Miracle-dz/UniFAR-FTUs huggingface dataset:
Review: Examining the Natural Role of Amphibian Antimicrobial Peptide Magainin

Host defense peptides (HDPs) are a group of antimicrobial peptides (AMPs) that are crucial components of the innate immune system of many different organisms. These small peptides actively kill microbes and prevent infection. Despite the presence of AMPs in the amphibian immune system, populations of these organisms are in decline globally. Magainin is an AMP derived from the African clawed frog (Xenopus laevis) and has displayed potent antimicrobial effects against a wide variety of microbes. Included in this group of microbes are known pathogens of the African clawed frog and other amphibian species. Arguably, the most deleterious amphibious pathogen is Batrachochytrium dendrobatidis, a chytrid fungus. Investigating the mechanism of action of magainin can help understand how to effectively fight off infection. By understanding amphibian AMPs’ role in the frog, a potential conservation strategy can be developed for other species of amphibians that are susceptible to infections, such as the North American green frog (Rana clamitans). Considering that population declines of these organisms are occurring globally, this effort is crucial to protect not only these organisms but the ecosystems they inhabit as well.
CATH: increased structural coverage of functional space

Abstract CATH (https://www.cathdb.info) identifies domains in protein structures from wwPDB and classifies these into evolutionary superfamilies, thereby providing structural and functional annotations. There are two levels: CATH-B, a daily snapshot of the latest domain structures and superfamily assignments, and CATH+, with additional derived data, such as predicted sequence domains, and functionally coherent sequence subsets (Functional Families or FunFams). The latest CATH+ release, version 4.3, significantly increases coverage of structural and sequence data, with an addition of 65,351 fully-classified domains structures (+15%), providing 500 238 structural domains, and 151 million predicted sequence domains (+59%) assigned to 5481 superfamilies. The FunFam generation pipeline has been re-engineered to cope with the increased influx of data. Three times more sequences are captured in FunFams, with a concomitant increase in functional purity, information content and structural coverage. FunFam expansion increases the structural annotations provided for experimental GO terms (+59%). We also present CATH-FunVar web-pages displaying variations in protein sequences and their proximity to known or predicted functional sites. We present two case studies (1) putative cancer drivers and (2) SARS-CoV-2 proteins. Finally, we have improved links to and from CATH including SCOP, InterPro, Aquaria and 2DProt.
Clinical characteristics and outcomes among 2347 patients aged ≥85 years with major lymphoma subtypes: a Nordic Lymphoma Group study

There is a lack of data regarding treatment and prognosis for the growing group of oldest old patients with lymphoma. Therefore, we studied 2347 patients aged ≥85 years from the Danish and Swedish lymphoma registers 2000–2016 (Denmark) and 2007–2013 (Sweden). Outcome was assessed using relative survival (RS). The 2‐year RS overall for patients with aggressive lymphomas was 38% [95% confidence interval (CI) 35–42%], of whom 845 (66%) patients received active treatment (chemotherapy, radiotherapy, immunotherapy, other). For aggressive lymphomas, not receiving active treatment was associated with an inferior 2‐year RS of 12% (95% CI 9–17%) compared to 49% (95% CI 45–53%) for patients who received active treatment (excess mortality rate ratio 2·84, 95% CI 2·3–3·5; P < 0·0001). For patients with indolent lymphoma, the 2‐year RS was 77% (95% CI 72–82%). Here, 383 (46%) patients received active treatment at diagnosis, but did not have better 2‐year RS (75%, 95% CI 67–81%) compared to those who did not receive active treatment (83%, 95% CI 74–89%). We conclude that outcomes for the oldest old patients with lymphoma are encouraging for several subtypes and that active treatment is associated with improved outcome amongst the oldest old patients with aggressive lymphomas, indicating that age itself should not be a contraindication to treatment.
Mechanisms for the Clinical Utility of Low‐Frequency Stimulation in Neuromodulation of the Dorsal Root Ganglion

Dorsal root ganglion stimulation (DRG‐S) involves the electrical modulation of the somata of afferent neural fibers to treat chronic pain. DRG‐S has demonstrated clinical efficacy at frequencies lower than typically used with spinal cord stimulation (SCS). In a clinical study, we found that the frequency of DRG‐S can be tapered to a frequency as low as 4 Hz with no loss of efficacy. This review discusses possible mechanisms of action underlying effective pain relief with very low‐frequency DRG‐S.
A systematic review and meta-analysis

