Miracle-dz/UniFAR-FTUs huggingface dataset:
Formulation Strategies to Improve Nose-to-Brain Delivery of Donepezil

Donepezil (DPZ) is widely used in the treatment of Alzheimer’s disease in tablet form for oral administration. The pharmacological efficacy of this drug can be enhanced by the use of intranasal administration because this route makes bypassing the blood–brain barrier (BBB) possible. The aim of this study was to develop a nanoemulsion (NE) as well as a nanoemulsion with a combination of bioadhesion and penetration enhancing properties (PNE) in order to facilitate the transport of DPZ from nose-to-brain. Composition of NE was established using three pseudo-ternary diagrams and PNE was developed by incorporating Pluronic F-127 to the aqueous phase. Parameters such as physical properties, stability, in vitro release profile, and ex vivo permeation were determined for both formulations. The tolerability was evaluated by in vitro and in vivo models. DPZ-NE and DPZ-PNE were transparent, monophasic, homogeneous, and physically stable with droplets of nanometric size and spherical shape. DPZ-NE showed Newtonian behavior whereas a shear thinning (pseudoplastic) behavior was observed for DPZ-PNE. The release profile of both formulations followed a hyperbolic kinetic. The permeation and prediction parameters were significantly higher for DPZ-PNE, suggesting the use of polymers to be an effective strategy to improve the bioadhesion and penetration of the drug through nasal mucosa, which consequently increase its bioavailability.
Safety and Efficacy of the Selective Costimulation Modulator Abatacept in Patients with Rheumatoid Arthritis Receiving Background Methotrexate: A 5-year Extended Phase IIB Study

Objective. To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years in patients with rheumatoid arthritis. Methods. Patients were randomized to abatacept 10 or 2 mg/kg or placebo, plus MTX. Patients completing the 1-year, double-blind period entered the longterm extension, where all patients received a fixed dose of abatacept ~10 mg/kg. We describe safety analyses for all patients who received at least 1 dose of abatacept and efficacy analyses for the original ~10 mg/kg abatacept-treated group, over 5 years. Results. Of the 235 abatacept- or placebo-treated patients completing the double-blind period, 219 entered the longterm extension; 130 (59.4%) were continuing at Year 5. No unexpected safety events were observed during the longterm extension compared with the double-blind period. Incidence rates of adverse events (AE) and serious AE were 489.7 and 20.0/100 patient-years in Year 1 versus 374.9 and 18.9/100 patient-years in the cumulative period, respectively. Using exploratory analyses, improvements observed at Year 1 in the 10 mg/kg group were maintained at Year 5, as assessed by ACR responses (ACR20 = 77.1% vs 82.7%; ACR50 = 53.0% vs 65.4%; ACR70 = 28.9% vs 40.4% at Years 1 and 5, respectively) and disease activity (Low Disease Activity State = 48.2% vs 58.5%; Disease Activity Score-28-defined remission = 25.3% vs 45.3% at Years 1 and 5, respectively). Conclusion. Abatacept maintained the efficacy observed at Year 1 over 5 years of treatment, and demonstrated consistent safety and tolerability. These data, along with relatively high retention rates, support the longterm clinical benefit provided by selective T cell costimulation modulation. Clinical trial registry: ClinicalTrials.gov; clinical trial registration number: NCT00254293.
A comparison of DSM‐5 and DSM‐IV agoraphobia in the World Mental Health Surveys

The Diagnostic and Statistical Manual of Mental Disorders, version 5 (DSM‐5) definition of agoraphobia (AG) as an independent diagnostic entity makes it timely to re‐examine the epidemiology of AG. Study objective was to present representative data on the characteristics of individuals who meet DSM‐IV criteria for AG (AG without a history of panic disorder [PD] and PD with AG) but not DSM‐5 criteria, DSM‐5 but not DSM‐IV criteria, or both sets of criteria.
Iron plaque formation in the roots of Pistia stratiotes L.: importance in phytoremediation of cadmium

