Miracle-dz/UniFAR-FTUs huggingface dataset:
Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the developed world. Antivascular endothelial growth factor therapy has transformed the management and outcome of neovascular AMD (nAMD), although the need for repeated intravitreal injections—even lifelong—and the related complications, high drug costs, frequent clinic visits and repeated imaging have resulted in an enormous burden both to healthcare systems and patients. The application of gene therapy approaches for sustained delivery of a range of antiangiogenic proteins has the promise of helping to address these aforementioned challenges. A number of early phase clinical trials of gene therapy in nAMD have provided encouraging results, with many more ongoing or anticipated. There remain significant areas of controversy, including regarding the optimal treatment targets, routes of administration and potential safety concerns. In this review we aim to provide an update of the current status of gene therapy for nAMD and briefly discuss future prospects.
In silico methods for drug repositioning and drug-drug interaction prediction

Drug repositioning and drug-drug interaction (DDI) prediction are two fundamental applications having a large impact on drug development and clinical care. Drug repositioning aims to identify new uses for existing drugs. Moreover, understanding harmful DDIs is essential to enhance the effects of clinical care. Exploring both therapeutic uses and adverse effects of drugs or a pair of drugs have significant benefits in pharmacology. The use of computational methods to support drug repositioning and DDI prediction enable improvements in the speed of drug development compared to in vivo and in vitro methods. This thesis investigates the consequences of employing a representative training sample in achieving better performance for DDI classification. The Positive-Unlabeled Learning method introduced in this thesis aims to employ representative positives as well as reliable negatives to train the binary classifier for inferring potential DDIs. Moreover, it explores the importance of a finer-grained similarity metric to represent the pairwise drug similarities. Drug repositioning can be approached by new indication detection. In this study, Anatomical Therapeutic Chemical (ATC) classification is used as the primary source to determine the indications/therapeutic uses of drugs for drug repositioning. This thesis presents a two-tiered clustering approach for obtaining pairwise drug similarity and heterogeneous drug data integration which is employed for large-scale drug repositioning. Moreover, this thesis demonstrates subnetwork identification as a suitable approach for new indication detection for existing drugs. Subnetwork identification method identifies a subgraph from a large drug similarity network, connecting a set of given drugs known as ‘terminals’. In this study, the ‘terminals’ are selected according to the ATC
The Serum Mac-2-binding Protein Glycosylation Isomer Dynamics in Acute Liver Injury

Objective We aimed to examine the dynamics of serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with acute liver injury. Methods Serum M2BPGi levels at the time of the diagnosis (n=77) and normalization of the serum alanine aminotransferase (ALT) level (n=26) were examined retrospectively. The difference in the serum M2BPGi level according to the etiology, and the correlations with other laboratory parameters were evaluated. Results The serum M2BPGi level at the time of the diagnosis was increased in 59 of 77 patients [2.3 cutoff index (COI); range, 0.31-11.1 COI] and was significantly decreased at the time of serum ALT normalization (0.68 COI; range, 0.15-1.87 COI; p<0.0001). The serum M2BPGi level was positively correlated with the duration for which serum ALT normalization was achieved (n=46, Spearman rho=0.53, p<0.0001). A multivariate analysis identified total bilirubin (T-bil), albumin, ALT, alkaline phosphatase, and etiology (e.g., drug-induced liver injury or etiology unknown) as independent factors for increased serum M2BPGi. In patients with infectious mononucleosis, the serum M2BPGi level was higher relative to the degree of increase of serum ALT or T-bil levels in comparison to other etiologies. Conclusion The serum M2BPGi level in patients with acute liver injury reflects the magnitude and duration of liver injury. However, it should be noted that the degree of increase of serum M2BPGi in patients with acute liver injury may differ according to the etiology.
Host suitability in the Diderik cuckoo Chrysococcyx caprius - ploceid brood parasitism breeding system.

