodevelopmental impairment (0.59 vs 0.45, difference = 0.14; 95% CI: 0.02, 0.26). CONCLUSIONS: Postnatal dexamethasone use in extremely preterm infants is associated with increased risks of respiratory hospital admissions and neurodevelopmental impairment. These associations were not explained by excess neonatal morbidities

Y-Chromosomal Diversity in Lebanon Is Structured by Recent Historical Events

Lebanon is an eastern Mediterranean country inhabited by approximately four million people with a wide variety of ethnicities and religions, including Muslim, Christian, and Druze. In the present study, 926 Lebanese men were typed with Y-chromosomal SNP and STR markers, and unusually, male genetic variation within Lebanon was found to be more strongly structured by religious affiliation than by geography. We therefore tested the hypothesis that migrations within historical times could have contributed to this situation. Y-haplogroup J∗(xJ2) was more frequent in the putative Muslim source region (the Arabian Peninsula) than in Lebanon, and it was also more frequent in Lebanese Muslims than in Lebanese non-Muslims. Conversely, haplogroup R1b was more frequent in the putative Christian source region (western Europe) than in Lebanon and was also more frequent in Lebanese Christians than in Lebanese non-Christians. The most common R1b STR-haplotype in Lebanese Christians was otherwise highly specific for western Europe and was unlikely to have reached its current frequency in Lebanese Christians without admixture. We therefore suggest that the Islamic expansion from the Arabian Peninsula beginning in the seventh century CE introduced lineages typical of this area into those who subsequently became Lebanese Muslims, whereas the Crusader activity in the 11th–13th centuries CE introduced western European lineages into Lebanese Christians

Long-term impacts of prenatal synthetic glucocorticoids exposure on functional brain correlates of cognitive monitoring in adolescence

The fetus is highly responsive to the level of glucocorticoids in the gestational environment. Perturbing glucocorticoids during fetal development could yield long-term consequences. Extending prior research about effects of prenatally exposed synthetic glucocorticoids (sGC) on brain structural development during childhood, we investigated functional brain correlates of cognitive conflict monitoring in term-born adolescents, who were prenatally exposed to sGC. Relative to the comparison group, behavioral response consistency (indexed by lower reaction time variability) and a brain correlate of conflict monitoring (the N2 event-related potential) were reduced in the sGC exposed group. Relatedly, source localization analyses showed that activations in the fronto-parietal network, most notably in the cingulate cortex and precuneus, were also attenuated in these adolescents. These regions are known to subserve conflict detection and response inhibition as well as top-down regulation of stress responses. Moreover, source activation in the anterior cingulate cortex correlated negatively with reaction time variability, whereas activation in the precuneus correlated positively with salivary cortisol reactivity to social stress in the sGC exposed group. Taken together, findings of this study indicate that prenatal exposure to sGC yields lasting impacts on the development of fronto-parietal brain functions during adolescence, affecting multiple facets of adaptive cognitive and behavioral control

Features of Mild-to-Moderate COVID-19 Patients with Dysphonia

Introduction To explore the prevalence of dysphonia in European patients with mild-to-moderate COVID-19 and the clinical features of dysphonic patients. Methods The clinical and epidemiological data of 702 patients with mild-to-moderate COVID-19 were collected from 19 European Hospitals. The following data were extracted: age, sex, ethnicity, tobacco consumption, comorbidities, general and otolaryngological symptoms. Dysphonia and otolaryngological symptoms were self-assessed through a 4-point scale. The prevalence of dysphonia, as part of the COVID-19 symptoms, was assessed. The outcomes were compared between dysphonic and non-dysphonic patients. The association between dysphonia severity and outcomes was studied through Bayesian analysis. Results A total of 188 patients were dysphonic, accounting for 26.8% of cases. Females developed more frequently dysphonia than males (p=0.022). The proportion of smokers was significantly higher in the dysphonic group (p=0.042). The prevalence of the following symptoms was higher in dysphonic patients compared with non-dysphonic patients: cough, chest pain, sticky sputum, arthralgia, diarrhea, headache, fatigue, nausea and vomiting. The severity of dyspnea, dysphagia, ear pain, face pain, throat pain and nasal obstruction was higher in dysphonic group compared with non-dysphonic group. There were significant associations between the severity of dysphonia, dysphagia and cough. Conclusion Dysphonia may be encountered in a quarter of patients with mild-to-moderate COVID-19 and should be considered as a symptom list of the infection. Dysphonic COVID-19 patients are more symptomatic than non-dysphonic individuals. Future studies are needed to investigate the relevance of dysphonia in the COVID-19 clinical presentation