Abstract Aquatic macrophytes play an important role in the removal of toxic metals from wastewater. Therefore, the induction of Fe plaque on the roots, and its consequences on Cd tolerance investigated in an aquatic macrophyte Pistia stratiotes L. The presence of Fe2+ ion but not Fe3+ resulted in Fe plaque formation. Induction of Fe plaque decreased Ca and increased K and Fe accumulations in the root. Plaque formed plants had accumulated less Cd until 50.0 µM CdCl2 treatments because plaque acted as a barrier to Cd exposure. However, at higher concentrations (500.0 µM CdCl2), plaque formed plants contained more Cd in the roots. Cadmium inducible ion leakage in the root and lowering of the photosynthetic pigment content were less in plants with a plaque. Stretching of aromatic carbonyl groups and alkyl groups among plaque formed plants upon Cd treatments indicated the putative role of phenolics in Cd detoxification.
Decrease of citric acid produced by Aspergillus niger through disruption of the gene encoding a putative mitochondrial citrate-oxoglutarate shuttle protein

ABSTRACT The transporter that exports citric acid (CA) generated in mitochondria to the cytosol is an important component of the CA production machinery of Aspergillus niger. In this report, we cloned and identified the gene cocA, encoding a 33.7-kDa putative mitochondrial citrate-oxoglutarate shuttle protein of the CA hyper-producer A. niger WU-2223L. The amount of CA produced by a representative cocA disruptant (35 g/L) was significantly lower than that produced by strain WU-2223L (63 g/L) after culture for 12 days under CA production conditions, and the phenotype of the cocA disruptant differed in part from that of strain WU-2223L. A cocA disruptant complemented with cocA exhibited the same phenotypes as those of strain WU-2223L. This report is the first to show that cocA and its protein product clearly contribute to substantial CA production by A. niger, and provides a significant insight into microbial organic acid production by fermentation. Abbreviations: CA: citric acid; CD medium: Czapek-Dox medium; CS: citrate synthase; CTP: citrate transport protein; HR: homologous recombination; MCF: mitochondrial carrier family; RT-PCR: reverse-transcription PCR; TCA: tricarboxylic acid Graphical Abstract The gene cocA encoding a putative mitochondrial citrate-oxoglutarate shuttle protein greatly contributes to hyper-production of citric acid by Aspergillus niger.
Retinal Ganglion Cell Topography and Spatial Resolving Power in Penguins

Penguins are a group of flightless seabirds that exhibit numerous morphological, behavioral and ecological adaptations to their amphibious lifestyle, but little is known about the topographic organization of neurons in their retinas. In this study, we used retinal wholemounts and stereological methods to estimate the total number and topographic distribution of retinal ganglion cells in addition to an anatomical estimate of spatial resolving power in two species of penguins: the little penguin, Eudyptula minor, and the king penguin, Aptenodytes patagonicus. The total number of ganglion cells per retina was approximately 1,200,000 in the little penguin and 1,110,000 in the king penguin. The topographic distribution of retinal ganglion cells in both species revealed the presence of a prominent horizontal visual streak with steeper gradients in the little penguin. The little penguin retinas showed ganglion cell density peaks of 21,867 cells/mm2, affording spatial resolution in water of 17.07–17.46 cycles/degree (12.81–13.09 cycles/degree in air). In contrast, the king penguin showed a relatively lower peak density of ganglion cells of 14,222 cells/mm2, but – due to its larger eye – slightly higher spatial resolution in water of 20.40 cycles/degree (15.30 cycles/degree in air). In addition, we mapped the distribution of giant ganglion cells in both penguin species using Nissl-stained wholemounts. In both species, topographic mapping of this cell type revealed the presence of an area gigantocellularis with a concentric organization of isodensity contours showing a peak in the far temporal retina of approximately 70 cells/mm2 in the little penguin and 39 cells/mm2 in the king penguin. Giant ganglion cell densities gradually fall towards the outermost isodensity contours revealing the presence of a vertically organized streak. In the little penguin, we confirmed our cytological characterization of giant ganglion cells using immunohistochemistry for microtubule-associated protein 2. This suite of retinal specializations, which is also observed in the closely related procellariiform seabirds, affords the eyes of the little and king penguins panoramic surveillance of the horizon and motion detection in the frontal visual field.
Clinical and Molecular Characteristics of qacA- and qacB-Positive Methicillin-Resistant Staphylococcus aureus Causing Bloodstream Infections