Host suitability is critically important to the success of brood parasitism. Parasites must select a host that not only accepts its egg but also is capable of successfully rearing the parasite to fledging. Nearly all brood-parasites appear to avoid low-quality hosts that are likely to reject their eggs, that are of inappropriate size, or that feed their nestlings nutritionally inadequate or insufficient food. The diderik cuckoo, (Chrysococcyx caprius), is an obligate brood parasite known to parasitise a wide spectrum of ploceids, including the yellow weaver (Ploceus subaureus) and the southern red bishop (Euplectes orix). Theory predicts that brood parasites should exploit insectivorous passerines of similar adult size to themselves that provision large quantities of high protein food to their young. However, the relatively smaller granivorous red bishop is the most heavily parasitised host species of the diderik cuckoo in southern Africa. To investigate why an apparently unsuitable host species was so heavily parasitized several populations of parasitised red bishops and yellow weavers (omnivores) were studied in the Pietermaritzburg region, KwaZulu-Natal, South Africa. Host suitability was assessed by examining diet quality, host-provisioning rates, cuckoo nestling growth and cuckoo fledging success. Diderik cuckoo nestlings were provisioned the same diet as the host nestlings in red bishop and yellow weaver nests. However, cuckoos in bishop nests received a protein-deficient seed diet from as early as six days following hatching. In contrast, weaver-cuckoo faeces contained 1~ times more insect than their bishop counterparts throughout their nestling period. Provisioning rates by bishop females were significantly slower than by yellow weavers, and neither bishop nor weaver hosts showed any 'supernormal' effort when feeding a young cuckoo. Both host species provisioned cuckoo nestlings at a similar rate and with a similar food mass as their own nestlings. Diderik cuckoos in bishop nests grew at a slower rate and fledged in a poorer condition than their yellow weaver counterparts. Red bishops are likely the most exploited host of the diderik cuckoo because i) cuckoo eggs are more readily accepted by the less discriminating bishop and ii) the bishop-breeding season coincides more closely with that ofthe diderik cuckoo than the yellow weaver. Thus, diderik cuckoos may preferentially exploit bishop hosts because of the low frequency of cuckoo egg rejection, which ultimately results in many cuckoos fledging from bishop nests despite the lowquality diet provisioned and 53% (n = 53) fledging success in nests of this species. In the yellow weaver system, the protein-rich diet and the greater probability of cuckoo nestling survival (80%, n = 5) may compensate for the high rejection rate of cuckoo eggs by this host. Thus, both host systems seem to represent evolutionary compromises for the diderik cuckoo, with neither red bishops nor yellow weavers being entirely ideal as host species. IV
Genetic variation of mitochondrial DNA in Phalacrocorax carbo in Japan

A Japanese resident bird, Phalacrocorax carbo hanedae (Japanese name: Kawa-u), was threatened with extinction due to deterioration of its habitat in the 1970s, but the population has since recovered thanks to environmental protection measures. This study analyzed the genetic diversity of 18 Kawa-u individuals living in the basins of the Abe and Warashina rivers in Shizuoka Prefecture, Japan. We obtained seven haplotypes of mitochondrial D-loop sequences and compared them with 49 European P. carbo D-loop haplotypes. We identified four new haplotypes but no clear genetic evidence distinguishing the Kawa-u as a distinct subspecies of P. carbo. Our results suggest the need for further surveillance of the P. carbo genetic lineage, regardless of the geographical distribution.
Sleep spindle and K-complex detection using tunable Q-factor wavelet transform and morphological component analysis

A novel framework for joint detection of sleep spindles and K-complex events, two hallmarks of sleep stage S2, is proposed. Sleep electroencephalography (EEG) signals are split into oscillatory (spindles) and transient (K-complex) components. This decomposition is conveniently achieved by applying morphological component analysis (MCA) to a sparse representation of EEG segments obtained by the recently introduced discrete tunable Q-factor wavelet transform (TQWT). Tuning the Q-factor provides a convenient and elegant tool to naturally decompose the signal into an oscillatory and a transient component. The actual detection step relies on thresholding (i) the transient component to reveal K-complexes and (ii) the time-frequency representation of the oscillatory component to identify sleep spindles. Optimal thresholds are derived from ROC-like curves (sensitivity vs. FDR) on training sets and the performance of the method is assessed on test data sets. We assessed the performance of our method using full-night sleep EEG data we collected from 14 participants. In comparison to visual scoring (Expert 1), the proposed method detected spindles with a sensitivity of 83.18% and false discovery rate (FDR) of 39%, while K-complexes were detected with a sensitivity of 81.57% and an FDR of 29.54%. Similar performances were obtained when using a second expert as benchmark. In addition, when the TQWT and MCA steps were excluded from the pipeline the detection sensitivities dropped down to 70% for spindles and to 76.97% for K-complexes, while the FDR rose up to 43.62 and 49.09%, respectively. Finally, we also evaluated the performance of the proposed method on a set of publicly available sleep EEG recordings. Overall, the results we obtained suggest that the TQWT-MCA method may be a valuable alternative to existing spindle and K-complex detection methods. Paths for improvements and further validations with large-scale standard open-access benchmarking data sets are discussed.
Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression

Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab’s effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab’s effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ2 = 9.275, p = 0.026), NF-κB (χ2 = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα)α (χ2 = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ2 = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = −0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.
Linking Motoneuron PIC Location to Motor Function in Closed-Loop Motor Unit System Including Afferent Feedback: A Computational Investigation

