Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of the NLRP3 Inflammasome: Insights Into Cancer Hallmarks

In response to a variety of stresses, mammalian cells activate the inflammasome for targeted caspase-dependent pyroptosis. The research community has recently begun to deduce that the activation of inflammasome is instigated by several known oncogenic stresses and metabolic perturbations; nevertheless, the role of inflammasomes in the context of cancer biology is less understood. In manipulating the expression of inflammasome, researchers have found that NLRP3 serves as a deterministic player in conducting tumor fate decisions. Understanding the mechanistic underpinning of pro-tumorigenic and anti-tumorigenic pathways might elucidate novel therapeutic onco-targets, thereby providing new opportunities to manipulate inflammasome in augmenting the anti-tumorigenic activity to prevent tumor expansion and achieve metastatic control. Accordingly, this review aims to decode the complexity of NLRP3, whereby summarizing and clustering findings into cancer hallmarks and tissue contexts may expedite consensus and underscore the potential of the inflammasome in drug translation.
Elastic anomalies accompanying phase transitions in (Ca,Sr)TiO3 perovskites: Part III. Experimental investigation of polycrystalline samples

Abstract Bulk and shear moduli of polycrystalline samples of perovskites with different compositions across the CaTiO3-SrTiO3 solid solution have been measured at ambient conditions and in-situ at high pressures by pulse-echo ultrasonic methods. The samples were prepared as dense pellets by hot pressing synthetic powders at ~7.5 GPa and ~1000 °C. Any variations of bulk modulus due to phase transitions are small, but signiÞ cant anomalies have been observed in the shear modulus at ambient conditions. These are associated with a sequence of symmetry changes Pm3̄ m → I4/mcm → Pbcm → Pnma with increasing CaTiO3 content. Comparison with variations in elastic properties predicted using Landau theory suggests that a substantial part of the elastic softening observed in tetragonal samples could be due to anelastic contributions from transformation twin walls. This additional softening does not occur in orthorhombic samples, and the transition from tetragonal to orthorhombic symmetry results in a stiffening of the shear modulus. No overt evidence was found for a phase transition I4/mcm ↔ Pnma at high pressures in Ca0.35Sr0. 65TiO3 but small changes in the trends of both bulk and shear moduli in the range 2.5. 3 GPa could be due either to a different transition or a change in compression mechanism. A Pm3̄ m ↔ I4/mcm transition at ~2 GPa in Ca0.05Sr0. 95TiO3 shows the same form of softening as observed for the transition as a function of composition. A simple model of twin wall contributions to the compliance of tetragonal samples failed to match the observed variations that, alternatively, seem to follow ΔG ∞ q4 where ΔG is the change in shear modulus and q4 the driving order parameter for the Pm3̄ m ↔ I4/mcm transition. Analogous elastic behavior is expected to occur in (Mg,Fe)SiO3 and CaSiO3 perovskites at high pressures and temperatures.
A Feasibility Study of Expanded Home-Based Telerehabilitation After Stroke

Introduction: High doses of activity-based rehabilitation therapy improve outcomes after stroke, but many patients do not receive this for various reasons such as poor access, transportation difficulties, and low compliance. Home-based telerehabilitation (TR) can address these issues. The current study evaluated the feasibility of an expanded TR program. Methods: Under the supervision of a licensed therapist, adults with stroke and limb weakness received home-based TR (1 h/day, 6 days/week) delivered using games and exercises. New features examined include extending therapy to 12 weeks duration, treating both arm and leg motor deficits, patient assessments performed with no therapist supervision, adding sensors to real objects, ingesting a daily experimental (placebo) pill, and generating automated actionable reports. Results: Enrollees (n = 13) were median age 61 (IQR 52–65.5), and 129 (52–486) days post-stroke. Patients initiated therapy on 79.9% of assigned days and completed therapy on 65.7% of days; median therapy dose was 50.4 (33.3–56.7) h. Non-compliance doubled during weeks 7–12. Modified Rankin scores improved in 6/13 patients, 3 of whom were >3 months post-stroke. Fugl-Meyer motor scores increased by 6 (2.5–12.5) points in the arm and 1 (−0.5 to 5) point in the leg. Assessments spanning numerous dimensions of stroke outcomes were successfully implemented; some, including a weekly measure that documented a decline in fatigue (p = 0.004), were successfully scored without therapist supervision. Using data from an attached sensor, real objects could be used to drive game play. The experimental pill was taken on 90.9% of therapy days. Automatic actionable reports reliably notified study personnel when critical values were reached. Conclusions: Several new features performed well, and useful insights were obtained for those that did not. A home-based telehealth system supports a holistic approach to rehabilitation care, including intensive rehabilitation therapy, secondary stroke prevention, screening for complications of stroke, and daily ingestion of a pill. This feasibility study informs future efforts to expand stroke TR. Clinical Trial Registration: Clinicaltrials.gov, # NCT03460587.
A Novel Body Plan Alters Diversification of Body Shape and Genitalia in Live-Bearing Fish