The increasing use of chlorhexidine for methicillin-resistant Staphylococcus aureus (MRSA) decolonization has raised concerns about the emergence of resistance to these agents. However, the clinical significance of MRSA positive for the qacA and qacB chlorhexidine tolerance genes has not been established. ABSTRACT The increasing use of chlorhexidine for methicillin-resistant Staphylococcus aureus (MRSA) decolonization has raised concerns about the emergence of resistance to these agents. However, the clinical significance of MRSA positive for the qacA and qacB chlorhexidine tolerance genes has not been established. We investigated the clinical features and predictive factors of MRSA bloodstream infection (BSI) isolates, caused by qacA- and qacB-positive MRSA, from 2010 to 2016 at a tertiary hospital in South Korea. A total of 246 MRSA BSI isolates were included; 71 (28.9%) isolates carried qacA/B. The annual frequency of qacA- and qacB-positive MRSA bacteremia did not change significantly over the study period. Patients infected with qacA- and qacB-positive MRSA had common risk factors for health care-associated infections, including prior antibiotic use, central venous catheterization in situ, intensive care unit-acquired bacteremia, and nosocomial infection. The qacA- and qacB-positive isolates were also associated with an increasing chlorhexidine MIC and resistance to non-β-lactam antibiotics. The qacA- and qacB-positive isolates were more likely to belong to sequence type 5 (ST5), which is a common health care-associated MRSA strain in South Korea. In multivariable analyses, qacA- and qacB-positive MRSA isolates were found to be associated with agr dysfunction (adjusted odds ratio [aOR], 6.45; 95% confidence interval [CI], 2.59 to 16.10), ST5 MRSA strain (aOR, 4.96; 95% CI, 1.85 to 13.26), nosocomial infection (aOR, 4.88; 95% CI, 2.20 to 10.83), and antibiotic use within the previous 3 months (aOR, 2.59; 95% CI, 1.20 to 5.59). These findings suggest that the microbiological features of qacA and qacB carriage provide a selective advantage for specific MRSA strains in hospital environments.
Additive manufacturing of patterned 2D semiconductor through recyclable masked growth

Significance Traditional semiconductor fabrication methods, such as lithography and etching, have been sufficient for the needs of integrated circuits over past decades. Their applicability has also been demonstrated in emerging 2D materials, which offers facile processing over large lateral dimensions, while unique and remarkable properties due to the confinement within atomic thicknesses. Nevertheless, each fabrication step adds cost to the manufacturing and increases the possibility of quality degradation. Here, we developed a method to directly synthesize arbitrary monolayer molybdenum disulfide patterns with high spatial resolution, excellent homogeneity, and electrical performance on insulating SiO2/Si. Significantly, our on-demand method allows for the repeated growth of patterned 2D materials with preserved structural integrity and material qualities, paving the way for simpler and cost-effective fabrication. The 2D van der Waals crystals have shown great promise as potential future electronic materials due to their atomically thin and smooth nature, highly tailorable electronic structure, and mass production compatibility through chemical synthesis. Electronic devices, such as field effect transistors (FETs), from these materials require patterning and fabrication into desired structures. Specifically, the scale up and future development of “2D”-based electronics will inevitably require large numbers of fabrication steps in the patterning of 2D semiconductors, such as transition metal dichalcogenides (TMDs). This is currently carried out via multiple steps of lithography, etching, and transfer. As 2D devices become more complex (e.g., numerous 2D materials, more layers, specific shapes, etc.), the patterning steps can become economically costly and time consuming. Here, we developed a method to directly synthesize a 2D semiconductor, monolayer molybdenum disulfide (MoS2), in arbitrary patterns on insulating SiO2/Si via seed-promoted chemical vapor deposition (CVD) and substrate engineering. This method shows the potential of using the prepatterned substrates as a master template for the repeated growth of monolayer MoS2 patterns. Our technique currently produces arbitrary monolayer MoS2 patterns at a spatial resolution of 2 μm with excellent homogeneity and transistor performance (room temperature electron mobility of 30 cm2 V−1 s−1 and on–off current ratio of 107). Extending this patterning method to other 2D materials can provide a facile method for the repeatable direct synthesis of 2D materials for future electronics and optoelectronics.
A Puna Collection of Senecio punae, Main Source of a Versatile Eremophilane-type Ketone

