Miracle-dz/UniFAR-FTUs huggingface dataset:
Neurokinin receptor antagonism: a patent review (2014-present)

ABSTRACT Introduction The tachykinin family of peptides (substance P, neurokinin A) via the neurokinin-1 (NK-1), NK-2, and NK-3 receptors is involved in many physiological/physiopathological actions. Antagonists of these receptors may be used to treat many human pathologies. Areas covered This review offers an overview (from 2014 to present) of the actions exerted by NK receptor (NK-R) antagonists on emesis, pruritus, cardiomyopathy, respiratory tract diseases, bacterial infection, cancer, ocular pain, corneal neovascularization, excess of body fat/weight, conditioned fear, social isolation stress, hot flush, melanogenesis, follicle development, fish reproduction, and sex-hormone-dependent diseases. Expert opinion From 2014, no invention has been published using NK-2R antagonists. Although the tachykinin/NK receptor system is involved in a great number of mechanisms, to date, the use of only five NK-1R antagonists have been approved in humans but no NK-2R or NK-3R antagonist. NK receptor antagonists are safe in human trials and are potential therapeutic agents, but this potential is currently minimized. In humans, more studies on molecules acting as NK receptor antagonists and exerting a potential therapeutic action must be carried out. The antipruritic or antitumor action of NK-1R antagonists must be explored in greater depth: the highest safe dose and the time of administration (for a long period of time) of these antagonists must be well established.
Biofilm Mode of Cultivation Leads to an Improvement of the Entomotoxic Patterns of Two Aspergillus Species

Two fungi, i.e., Aspergillus flavus Link and Aspergillus oryzae (Ahlb.) E. Cohn, were cultivated according to two methodologies, namely submerged and biofilm cultures with the primary aim to use their secondary metabolites the supernatant CL50, and CL90 varied between 1.3% (v/v) to 12.7% (v/v) for incubation times from 24 to 72 h. While the A. flavus supernatant entomotoxicity was higher than this of A. oryzae, the biofilm culture application increased the efficiency of the former. Proteomic analysis of the supernatants revealed discrepancies among the two species and modes of cultivation. Furthermore, the secondary metabolite profiles of both Aspergillus cultures were verified. Aspergillic acid, beta-cyclopiazonic acid, cyclopiazonic acid, ferrineospergillin, flavacol, and spermadin A were most predominant. Generally, these secondary metabolites were present in higher concentrations in the supernatants of A. flavus and biofilm cultures. These molecular identifications correlated positively with entomotoxic activity. Noteworthy, the absence of carcinogenic aflatoxins was remarkable, and it will allow further valorization to produce A. flavus to develop potential biopesticides.
No Evidence of QoI Resistance in Apple Powdery Mildew (Podosphaera leucotricha)

Sensitivity monitoring studies using detached leaf tests with isolates of Podosphaera leucotricha showed no adaptation to pyraclostrobin in the last years. Sequence analysis of the target gene of QoIs, cytochrome b, of different isolates of P. leucotricha showed the presence of an intron directly after codon 143. This makes the occurrence of the G143A mutation unlikely. On the other hand, intron sequences have not been detected in immediate vicinity to the codons 129 and 137; therefore, the occurrence of those two mutations cannot be excluded. As the effects of these mutations on field performance on QoI fungicides are rather low, the overall resistance risk of P. leucotricha to this fungicide class is estimated to be low. The amplified cytochrome b gene fragments (exons and introns) for samples from different European countries and Australia were highly conserved.
Thermoregulatory sweating and evaporative heat loss during exercise: is the whole greater than the sum of its parts?

where S is body heat storage, M is metabolic rate, W is external work rate and E, C, K and R represent evaporative, convective, conductive and radiant heat losses. Physical activity (exercise) can increase metabolic rate (M) more than twenty-fold, but not all this energy is translated to mechanical work (W), resulting in increased heat production (H, i.e. M – W). Even the most efficient form of human movement (cycling) results in 75% of energy being transferred to heat, yet this heat load can be matched by our powerful heat loss mechanisms (the righthand side of the above equation) to allow exercise to be continued by achieving heat balance, thereby preventing overheating. In a series of experiments Nielsen (1938) methodically demonstrated that an increase in work rate (exercise intensity) and ambient temperature (heat stress) increased both the reliance on evaporative heat loss from the skin ( 80%) to offset this metabolic heat production, and core temperature (derived thermometrically, and the usual index of heat balance), which increased in proportion to work rate despite extensive differences in heat/sweat loss. One can use Nielsen’s results to rearrange the classic heat balance equation to demonstrate that during constant load exercise in a compensable environment (i.e. heat balance can be achieved) steady-state sweat rate is determined by the evaporative requirement for heat balance (Ereq), which is a function of metabolic heat production and the ambient environment, and not body temperature per se:
Evidence for Freeze Tolerance in the Eastern Fence Lizard (Sceloporus undulatus)