Abstract The autonomic nervous system (ANS)maintains homeostasis in the gastrointestinal tract, including immunity, inflammation andmotility, through the brain-gut axis. To date, the associations between ANS function and inflammatory bowel disease (IBD) have been controversial and inconclusive in human studies. PubMed, Cochrane Library, and Embase were searched through February 2020 for articles reporting these association between heart rate variability (HRV), an indirect measure of ANS activity, and IBD. The standardized mean differences and 95% confidence intervals (CIs) were calculated. Ten eligible studies involving 273 ulcerative colitis patients, 167 Crohn’sdiseasepatients and208healthy controlswere included. Thevaluesof the total power (SMD= 0.83, 95%CI= 1.44, 0.21), high frequency (SMD= 0.79, 95%CI= 1.20, 0.38), RR interval (SMD= 0.66, 95%CI= 1.04, 0.27), standard deviation of the RR intervals (SMD= 1.00, 95%CI= 1.73, 0.27), percentage of RR intervals with a greater than 50-millisecond variation (SMD= 0.82, 95% CI= 1.33, 0.30) and the square root of the mean squared differences in successive RR intervals (SMD= 0.71, 95% CI= 1.15, 0.26) of the IBDpatientswere lower than those of the healthy controls, andmoderate to large effect sizeswere observed in all HRV indices, except for low frequency (SMD= 0.41, 95%CI=0.95, 0.13). IBD was strongly associated with an overall decrease in HRV, indicating substantially decreasedANS activity. Furthermore, the parasympathetic nerve displayed a stronger inverse association with ANS activity than the sympathetic nerve, indicating ANS dysfunction in patients with IBD.
Latency of Multifocal Visual Evoked Potential in Multiple Sclerosis: A Visual Pathway Biomarker for Clinical Trials of Remyelinating Therapies

Purpose: Acute focal demyelination is the characteristic feature of multiple sclerosis, with the majority of damaged axons undergoing limited remyelination and forming chronic lesions. Potential remyelinating agents are currently under development and there is therefore an urgent need for reliable in vivo biomarkers of remyelination. This study aimed to investigate potential changes in multifocal visual evoked potentials' (mfVEPs) latency in a cohort of relapsing–remitting multiple sclerosis (RRMS) patients. The potential sample size required for a remyelination-based clinical trial using different treatment effect sizes and the mfVEP latency as an outcome measure was also estimated. Methods: A total of 50 RRMS consecutive patients with no previous history of optic neuritis in at least one eye and 15 normal controls of similar age and gender composition were prospectively enrolled. Fifteen patients had a history of unilateral ON more than 12 months earlier, whereas 41 patients demonstrated optic radiations lesions on MRI at baseline. Most patients were on disease modifying therapy. A mfVEP was recorded at baseline and 12 months later. Results: At baseline, the mfVEP latency in RRMS patients was delayed compared with normal controls in both optic neuritis and nonoptic neuritis eyes. Latency delay was significantly correlated to optic radiation lesion volume (R2 = 0.38, P < 0.001). There was no significant latency change in multiple sclerosis patients' eyes or optic neuritis and nonoptic neuritis eyes over the follow-up period with latency remaining remarkably constant. This was despite the fact that 46 of 50 patients were on disease-modifying therapies, implying current treatments do not affect myelination in chronic RRMS cases. Sample size calculations to evaluate an additional or alternative remyelinating agent, based on a 40% treatment effect, revealed that a relatively small sample size (78 patients) would be required to demonstrate efficacy in future trials of remyelination therapies. Conclusions: Given its known sensitivity for latency changes and the stability found in this RRMS population, the mfVEP represents an ideal biomarker to assess the degree of latency recovery that may be achieved by remyelination in multiple sclerosis.
Dynamic ordering design for dose finding in drug‐combination trials