Senecio punae Cabrera (Asteraceae-Senecioneae) is an endemic species from Puna semi-desert region of Argentina. The major compound, 4β,5β-eremophil-7(11)9-dien-8-one, also known as dehydrofukinone (D), was isolated from the diethyl ether extract (E) of the plant. The phytochemical constituents from S punae are presented here for the first time, as well as bioassays employing D, a molecule with versatility to carry out many different biological activities. E and D showed acute molluscicidal activity against the bilharzia vector snail Biomphalaria peregrina with LD50 values of 68.6 and 16.7 μg/mL, respectively. D exerted moderate and strong effects against promastigotes of Leishmania amazonensis and L. braziliensis, with IC50 values of 34.3±1.2 and 9.93±0.17 μg/mL, respectively. Antibacterial effects were also found. Diethyl ether extract (E) and dehydrofukinone (D) were slightly active against Pseudomonas aeruginosa and Staphylococcus aureus at 50 and 25 μg/mL, respectively. However, D and E improved the effectiveness of oxacillin at 6 μg/mL against S aureus growth and its biofilm, but did not affect beneficial lactobacilli strains. Synergistic effects were also measured between D (23 μg/mL) and ciprofloxacin (0.25 μg/mL) against two P. aeruginosa strains (FIC index = 0.38), as well as against two S aureus strains (FIC indexes = 0.38 and 0.25). Finally, when 250 μg of either dehydrofukinone (D) or diethyl ether extract (E) were incorporated into the diet of the pest Oryzaephillus surinamensis, an alteration in the feeding behavior of the insect (Repellency indexes = +60 and +10, respectively) was observed.
Long-term results of secondary biliary repair for cholecystectomy-related bile duct injury: results of a tertiary referral center

Abstract Background: Management of bile duct injury (BDI) after cholecystectomy is challenging. The authors analyzed their center’s 49-year experience. Methods: From 1968 to 2016, 120 consecutive patients were managed in a tertiary HBP center, 105 referred from other centers (Group A), 15 from our center (Group B). Surgical strategies and long-term outcomes were retrospectively reviewed. Results: Primary cholecystectomy approach was open in 35% and laparoscopic in 65%. In Group A, intraoperative BDI diagnosis was made in 25/105 patients, including 13 via intraoperative cholangiography (IOC) which was used in 21% of cases. Median time from BDI to referral was 148 days (range 0–10,758), and 3 patients had BDI-related secondary cirrhosis. Ninety-four patients underwent secondary surgical repair, mostly a complex biliary procedure (97%). Postoperative overall and severe morbidity rates were 26% and 6%, respectively. One patient with biliary cirrhosis at referral died postoperatively from hepatic failure. Nine patients (9.6%) developed a secondary biliary stricture after a median of 54 months from repair (6–228 months). In Group B, IOC was performed in 14/15 in whom BDI were intraoperatively detected and immediately repaired. There were 13 minor and 2 major BDIs, all repaired by uncomplex procedures with uneventful postoperative course. One patient had a secondary biliary stricture after 5 months, successfully treated by temporary endoprosthesis. Conclusion: Late follow-up after primary or secondary repair of BDI is recommended to detect recurrent biliary stricture. Bile duct injuries may occur in a tertiary center, but are intraoperatively detected with routine IOC and immediately repaired resulting in satisfactory outcome.
Navigation and the developing brain