Major evolutionary innovations can greatly influence subsequent evolution. While many major transitions occurred in the deep past, male live-bearing fishes (family Poeciliidae) more recently evolved a novel body plan. This group possesses a three-region axial skeleton, with one region—the ano-urogenital region—representing a unique body region accommodating male genitalic structures (gonopodial complex). Here we evaluate several hypotheses for the evolution of diversity in this region and examine its role in the evolution of male body shape. Examining Gambusia fishes, we tested a priori predictions for (1) joint influence of gonopodial-complex traits on mating performance, (2) correlated evolution of gonopodial-complex traits at macro- and microevolutionary scales, and (3) predator-driven evolution of gonopodial-complex traits in a post-Pleistocene radiation of Bahamas mosquitofish. We found the length of the sperm-transfer organ (gonopodium) and its placement along the body (gonopodial anterior transposition) jointly influenced mating success, with correlational selection favoring particular trait combinations. Despite these two traits functionally interacting during mating, we found no evidence for their correlated evolution at macro- or microevolutionary scales. In contrast, we did uncover correlated evolution of modified vertebral hemal spines (part of the novel body region) and gonopodial anterior transposition at both evolutionary scales, matching predictions of developmental connections between these components. Developmental linkages in the ano-urogenital region apparently play key roles in evolutionary trajectories, but multiple selective agents likely act on gonopodium length and cause less predictable evolution. Within Bahamas mosquitofish, evolution of hemal-spine morphology, and gonopodial anterior transposition across predation regimes was quite predictable, with populations evolving under high predation risk showing more modified hemal spines with greater modifications and a more anteriorly positioned gonopodium. These changes in the ano-urogenital vertebral region have facilitated adaptive divergence in swimming abilities and body shape between predation regimes. Gonopodium surface area, but not length, evolved as predicted in Bahamas mosquitofish, consistent with a previously suggested tradeoff between natural and sexual selection on gonopodium size. These results provide insight into how restructured body plans offer novel evolutionary solutions. Here, a novel body region—originally evolved to aid sperm transfer—was apparently co-opted to alter whole-organism performance, facilitating phenotypic diversification.
Radiotherapy and Immunotherapy for Head and Neck Cancer: Current Evidence and Challenges

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment over the past decade. However, although the immune landscape suggests a strong rationale for the use of these agents in patients with head and neck squamous cell carcinoma, the available clinical evidence indicates that most patients currently do not respond to ICI monotherapy. Radiotherapy is a primary treatment modality for many patients with locally advanced head and neck cancer. While ionizing radiation traditionally has been thought to act in a purely cytotoxic fashion, a growing body of preclinical studies have demonstrated additional profound immunomodulatory effects. Consequently, there has been a surge of interest in the potential synergy between radiotherapy and immunotherapy, both the potential for radiotherapy to augment the systemic anti-tumor immune response and the potential for immunotherapy to improve in-field tumor response to radiation. In this review, we summarize the current preclinical and clinical evidence for radioimmunotherapy, with a particular focus on studies directly relevant to head and neck squamous cell carcinoma, as well as existing challenges and future directions for this emerging field.
Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals

Background: Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. Aim: Evaluate changes in resting-state functional connectivity (RSFC) at 1 week and 3 months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures. Methods: Participants received 0.2–0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state functional magnetic resonance imaging (fMRI) scans at baseline, 1-week and 3-month post-administration and [11C]Cimbi-36 PET scans at baseline and 1 week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding. Results: Psilocybin was well tolerated and produced positive changes in well-being. At 1 week only, executive control network (ECN) RSFC was significantly decreased (Cohen’s d = −1.73, pFWE = 0.010). We observed no other significant changes in RSFC at 1 week or 3 months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at 1 week predicted increased mindfulness at 3 months (r = −0.65). Conclusions: These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic ‘afterglow’ period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at 3 months, when personality changes are observed, remain to be identified.
Transcranial magnetic stimulation of right dorsolateral prefrontal cortex does not affect associative retrieval in healthy young or older adults

We examined whether post-retrieval monitoring processes supporting memory performance are more resource limited in older adults relative to younger individuals. We predicted that older adults would be more susceptible to an experimental manipulation that reduced the neurocognitive resources available to support post-retrieval monitoring. Young and older adults received transcranial magnetic stimulation (TMS) to the right dorsolateral prefrontal cortex (DLPFC) or a vertex control site during an associative recognition task. The right DLPFC was selected as a TMS target because the region is held to be a key member of a network of regions engaged during retrieval monitoring and is readily accessible to administration of TMS. We predicted that TMS to the right DLPFC would lead to reduced associative recognition accuracy, and that this effect would be more prominent in older adults. The results did not support this prediction. Recognition accuracy was significantly reduced in older adults relative to their younger counterparts but the magnitude of this age difference was unaffected following TMS to the right DLPFC or vertex. These findings suggest that TMS to the right DLPFC was insufficient to deplete the neurocognitive resources necessary to support post-retrieval monitoring.
Youthful and age-related matreotypes predict drugs promoting longevity

The identification and validation of drugs that promote health during aging (‘geroprotectors’) is key to the retardation or prevention of chronic age-related diseases. Here we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this novel observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a ‘youthful’ matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for C. elegans longevity. With this reporter, we were able to eliminate false positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging. Highlights Many geroprotective drugs alter extracellular matrix gene expression Defined young and old human matreotype signatures can identify novel potential geroprotective compounds Prolonged collagen homeostasis as a surrogate marker for longevity
Effect of concentration and hydraulic reaction time on the removal of pharmaceutical compounds in a membrane bioreactor inoculated with activated sludge

Pharmaceuticals are often not fully removed in wastewater treatment plants (WWTPs) and are thus being detected at trace levels in water bodies all over the world posing a risk to numerous organisms. These organic micropollutants (OMPs) reach WWTPs at concentrations sometimes too low to serve as growth substrate for microorganisms, thus co-metabolism is thought to be the main conversion mechanism. In this study, the microbial removal of six pharmaceuticals was investigated in a membrane bioreactor at increasing concentrations (4-800 nM) of the compounds and using three different hydraulic retention times (HRT; 1, 3.5, 5 days). The bioreactor was inoculated with activated sludge from a Dutch WWTP and fed with ammonium, acetate, and methanol as main growth substrates to stimulate and mimic co-metabolism in a WWTP. Each pharmaceutical compound had a different average removal efficiency: acetaminophen (100%) > fluoxetine (50%) > metoprolol (25%) > diclofenac (20%) > metformin (15%) > carbamazepine (10%). Higher pharmaceutical influent concentrations proportionally increased the removal rate of each compound, but surprisingly not the removal percentage. Furthermore, only metformin removal improved to 80-100% when HRT or biomass concentration was increased in the reactor. Microbial community changes were followed with 16S rRNA gene amplicon sequencing in response to the increment of supplied pharmaceutical concentration: it was found that Nitrospirae and Planctomycetes 16S rRNA relative gene abundance decreased, whereas Acidobacteria and Bacteroidetes increased. Remarkably, the Dokdonella genus, previously implicated in acetaminophen metabolism, showed a 30-fold increase in abundance at the highest (800 nM) concentration of pharmaceuticals applied. Taken together, these results suggest that the incomplete removal of most pharmaceutical compounds in WWTPs is neither dependent on concentration nor HRT. Accordingly, we propose a chemical equilibrium or a growth substrate limitation as the responsible mechanisms of the incomplete removal. Finally, Dokdonella could be the main acetaminophen degrader under activated sludge conditions, and non-antimicrobial pharmaceuticals might still be toxic to relevant WWTP bacteria.
Talker discontinuity disrupts attention to speech: Evidence from EEG and pupillometry