Drug‐combination studies have become increasingly popular in oncology. One of the critical concerns in phase I drug‐combination trials is the uncertainty in toxicity evaluation. Most of the existing phase I designs aim to identify the maximum tolerated dose (MTD) by reducing the two‐dimensional searching space to one dimension via a prespecified model or splitting the two‐dimensional space into multiple one‐dimensional subspaces based on the partially known toxicity order. Nevertheless, both strategies often lead to complicated trials which may either be sensitive to model assumptions or induce longer trial durations due to subtrial split. We develop two versions of dynamic ordering design (DOD) for dose finding in drug‐combination trials, where the dose‐finding problem is cast in the Bayesian model selection framework. The toxicity order of dose combinations is continuously updated via a two‐dimensional pool‐adjacent‐violators algorithm, and then the dose assignment for each incoming cohort is selected based on the optimal model under the dynamic toxicity order. We conduct extensive simulation studies to evaluate the performance of DOD in comparison with four other commonly used designs under various scenarios. Simulation results show that the two versions of DOD possess competitive performances in terms of correct MTD selection as well as safety, and we apply both versions of DOD to two real oncology trials for illustration.
Elevated intracranial pressure induces IL-1β and IL-18 overproduction via activation of the NLRP3 inflammasome in microglia of ischemic adult rats

Elevated intracranial pressure (ICP) is one of the most common complications following an ischemic stroke, and has implications for the clinical and neurological outcomes. The aim of the present study was to examine whether elevated ICP may increase IL-1β and IL-18 secretion by activating the NOD-like receptor protein 3 (NLRP3) inflammasome in microglia of ischemic adult rats. Sprague-Dawley rats that underwent middle cerebral artery occlusion were used for assessment of ICP. Reactive oxygen species (ROS) production was detected, and western blotting and immunofluorescence staining were used to determine the expression levels of Caspase-1, gasdermin D-N domains (GSDMD-N), IL-1β and IL-18 in microglial cells. ICP levels were significantly increased, which was accompanied by ROS overproduction, in the brain tissue following ischemia-reperfusion (IR) injury in rats. Treatment with 10% hypertonic saline by intravenous injection significantly reduced the ICP and ROS levels of the rats. Furthermore, high pressure (20 mmHg) combined with oxygen-glucose deprivation (OGD) treatment resulted in increased ROS production in BV-2 microglial cells compared with those subjected to OGD treatment alone in vitro. Elevated pressure upregulated the expression of Caspase-1, GSDMD-N, IL-18 and IL-1β in IR-treated or OGD-treated microglia both in vivo and in vitro. More importantly, Caspase-1, GSDMD-N, IL-18 and IL-1β expression in microglia was significantly downregulated when elevated pressure was reduced or removed. These results suggested that elevated ICP-induced IL-1β and IL-18 overproduction via activation of the NLRP3 inflammasome by ischemia-activated microglia may augment neuroinflammation.
Effect of capsaicin on the protozoan parasite Trypanosoma cruzi.

Trypanosoma cruzi is the causative agent of Chagas disease. There are only two approved treatments, both of them unsuitable for the chronic phase, therefore the development of new drugs is a priority. T. cruzi arginine kinase (TcAK) is a promising drug target since it is absent in humans and it is involved in cellular stress responses. In a previous study, possible TcAK inhibitors were identified through computer simulations resulting the best compounds capsaicin and cyanidin derivatives. Here we evaluate the effect of capsaicin on TcAK activity and its trypanocidal effect. Although capsaicin produced a weak enzyme inhibition, it had a strong trypanocidal effect on epimastigotes and trypomastigotes (IC50 = 6.26 µM and 0.26 µM, respectively) being 20-fold more active on trypomastigotes than mammalian cells. Capsaicin was also active on the intracellular cycle reducing by half the burst of trypomastigotes at approximately 2 µM. Considering the difference between the concentrations at which parasite death and TcAK inhibition occur, other possible targets were predicted. Capsaicin is a selective trypanocidal agent active in nanomolar concentrations, with an IC50 57-fold lower than benznidazole, the drug currently used for treating Chagas disease.
The Search for New Anticonvulsants in a Group of (2,5-Dioxopyrrolidin-1-yl)(phenyl)Acetamides with Hybrid Structure—Synthesis and In Vivo/In Vitro Studies

Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound 30 (median effective dose (ED50) MES = 45.6 mg/kg, ED50 6 Hz (32 mA) = 39.5 mg/kg, median toxic dose (TD50) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound 30 was also proven effective in the formalin test of tonic pain, the capsaicin-induced pain model, and the oxaliplatin (OXPT)-induced neuropathic pain model in mice. Our studies showed that the most plausible mechanism of action of 30 involves inhibition of calcium currents mediated by Cav1.2 (L-type) channels. Importantly, 30 revealed high metabolic stability on human liver microsomes, negligible hepatotoxicity, and relatively weak inhibition of CYP3A4, CYP2D6, and CYP2C9 isoforms of cytochrome P450, compared to reference compounds. The promising in vivo activity profile and drug-like properties of compound 30 make it an interesting candidate for further preclinical development.
Lucidity in the Context of Advanced Neurodegenerative Disorders: A Concept Analysis.