ABSTRACT As babies rapidly acquire motor skills that give them increasingly independent and wide-ranging access to the environment over the first two years of human life, they decrease their reliance on habit systems for spatial localization, switching to their emerging inertial navigation system and to allocentric frameworks. Initial place learning is evident towards the end of the period. From 3 to 10 years, children calibrate their ability to encode various sources of spatial information (inertial information, geometric cues, beacons, proximal landmarks and distal landmarks) and begin to combine cues, both within and across systems. Geometric cues are important, but do not constitute an innate and encapsulated module. In addition, from 3 to 10 years, children build the capacity to think about frames of reference different from their current one (i.e. to perform perspective taking). By around 12 years, we see adult-level performance and adult patterns of individual differences on cognitive mapping tasks requiring the integration of vista views of space into environmental space. These lines of development are continuous rather than stage-like. Spatial development builds on important beginnings in the neural systems of newborns, but changes in experience-expectant ways with motor development, action in the world and success–failure feedback. Human systems for integrating and manipulating spatial information also benefit from symbolic capacities and technological inventions. Summary: Spatial development in humans takes a decade or more to unfold, and involves tuning initial systems in response to changing motor capacities and environmental feedback.
Immunotherapy in tyrosine kinase inhibitor-naïve advanced epidermal growth factor receptor-mutant non-small cell lung cancer-driving down a precarious road in driver-mutated lung cancer.

In patients with advanced non-small cell lung cancer (NSCLC) whose tumour harbour a sensitising epidermal growth factor receptor (EGFR) mutation, international guidelines recommend first-line therapy with an EGFR tyrosine kinase inhibitor (TKI) due to longer progression free survival (PFS), higher overall response rate (ORR) and improved quality of life compared to platinum doublet chemotherapy (1,2).
The efficacy, sensitivity, and specificity of strip meniscometry in conjunction with tear function tests in the assessment of tear meniscus.

PURPOSE To evaluate the specificity and sensitivity of strip meniscometry (SM) testing in conjunction with tear function tests in the diagnosis of dry eye (DE) disease and to investigate the effect of SM on reflex tearing. METHODS One hundred seven left eyes of 107 patients with definite DE disease according to the Japanese DE diagnostic criteria and 68 left eyes of 68 age- and sex-matched control subjects were studied. Tear meniscus height (TMH) measurements, fluorescein tear film break-up time (FTBUT), fluorescein (F) and rose bengal (RB) staining, and Schirmer's test-1 (ST) were also performed. The assessment of reflex tearing before and after SM application was assessed with a graticule scale at the slit lamp and by optical coherence tomography. The sensitivity and specificity of SM alone and in combination with tear function tests were also sought. RESULTS The SM scores, TMH measurements, FTBUTs, and STs were significantly lower in dry eye patients than in the controls (P < 0.001). The RB and F staining scores were significantly higher in the dry eye group than in the control group (P < 0.001). The meniscometry strips did not induce significant changes in relation to reflex tearing. SM had an acceptable sensitivity and specificity. CONCLUSIONS SM is a swift, noninvasive, promising method of assessing tear meniscus volume. The combined SM and FTBUT examination appears to be a sensitive approach to the assessment of dry eye disease.
A surface‐in gradient of thalamic damage evolves in pediatric multiple sclerosis

Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface‐in" process of injury suggesting progressive biology may begin.
Social Integration and Indigenous Suicidality

Aspects of social integration including religion and residential stability have often been found to serve as protective factors against suicide in sociological analyses. However, empirical research on Canadian indigenous suicidality has neglected these dimensions of integration. The present study fills this gap, while controlling for other major predictors of suicide ideation (SI). Methods: Data are from a national representative sample (N = 15,294) from the 2012 Aboriginal Peoples Survey. The dependent variable is a dichotomy: lifetime prevalence of SI. Measures of social integration include religious affiliation, marital status, family ties, and residential stability. Controls are incorporated for alternative predictors of SI including psychiatric symptoms (e.g., mood disorder), economic strain, ethnicity, and demographics. Results: Findings from a multivariate logistic regression analysis confirmed an association between SI and most measures of social integration (e.g., married persons were 14% less apt to report SI than non married persons), but not with religious affiliation. Further, each unit increase in income reduced the risk of SI by 3.8%. Psychiatric symptoms increased risk of SI (e.g., mood disorder, OR = 3.16, substance abuse, OR = 2.38), and Inuit ethnicity increased SI risk by 57% (OR = 1.57). The model explained 26.1% of the variance in SI. Conclusions: Generally, measures of social integration, psychiatric symptoms, and economic strain predicted SI. However, there was no evidence that religion acted as a protective factor against SI. Future research is needed on other dimensions of religion such as self-reported religiousness, which may protect against suicidality.