Abstract Freeze tolerance is the ability of an organism to survive from water in portions of its body freezing due to molecular, biochemical, physiological, or a combination of these adaptations. Within squamates, freeze tolerance is documented or suspected, based on observations of freezing survival in only five species. I report an observation of survival of short-term freezing in the eastern fence lizard, Sceloporus undulatus. Resumen La tolerancia al congelamiento es definida como la habilidad de un organismo para sobrevivir ileso al congelamiento del agua en partes de su cuerpo, debido a una o varias adaptaciones moleculares, bioquímicas, y fisiológicas. En Squamata, la tolerancia al congelamiento ha sido documentada o sospechada únicamente en cinco especies, basado en observaciones de sobrevivencia al congelamiento. Reporto una observación de tolerancia al congelamiento a corto plazo en la lagartija escamosa de pradera, Sceloporus undulatus.
The Microbiome in Cystic Fibrosis Pulmonary Disease

Cystic fibrosis (CF) is a genetic disease with mutational changes leading to profound dysbiosis, both pulmonary and intestinal, from a very young age. This dysbiosis plays an important role in clinical manifestations, particularly in the lungs, affected by chronic infection. The range of microbiological tools has recently been enriched by metagenomics based on next-generation sequencing (NGS). Currently applied essentially in a gene-targeted manner, metagenomics has enabled very exhaustive description of bacterial communities in the CF lung niche and, to a lesser extent, the fungi. Aided by progress in bioinformatics, this now makes it possible to envisage shotgun sequencing and opens the door to other areas of the microbial world, the virome, and the archaeome, for which almost everything remains to be described in cystic fibrosis. Paradoxically, applying NGS in microbiology has seen a rebirth of bacterial culture, but in an extended manner (culturomics), which has proved to be a perfectly complementary approach to NGS. Animal models have also proved indispensable for validating microbiome pathophysiological hypotheses. Description of pathological microbiomes and correlation with clinical status and therapeutics (antibiotic therapy, cystic fibrosis transmembrane conductance regulator (CFTR) modulators) revealed the richness of microbiome data, enabling description of predictive and follow-up biomarkers. Although monogenic, CF is a multifactorial disease, and both genotype and microbiome profiles are crucial interconnected factors in disease progression. Microbiome-genome interactions are thus important to decipher.
Deep learning for identification of critical regions associated with toxicities after liver stereotactic body radiation therapy.

PURPOSE Radiation therapy (RT) is prescribed for curative and palliative treatment for around 50% of patients with solid tumors. Radiation-induced toxicities of healthy organs accompany many RTs and represent one of the main limiting factors during dose delivery. The existing RT planning solutions generally discard spatial dose distribution information and lose the ability to recognize radiosensitive regions of healthy organs potentially linked to toxicity manifestation. This study proposes a universal deep learning-based algorithm for recognitions of consistent dose patterns and generation of toxicity risk maps for the abdominal area. METHODS We investigated whether convolutional neural networks (CNNs) can automatically associate abdominal computed tomography (CT) images and RT dose plans with post-RT toxicities without being provided segmentation of abdominal organs. The CNNs were also applied to study RT plans, where doses at specific anatomical regions were reduced/increased, with the aim to pinpoint critical regions sparing of which significantly reduces toxicity risks. The obtained risk maps were computed for individual anatomical regions inside the liver and statistically compared to the existing clinical studies. RESULTS A database of 122 liver stereotactic body RT (SBRT) executed at Stanford Hospital from July 2004 and November 2015 was assembled. All patients treated for primary liver cancer, mainly hepatocellular carcinoma and cholangiocarcinoma, with complete follow-ups were extracted from the database. The SBRT treatment doses ranged from 26 to 50 Gy delivered in 1-5 fractions for primary liver cancer. The patients were followed up for 1-68 months depending on the survival time. The CNNs were trained to recognize acute and late grade 3+ biliary stricture/obstruction, hepatic failure or decompensation, hepatobiliary infection, liver function test (LFT) elevation or/and portal vein thrombosis, named for convenience hepatobiliary (HB) toxicities. The toxicity prediction accuracy was of 0.73 measured in terms of the area under the receiving operator characteristic curve. Significantly higher risk scores (p < 0.05) of HB toxicity manifestation were associated with irradiation for the hepatobiliary tract in comparison to the risk scores for liver segments I-VIII and portal vein. This observation is in strong agreement with anatomical and clinical expectations. CONCLUSION In this work, we proposed and validated a universal deep learning-based solution for the identification of radiosensitive anatomical regions. Without any prior anatomical knowledge, CNNs automatically recognized the importance of hepatobiliary tract sparing during liver SBRT.
Alcohol Cue-Induced Ventral Striatum Activity Predicts Subsequent Alcohol Self-Administration.