Individuals with advanced dementias resulting from neurodegenerative disorders (NDs) occasionally surprise caregivers with episodes of clarity and cognitive function that are not usually present. Lucid episodes-aptly named paradoxical lucidity in the literature-seem to involve a return of the "old self" during advanced neurodegenerative changes. Lucid episodes pose a problem for theories of neurological degeneration, which position dementias as progressive, incurable, and irreversible. In addition, lucid episodes raise ethical questions about whether information gleaned during lucid episodes is appropriate to direct future patient-centered care. The concept requires analysis and clarification if it is to guide future theorizing and research. The underlying goals of the current concept analysis are twofold: (a) to clarify the meaning of lucidity in the context of advanced NDs; and (b) to develop a theoretical definition that can guide future practice, research, and policy development. Walker and Avant's method is used to identify uses of the concept, defining attributes, antecedents, consequences, and empirical referents. [Journal of Gerontological Nursing, 46(12), 42-50. ].
Quantifying alcohol use among Ecuadorian human immunodeficiency virus positive individuals and assessing alcohol as an independent risk factor for human immunodeficiency virus

Abstract Alcohol abuse has been identified as a risk factor for contracting human immunodeficiency virus (HIV) and accelerating disease progression. Our study aims to determine alcohol consumption rates among Ecuadorian HIV positive (HIV+) patients prior to diagnosis to evaluate its impact as an independent risk factor for contracting HIV. Additionally, we will examine post-diagnosis consumption rates among the HIV+ population. We provided anonymous questionnaires to 300 HIV+ patients and 600 internal medicine patients at 3 hospitals in Quito, Ecuador. Questionnaires quantified alcohol usage prior to HIV diagnosis, at time of diagnosis, and post-diagnosis while accounting for other potential HIV risk factors. We then determined frequencies of alcohol consumption and confounding variables. Finally, we performed a multivariable logistic regression controlling for confounders to determine the statistical significance of alcohol consumption as an independent risk factor for HIV. Our results showed increased odds for contracting HIV among those who drank daily (OR 5.3, CI 2.0–14.0) and those who consumed 6 or more alcoholic beverages on days they drank (OR 5.0, CI 3.1–8.2). Through multivariable analysis, we found that abstaining from binge drinking was a protective factor with an OR 0.5 (0.3–0.96). The percentage of HIV+ patients abstaining from alcohol increased from 30% twelve months prior to diagnosis to 57% after diagnosis. Our results show that alcohol abuse significantly increases the risk of contracting HIV. We found that prior to diagnosis, HIV patients consistently drank more frequently and a greater amount than the control group. Alcohol use significantly decreased among HIV+ patients after diagnosis.
Bacterioplankton response to nitrogen and dissolved organic matter produced from salmon mucus

Aquaculture releases organic matter to the water column through excretion, fecal pellets, and uneaten food, but also by the continuous release of fish epithelium mucus. The effect of the latter on natural bacterial assemblages was determined using ammonium amended experiments at Puyuhuapi fjord in Chilean Patagonia. Mucus was added to seawater coming from 2 and 100 m depth and ammonium, nitrite and nitrate, dissolved organic carbon (DOC), picoplankton abundance, and active composition (i‐tag 16S rRNA) were followed for 24 h. The results showed a significant response from the microbial community but only at surface depth after 2 and 6 h of incubation. A reduction of DOC and ammonium concentration and accumulation of nitrite and nitrate over time was observed, mainly at 100 m. Changes in the composition of active bacteria between treatments were observed at different taxonomic levels, associated with Alphaproteobacteria (Clade SAR11), Bacteroidetes (Polaribacter) and Gammaproteobacteria (Colwellia, Oceaniserpentilla) and other bacteria such as Nitrospina sp, a nitrite‐oxidizing bacteria at some hours during the incubation. Fish pathogens, such as Vibrio and Piscirickettsia were rare (<0.02%). Overall, our study suggests that fish mucus can cause rapid modifications in microbial assemblages and stimulate organic matter and nutrient cycling, including heterotrophic and autotrophic (nitrification) in areas influenced by aquaculture.
Long-term outcomes of liver resection for multiple hepatocellular carcinomas: Single-institution experience with 187 patients