Abstract The goal of this study is to investigate how the activation location of persistent inward current (PIC) over motoneuron dendrites is linked to motor output in the closed-loop motor unit. Here, a physiologically realistic model of a motor unit including afferent inputs from muscle spindles was comprehensively analyzed under intracellular stimulation at the soma and synaptic inputs over the dendrites during isometric contractions over a full physiological range of muscle lengths. The motor output of the motor unit model was operationally assessed by evaluating the rate of force development, the degree of force potentiation and the capability of self-sustaining force production. Simulations of the model motor unit demonstrated a tendency for a faster rate of force development, a greater degree of force potentiation, and greater capacity for self-sustaining force production under both somatic and dendritic stimulation of the motoneuron as the PIC channels were positioned farther from the soma along the path of motoneuron dendrites. Interestingly, these effects of PIC activation location on force generation significantly differed among different states of muscle length. The rate of force development and the degree of force potentiation were systematically modulated by the variation of PIC channel location for shorter-than-optimal muscles but not for optimal and longer-than-optimal muscles. Similarly, the warm-up behavior of the motor unit depended on the interplay between PIC channel location and muscle length variation. These results suggest that the location of PIC activation over motoneuron dendrites may be distinctively reflected in the motor performance during shortening muscle contractions.
Human Leukocyte Antigen B*14:01 and B*35:01 Are Associated With Trimethoprim‐Sulfamethoxazole Induced Liver Injury

Trimethoprim (TMP)–sulfamethoxazole (SMX) is an important cause of idiosyncratic drug‐induced liver injury (DILI), but its genetic risk factors are not well understood. This study investigated the relationship between variants in the human leukocyte antigen (HLA) class 1 and 2 genes and well‐characterized cases of TMP‐SMX DILI.
Clinical Practice Guideline: Ménière’s Disease

Objective Ménière’s disease (MD) is a clinical condition defined by spontaneous vertigo attacks (each lasting 20 minutes to 12 hours) with documented low- to midfrequency sensorineural hearing loss in the affected ear before, during, or after one of the episodes of vertigo. It also presents with fluctuating aural symptoms (hearing loss, tinnitus, or ear fullness) in the affected ear. The underlying etiology of MD is not completely clear, yet it has been associated with inner ear fluid (endolymph) volume increases, culminating in episodic ear symptoms (vertigo, fluctuating hearing loss, tinnitus, and aural fullness). Physical examination findings are often unremarkable, and audiometric testing may or may not show low- to midfrequency sensorineural hearing loss. Conventional imaging, if performed, is also typically normal. The goals of MD treatment are to prevent or reduce vertigo severity and frequency; relieve or prevent hearing loss, tinnitus, and aural fullness; and improve quality of life. Treatment approaches to MD are many and typically include modifications of lifestyle factors (eg, diet) and medical, surgical, or a combination of therapies. Purpose The primary purpose of this clinical practice guideline is to improve the quality of the diagnostic workup and treatment outcomes of MD. To achieve this purpose, the goals of this guideline are to use the best available published scientific and/or clinical evidence to enhance diagnostic accuracy and appropriate therapeutic interventions (medical and surgical) while reducing unindicated diagnostic testing and/or imaging.
The home and school environments, physical activity levels, and adiposity indices of school-age children

The home and school environments as well as physical activity may be linked to the development of childhood obesity. We evaluated the home and school environments (HSEs), physical activity levels (PAL), television viewing (TVV) and their associations with adiposity indices of school-age children. This cross-sectional study included children aged 6-12 years and their parents from Tamale, Ghana. HSEs and TVV were assessed using questionnaires. The physical activity questionnaire for children (PAQ-C) was used to assess children’s PALs. Weight, height and waist circumferences were measured using standard tools. About 45% of children lived within a walking distance to parks or outdoor recreation centres. Majority of the parents considered their neighbourhoods to be safe for children to engage in physical activity. Only 27% of the schools had a food and nutrition policy, and more than 70% had a field for outdoor activities. Children watched TV for an average of 1.7 hours/day. Mean physical activity scores was 2.51. The school-age children had mean (SD) BMI-for-age z-scores was -0.23(1.47). Time spent watching TV or playing video games was associated with children’s BMI-for-age z-scores (β=0.48, p=0.043), BMI (β=2.28 p=0.005), and % body fat (β=3.80, p=0.005). Child’s level of activity was negatively associated with waist circumference (β =-0.65, p<0.001). Lack of nutrition policy in schools was common. TVV hours predisposed children to excess weight whiles physical activity decreased the likelihood of being obese.
Hoxd10 and Hoxd11 regulate motor column patterning in the lumbosacral spinal cord