BACKGROUND Human laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory. METHODS Non-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm. RESULTS Multilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2 = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes. CONCLUSIONS Neuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.
Modulation of cortical slow oscillatory rhythm by GABAB receptors: an in vitro experimental and computational study

We confirm that GABAB receptors (GABAB‐Rs) are involved in the termination of Up‐states; their blockade consistently elongates Up‐states. GABAB‐Rs also modulate Down‐states and the oscillatory cycle, thus having an impact on slow oscillation rhythm and its regularity. The most frequent effect of GABAB‐R blockade is elongation of Down‐states and subsequent decrease of oscillatory frequency, with an increased regularity. In a quarter of cases, GABAB‐R blockade shortened Down‐states and increased oscillatory frequency, changes that are independent of firing rates in Up‐states. Our computer model provides mechanisms for the experimentally observed dynamics following blockade of GABAB‐Rs, for Up/Down durations, oscillatory frequency and regularity. The time course of excitation, inhibition and adaptation can explain the observed dynamics of the network. This study brings novel insights into the role of GABAB‐R‐mediated slow inhibition on the slow oscillatory activity, which is considered the default activity pattern of the cortical network.
Estimating postfire survival of Douglas-fir in the Cascade Range

Factors related to survival of Douglas-fir (Pseudotsugamenziesii (Mirb.) Franco) 2 years after spring wildfires were evaluated at four sites in the Cascade Range. A logistic regression model was developed to estimate postfire survival. Crown scorch and three variables related to bole damage were significant in the regression model, with differences in response among sites attributed to differences in size class. The regression model predicted postfire response of live trees more accurately than that of dead trees, based on estimates of survival probability. Crown scorch was the most significant predictor of tree response, although the importance of additional variables indicated that evaluating bole damage greatly improves postfire survival estimates.
Multiple Paternity and Similar Variance in Reproductive Success of Male and Female Wood Mice (Apodemus sylvaticus) Housed in an Enclosure

The mating system and variance in individual reproductive success in wood mice (Apodemus sylvaticus) were analysed genetically and using observational studies within a large cage system in an outdoor enclosure. Four experimental groups contained four males and four females, each individually marked with a transponder (small computer chips injected under the skin) allowing individual detection of animals underground or within nest boxes without disturbance. The probability of paternity was analysed by comparing frequencies of cohabitation of males and females. In addition, DNA microsatellite analysis revealed reproductive success of each individual. Multiple paternity was found in 85% of all litters, which were sired by up to all four males. Males with a greater body mass, possibly indicative of a higher rank, sired more offspring than those with lower body mass. Interestingly, variance in the reproductive success of males and females did not differ. There was no indication that paternity could be assessed by the time males resided with a female shortly before she became pregnant. Our results indicate wood mice probably have a promiscuous mating system.
Higher methylation subtype of malignant melanoma and its correlation with thicker progression and worse prognosis

Malignant melanoma (MM) is the most life‐threatening disease among all skin malignancies, and recent genome‐wide studies reported BRAF, RAS, and NF1 as the most frequently mutated driver genes. While epigenetic aberrations are known to contribute to the oncogenic activity seen in various cancers, their role in MM has not been fully investigated. To investigate the role of epigenetic aberrations in MM, we performed genome‐wide DNA methylation analysis of 51 clinical MM samples using Infinium 450k beadarray. Hierarchical clustering analysis stratified MM into two DNA methylation epigenotypes: high‐ and low‐methylation subgroups. Tumor thickness was significantly greater in case of high‐methylation tumors than low‐methylation tumors (8.3 ± 5.3 mm vs 4.5 ± 2.9 mm, P = .003). Moreover, prognosis was significantly worse in high‐methylation cases (P = .03). Twenty‐seven genes were found to undergo significant and frequent hypermethylation in high‐methylation subgroup, where TFPI2 was identified as the most frequently hypermethylated gene. MM cases with lower expression levels of TFPI2 showed significantly worse prognosis (P = .001). Knockdown of TFPI2 in two MM cell lines, CHL‐1 and G361, resulted in significant increases of cell proliferation and invasion. These indicate that MM can be stratified into at least two different epigenetic subgroups, that the MM subgroup with higher DNA methylation shows a more progressive phenotype, and that methylation of TFPI2 may contribute to the tumor progression of MM.
From a Food Safety Prospective: The Role of Earthworms as Food and Feed in Assuring Food Security and in Valuing Food Waste