Backgrounds/Aims Surgical resection for the treatment of multiple hepatocellular carcinomas (HCCs) is controversial. This study aimed to evaluate the clinical and oncological outcomes after liver resection in patients with multiple HCCs. Methods Clinicopathological and survival data of 187 patients who underwent curative resection for multiple HCCs between June 2004 and December 2016 at Asan Medical Center, Seoul, South Korea were retrospectively reviewed. The prognostic factors for recurrence and survival were identified using univariate and multivariate analyses. Results Of the 187 patients, 153 (81.8%) had two nodules, 23 (12.3%) had three nodules, and 11 (5.9%) had more than three nodules. Multiple tumors were located in the ipsilateral lobe in 163 (87.2%) patients. Anatomical resection, non-anatomical resection, and both types of resections were performed in 81.3%, 8.0%, and 10.7% patients, respectively. Recurrence occurred in 133 (71.1%) patients, and the mean time to recurrence after surgery was 34.2 months. Independent risk factors for tumor recurrence in multivariate analyses were indocyanine green retention rate at 15 min ≥15%, preoperative alpha-fetoprotein level ≥400 ng/ml, and total tumor diameter ≥6 cm. The 1-, 3-, 5-, and 10-year disease-free survival rates were 94.1%, 81.7%, 69.7%, and 39.4%, respectively, and the 1-, 3-, 5-, and 10-year survival rates were 93.5%, 74.2%, 64.9%, and 38.8%, respectively. Conclusions Our experience shows that liver resection can be considered a first-line treatment option for selected patients with multiple HCCs who have well-preserved liver function.
Characteristics and Outcome for Persons with Diabetic Foot Ulcer and No-Option Critical Limb Ischemia

The study aimed to evaluate clinical and vascular characteristics, as well as outcomes, for diabetic persons with foot ulceration and no-option critical limb ischemia (CLI). The study group included a sample of patients admitted to our diabetic foot unit because of a new diabetic foot ulcer and CLI. All subjects were managed using a limb salvage protocol which includes lower-limb revascularization. According to whether or not the revascularization procedure was a success, patients were respectively divided into two groups: successfully treated CLI patients (ST-CLI) and no-option CLI patients (NO-CLI). Failed revascularization was considered in the case of technical recanalization failure of occluded vessels (inability to overcome the obstruction) and/or absence of arterial flow to the foot. Limb salvage, major amputation, and death after 1 year of follow-up were evaluated and compared between the two groups. Overall, 239 patients were included, 74.9% belonging to ST-CLI and 25.1% to NO-CLI. NO-CLI patients reported more cases of ischemic heart disease (80 vs. 62.1, p = 0.008), heart failure (63.3 vs. 32.4%, p < 0.0001), and end-stage renal disease (ESRD) (60 vs. 25.7%) than ST-CLI patients. In addition, more vessels were affected in the NO-CLI group (5.2 ± 1.6 vs. 4 ± 1.5, p < 0.0001), and there was more involvement of tibio-peroneal trunk (50 vs. 30.2%, p = 0.006), anterior tibial (93.3 vs. 82.7, p = 0.03), posterior tibial (93.3 vs. 73.7%, p = 0.0005), peroneal (70 vs. 48%, p = 0.002), and below-the-ankle arteries (73.3 vs. 39.1%, p < 0.0001) than ST-CLI. The 1 year outcomes for the whole population were 69.9% limb salvage, 10.9% major amputation, and 19.2% death. The outcomes for NO-CLI and ST-CLI were, respectively, as follows: limb salvage (13.8 vs. 73.4%, p < 0.0001), amputation (30 vs. 4.5%, p = 0.0001), and mortality (50 vs. 8.9%, p < 0.0001). NO-CLI patients showed a more severe pattern of peripheral arterial disease (PAD) with distal arterial lesions and worse outcomes than ST-CLI.