Li2_2100depl^{100\textrm{depl}}MoO4_4 Scintillating Bolometers for Rare-Event Search Experiments

We report on the development of scintillating bolometers based on lithium molybdate crystals containing molybdenum depleted in the double-$\beta$ active isotope $^{100}$Mo (Li$_2$$^{100\textrm{depl}}$MoO$_4$). We used two Li$_2$$^{100\textrm{depl}}$MoO$_4$ cubic samples, 45 mm side and 0.28 kg each, produced following purification and crystallization protocols developed for double-$\beta$ search experiments with $^{100}$Mo-enriched Li$_2$MoO$_4$ crystals. Bolometric Ge detectors were utilized to register scintillation photons emitted by the Li$_2$$^{100\textrm{depl}}$MoO$_4$ crystal scintillators. The measurements were performed in the CROSS cryogenic set-up at the Canfranc underground laboratory (Spain). We observed that the Li$_2$$^{100\textrm{depl}}$MoO$_4$ scintillating bolometers are characterized by excellent spectrometric performance ($\sim$3--6 keV FWHM at 0.24--2.6 MeV $\gamma$'s), moderate scintillation signal ($\sim$0.3--0.6 keV/MeV depending on light collection conditions) and high radiopurity ($^{228}$Th and $^{226}$Ra activities are below a few $\mu$Bq/kg), comparable to the best reported results of low-temperature detectors based on Li$_2$MoO$_4$ with natural or $^{100}$Mo-enriched molybdenum content. Prospects of Li$_2$$^{100\textrm{depl}}$MoO$_4$ bolometers for use in rare-event search experiments are briefly discussed.Comment: Prepared for submission to MDPI Sensors; 16 pages, 7 figures, and 3 table

Inflammatory pseudo-tumor of the liver: a rare pathological entity

Inflammatory pseudo-tumor (IPT) of the liver is a rare benign neoplasm and is often mistaken as a malignant entity. Few cases have been reported in the literature and the precise etiology of inflammatory pseudotumor remains unknown. Patients usually present with fever, abdominal pain and jaundice. The proliferation of spindled myofibroblast cells mixed with variable amounts of reactive inflammatory cells is characteristics of IPT. We reviewed the literature regarding possible etiology for IPT with a possible suggested etiology

Final results on the 0νββ decay half-life limit of 100^{100} Mo from the CUPID-Mo experiment

The CUPID-Mo experiment to search for 0νββ decay in $^{100}$Mo has been recently completed after about 1.5 years of operation at Laboratoire Souterrain de Modane (France). It served as a demonstrator for CUPID, a next generation 0νββ decay experiment. CUPID-Mo was comprised of 20 enriched Li$_2^{100}$MoO$_4$ scintillating calorimeters, each with a mass of ∼0.2 kg, operated at ∼20 mK. We present here the final analysis with the full exposure of CUPID-Mo ($^{100}$Mo exposure of 1.47 kg×year) used to search for lepton number violation via 0νββ decay. We report on various analysis improvements since the previous result on a subset of data, reprocessing all data with these new techniques. We observe zero events in the region of interest and set a new limit on the $^{100}$Mo 0νββ decay half-life of T$^{0ν}_{1/2}$ >1.8×10$^{24}$ year (stat. + syst.) at 90% CI. Under the light Majorana neutrino exchange mechanism this corresponds to an effective Majorana neutrino mass of ⟨m$_{ββ}$⟩ < (0.28−0.49) eV, dependent upon the nuclear matrix element utilized