Speech is processed less efficiently from discontinuous, mixed talkers than one consistent talker, but little is known about the neural mechanisms for processing talker variability. Here, we measured psychophysiological responses to talker variability using electroencephalography (EEG) and pupillometry while listeners performed a delayed recall of digit span task. Listeners heard and recalled seven-digit sequences with both talker (single- vs. mixed-talker digits) and temporal (0- vs. 500-ms inter-digit intervals) discontinuities. Talker discontinuity reduced serial recall accuracy. Both talker and temporal discontinuities elicited P3a-like neural evoked response, while rapid processing of mixed-talkers’ speech led to increased phasic pupil dilation. Furthermore, mixed-talkers’ speech produced less alpha oscillatory power during working memory maintenance, but not during speech encoding. Overall, these results are consistent with an auditory attention and streaming framework in which talker discontinuity leads to involuntary, stimulus-driven attentional reorientation to novel speech sources, resulting in the processing interference classically associated with talker variability.
Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever

Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAA, Valine, Leucine, and Isoleucine) are essential for anabolic processes like protein synthesis, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood. The present study reports the role of SLC25A44, a recently identified mitochondrial BCAA carrier (MBC), in the regulation of mitochondrial BCAA catabolism and adaptive response to fever. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E2 (PGE2) and psychological stress. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2 administration. At a cellular level, MBC is required for mitochondrial BCAA deamination as well as the synthesis of mitochondrial amino acids and TCA intermediates. Together, these results illuminate the role of MBC as a determinant of metabolic flexibility to mitochondrial BCAA catabolism and optimal febrile responses. This study also offers an opportunity to control fever by rewiring the subcellular BCAA fate.
MMP12 Knockout Prevent Weight and Muscle Loss Induced by Cancer Cachexia

Weight loss and muscle wasting can have devastating impacts on survival and quality of life of patients with cancer cachexia. Here, we have established a hybrid mouse of ApcMin/+ mice and MMP12 knockout mice (ApcMin/+; MMP12-/-) and found that knockout MMP12 can suppress the weight and muscle loss of ApcMin/+ mice. In detail, we found that interleukin 6 was highly upregulated in the serum of cancer patients and MMP12 was increased in muscle of tumor-bearing mice. Interestingly, the interleukin 6 secreted by tumor cells led to MMP12 overexpression in the macrophages, which further resulted in degradation of insulin and insulin-like growth factor 1 and interruption of glycolipid metabolism. Notably, depletion of MMP12 prevented weight loss of ApcMin/+ mice. Our study uncovers the critical role of MMP12 in controlling weight and highlights the great potential of MMP12 in the treatment of cancer cachexia.
An agnostic study of associations between ABO and RhD blood group and phenome-wide disease risk

There are multiple known associations between the ABO and RhD blood groups and disease. However, no systematic population-based studies elucidating associations between a large number of disease states and blood group have been conducted. Using SCANDAT3-S, a comprehensive nationwide blood donation-transfusion database, we modelled outcomes for 1,217 disease categories including 70 million person-years of follow-up, accruing from 5.1 million unique individuals. We discovered 49 and 1 associations between a disease and ABO and RhD blood group, respectively, after adjustment for multiple testing. We identified new associations such as kidney stones and blood group B as compared to O. We also expanded previous knowledge on other associations such as pregnancy-induced hypertension and blood group A and AB as compared to O and RhD positive as compared to negative. Our findings generate strong further support for previously known associations, but also indicate new interesting relations.