The Sustainable Development Goals are a set of global goals that provide a framework for shared action. These goals also include the reduction of food waste and the definition of sustainable solutions to achieve food security. In this context, the aim of the study was to describe all phases of a pilot earthworm rearing project started in September 2017 and concluded in December 2017, together with a risk analysis carried out in order to evaluate if earthworms can represent a safe and sustainable protein source for human consumption and/or animal nutrition. The conversion rate, that in this study is more appropriately identified as the “waste reduction efficiency,” was also calculated in order to define the extent to which earthworm rearing can contribute to the objective of reducing fruit and vegetable waste (FVW). The results showed that earthworms can bio-convert 3750 kg of FVW in three months producing 1050 kg of compost and 82 kg of fresh earthworms with minimal environmental impact showing good waste reduction efficiency. Moreover, the risk analysis conducted on earthworm rearing highlighted a microbiological hazard after the freeze-drying phase. The critical control point was therefore identified, and, in order to guarantee the total food safety of the finished product, corrective action was taken consisting in the implementation of heat treatment—sterilization at 121 °C for 20 min. The results of microbiological analyses carried out on the earthworm meal after the sterilization treatment showed that the treatment guarantees microbiological safety for the consumer and ensures a balanced approach in relation to two main topics—public health and food-borne diseases. In conclusion, earthworm meal is a concentrate of valuable nutrients useful for human and animal nutrition and can also transform fruit and vegetable waste into a resource.
miR-22-3p regulates muscle fiber-type conversion through inhibiting AMPK/SIRT1/PGC-1α pathway

Abstract MicroRNAs (miRNAs) are a class of conserved non-coding RNAs that are widely regarded as important regulators in a variety of biological processes. Increasing evidence has revealed that skeletal muscle fiber-type conversion is regulated by miRNAs, but the molecular mechanism is still not fully understood. In this study, we confirmed the role of miR-22-3p on skeletal muscle fiber-type conversion and investigated its potential mechanism in C2C12 myotubes. Here, we found that the miR-22-3p mimics inhibited the expressions of myosin heavy chain I (MyHC I), MyHC IIa and promoted the expression of MyHC IIb, while miR-22-3p inhibitor got inverse results. miR-22-3p mimics also downregulated phosphorylated AMPK, SIRT1 and PGC-1ɑ protein levels, which control the expression of oxidative fiber-related genes. Furthermore, Compound C (AMPK inhibitor) eliminated the effect of miR-22-3p inhibitor on MyHC I, MyHC IIa and MyHC IIb expressions. However, AICAR (AMPK activator) also abolished the effect of miR-22-3p mimics on MyHC I, MyHC IIa and MyHC IIb expressions. Collectively, our results suggest that miR-22-3p regulates skeletal muscle fiber-type conversion through inhibiting AMPK/SIRT1/PGC-1ɑ signaling pathway.
Economic evaluation alongside a randomised controlled trial to assess the effectiveness and cost-effectiveness of acupuncture in the management of chemotherapy-induced peripheral neuropathy

Objective To assess the cost-effectiveness of acupuncture in the management of chemotherapy-induced peripheral neuropathy (CIPN) in Hong Kong. Methods A within trial cost-utility analysis with the primary endpoint for the economic evaluation being the Quality Adjusted Life Year (QALY) and associated Incremental Cost Effectiveness Ratio (ICER) over 14 weeks of treatment. A secondary cost-effectiveness analysis was undertaken with the endpoint being change in pain as measured on the Brief Pain Inventory (BPI). Results Eighty-seven patients were randomised to acupuncture or usual care. Acupuncture resulted in significant improvements in pain intensity (8- and 14-week mean changes compared to usual care of −1.8 and −1.8, respectively), pain interference (8- and 14-week mean changes compared to usual care of −1.5 and −0.9, respectively) and indicators of quality of life and neurotoxicity-related symptoms. However, in the economic evaluation there was little difference in QALYs between the two arms (mean change 0.209 and 0.200 in the acupuncture and usual care arms, respectively). Also, costs yielded deterministic ICERs of HK$616,965.62, HK$824,083.44 and HK$540,727.56 per QALY gained from the health care provider perspective, the societal perspective and the patient perspective, respectively. These costs are significantly higher than the cost-effectiveness threshold of HK$180,450 that was used for the base case analysis. Conclusion While acupuncture can improve symptoms and quality of life indicators related to CIPN, it is unlikely to be a cost-effective treatment for CIPN-related pain in health care systems with limited resources. Trial registration number NCT02553863 (ClinicalTrials.gov) post-results.