Hox transcription factors have been implicated in many aspects of embryonic rostrocaudal (or anteroposterior) patterning. I have examined the roles of two members of this family, Hoxd10 and Hoxd11, in the development of the lumbosacral (LS) region of the embryonic chick spinal cord. Hoxd10 is expressed uniformly throughout the LS spinal cord at early stages of motoneuron development, but later restricted to subsets of motoneurons in rostral segments. In contrast, Hoxd11 is expressed exclusively in caudal LS segments. Data presented here from overexpression experiments provide evidence that Hoxd10 promotes the development of motoneurons of the lateral subdivision of the lateral motor column (LMCl). Motoneurons transfected with Hoxd10 were likely to acquire a molecular profile, position, and peripheral axonal trajectory consistent with an LMCl identity. In contrast, Hoxd11 suppresses LMCl formation, and imparts a caudal and medial identity upon motoneurons, most likely via repressive interactions with Hoxd10 and the retinoic acid synthetic enzyme RALDH2. To further elucidate the mechanisms governing these opposing actions, I have also created a hybrid protein in which the DNA-binding homeodomain of Hoxd10 is replaced with that of Hoxd11 (Hoxd10d11HD). Hoxd10d11HD, when expressed in LS segments, behaves in a manner similar to Hoxd11, and in direct opposition to Hoxd10, by suppressing the development of the LMCl. It is therefore likely that some of the functionally specific actions of Hoxd11 are governed by the properties of its homeodomain.
Caring for the Psychological Well-Being of Healthcare Professionals in the Covid-19 Pandemic Crisis.

During a pandemic, the demands on healthcare staff are extraordinary and long lasting. Successful public health outcomes are hugely contingent on effective functioning of the healthcare workforce, notwithstanding the absolute need for a whole-of-society response. A full complement of staff with minimum infection-related absenteeism, working to their maximum potential, with low level of work-related burnout is optimal. Attending to staff psychological well-being becomes imperative.
Dasheen Mosaic of Edible and Ornamental Aroids

Published by the College of Tropical Agriculture and Human Resources (CTAHR) and issued in furtherance of Cooperative Extension work, Acts of May 8 and June 30, 1914, in cooperation with the U.S. Department of Agriculture. Andrew G. Hashimoto, Director/Dean, Cooperative Extension Service/CTAHR, University of Hawai‘i at Mänoa, Honolulu, Hawai‘i 96822. An equal opportunity/affirmative action institution providing programs and services to the people of Hawai‘i without regard to race, sex, age, religion, color, national origin, ancestry, disability, marital status, arrest and court record, sexual orientation, or status as a covered veteran. CTAHR publications can be found on the Web site <http://www.ctahr. hawaii.edu/freepubs>. Dasheen Mosaic of Edible and Ornamental Aroids
Gastrointestinal tract and metabolic response of broilers to diets with the Macleaya cordata alkaloid extract.

The ban on the use of antibiotic growth promoters in animal feed in the European Union increased the interest in finding alternative products to replace feed antibiotics. The results of many experiments indicate that natural plant products perform a similar function, e.g. extract containing quaternary benzo [c] phenanthridine alkaloids, mainly sanguinarine (ALLEN, 2003; COWAN, 1999; DORMAN and DEANS, 2000; MANZANILLA et al., 2004). The results of many medical and pharmacological experiments indicate that small doses of sanguinarine extracts exert a wide spectrum of biological activity, including antibacterial, anti-inflammatory and adrenolytic, i.e. blocking the release or action of adrenaline at nerve endings (SIMANEK et al., 2003). Due to the induction of apoptosis in primary effusion lymphoma cells, the sanguinarine demonstrates anticancerogenic activity (CHATURVEDI et al., 1997; HUSSAIN et al., 2007). By suppressing vascular endothelial growth factor, the main regulator of sprouting preexisting vessels, dietary sanguinarine causes an antiangiogenic effect (EUN and KOH, 2004; BASINI et al., 2007). It was also observed that sanguinarine inhibits HIV reverse transcriptases (TAN et al., 1992). In human consuming argemone seeds containing sanguinarine symptomatically poisoning symptoms popularly referred to as Epidemic Dropsy (vomiting, diarrhoea, nausea, swelling of limbs, erythema, pitting edema, breathlessness, ect) were observed (DAS and KHANNA, 1997). In animals consuming a diet with a low content of sanguinarine (2 or 100 mg/kg of diet), no symptoms linked with epidemic drops syndrome nor differences in haematological, biochemical or histological parameters were observed, in comparison with control animals (KOSINA et al., 2004; PSOTOVA et al., 2006). Subchronic studies on rats provided minor evidence of treatment-related toxicity of sanguinarine by doses over 30 mg/kg/day (BECCI et al., 1987). Some experiments with application 25–50 mg/kg of sanguinarine in diet preparation in animal diets resulted in increased secretion of pancreas enzymes (HENSEL, 1993). Due to