Miracle-dz/UniFAR-FTUs huggingface dataset:
Reduced physiological plasticity in a fish adapted to stable temperatures

Significance Plastic individuals can buffer environmental changes, maintaining a stable performance across gradients. Plasticity is therefore thought to be particularly beneficial for the survival of wild populations that experience large environmental fluctuations, such as diel and seasonal temperature changes. Maintaining plasticity is widely assumed to be costly; however, empirical evidence demonstrating this cost is scarce. Here, we predict that if plasticity is costly, it would be readily lost in a stable environment, such as a laboratory. To test this, we measured a diverse range of phenotypic traits, spanning gene expression, physiology, and behavior, in wild and laboratory zebrafish acclimated to 15 temperatures. We show that laboratory fish have lost plasticity in many traits, demonstrating that maintaining plasticity carries a cost.
Perceptions of Inuit Women and Non-Inuit Healthcare Providers on the Implementation of Human Papillomavirus Self-Sampling as an Alternative Cervical Cancer Screening Method in Nunavik, Northern Quebec

Human papillomavirus (HPV) self-sampling offers a cervical cancer (CC) screening alternative that can address certain barriers to the Papanicolaou test. As part of a larger community-based participatory project in Nunavik, Northern Québec, we travelled to two communities to gather perspectives from Inuit women and healthcare professionals (HCPs) on CC screening services and the possible implementation of HPV self-sampling. We held 10 group discussions with 28 Inuit women and 10 semi-structured interviews with 20 HCPs. The thematic analysis extracted themes reflecting one barrier and seven facilitators to accessing CC screening and the implementation of HPV self-sampling in Nunavik. Themes included, though not limited to, language and communication in health settings, access to culturally responsive educational resources on CC, and the noninvasive nature of HPV self-sampling. This study may serve to contribute to the co-development of a strategy for implementation that is designed according to the needs and priorities of the communities.
Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit

Significance Resolution of inflammation is an active process that restores tissue homeostasis and prevents the development of chronic inflammatory diseases. The mechanisms that regulate resolution of inflammation are only partially understood. Here, we showed that activation of the vagus nerve accelerated resolution of inflammation. Electrical stimulation of the vagus nerve in vivo increased levels of select specialized proresolving mediators in inflammation. Experiments in genetic mouse models revealed that the mechanism involved 12/15-lipoxgenase (Alox15), a key enzyme for biosynthesis of the identified mediators, and required the α7-nicotinic acetylcholine receptor subunit. The findings indicate that electrical signals in the vagus nerve activate a cholinergic signal promoting Alox15-dependent lipid mediator biosynthesis and accelerating resolution of inflammation, providing additional insights into neural regulation of inflammation.
Further refining 2020 ESGO/ESTRO/ESP molecular risk classes in patients with early‐stage endometrial cancer: A propensity score–matched analysis

The integration of molecular features with clinicopathological findings in endometrial cancer classification seems to be able to significantly refine risk assessment. Nevertheless, clinical management remains challenging, and different therapeutic options are available for each class. Further prognostic characterization of the subgroups within each risk class could be helpful in the decision‐making process.
Three months of melatonin treatment reduces insulin sensitivity in patients with type 2 diabetes—A randomized placebo‐controlled crossover trial

The use of the sleep‐promoting hormone melatonin is rapidly increasing as an assumed safe sleep aid. During the last decade, accumulating observations suggest that melatonin affects glucose homeostasis, but the precise role remains to be defined. We investigated the metabolic effects of long‐term melatonin treatment in patients with type 2 diabetes including determinations of insulin sensitivity and glucose‐stimulated insulin secretion. We used a double‐blinded, randomized, placebo‐controlled, crossover design. Seventeen male participants with type 2 diabetes completed (1) 3 months of daily melatonin treatment (10 mg) 1 h before bedtime (M) and (2) 3 months of placebo treatment 1 h before bedtime (P). At the end of each treatment period, insulin secretion was assessed by an intravenous glucose tolerance test (0.3 g/kg) (IVGTT) and insulin sensitivity was assessed by a hyperinsulinemic‐euglycemic clamp (insulin infusion rate 1.5 mU/kg/min) (primary endpoints). Insulin sensitivity decreased after melatonin (3.6 [2.9–4.4] vs. 4.1 [3.2–5.2] mg/(kg × min), p = . 016). During the IVGTT, the second‐phase insulin response was increased after melatonin (p = .03). In conclusion, melatonin treatment of male patients with type 2 diabetes for 3 months decreased insulin sensitivity by 12%. Clinical use of melatonin treatment in dosages of 10 mg should be reserved for conditions where the benefits will outweigh the potential negative impact on insulin sensitivity.
Production of 3′,3′-cGAMP by a Bdellovibrio bacteriovorus promiscuous GGDEF enzyme, Bd0367, regulates exit from prey by gliding motility

Bacterial second messengers are important for regulating diverse bacterial lifestyles. Cyclic di-GMP (c-di-GMP) is produced by diguanylate cyclase enzymes, named GGDEF proteins, which are widespread across bacteria. Recently, hybrid promiscuous (Hypr) GGDEF proteins have been described in some bacteria, which produce both c-di-GMP and a more recently identified bacterial second messenger, 3′,3′-cyclic-GMP-AMP (cGAMP). One of these proteins was found in the predatory Bdellovibrio bacteriovorus, Bd0367. The bd0367 GGDEF gene deletion strain was found to enter prey cells, but was incapable of leaving exhausted prey remnants via gliding motility on a solid surface once predator cell division was complete. However, it was unclear which signal regulated this process. We show that cGAMP signalling is active within B. bacteriovorus and that, in addition to producing c-di-GMP and some c-di-AMP, Bd0367 is a primary producer of cGAMP in vivo. Site-directed mutagenesis of serine 214 to an aspartate rendered Bd0367 into primarily a c-di-GMP synthase. B. bacteriovorus strain bd0367S214D phenocopies the bd0367 deletion strain by being unable to glide on a solid surface, leading to an inability of new progeny to exit from prey cells post-replication. Thus, this process is regulated by cGAMP. Deletion of bd0367 was also found to be incompatible with wild-type flagellar biogenesis, as a result of an acquired mutation in flagellin chaperone gene homologue fliS, implicating c-di-GMP in regulation of swimming motility. Thus the single Bd0367 enzyme produces two secondary messengers by action of the same GGDEF domain, the first reported example of a synthase that regulates multiple second messengers in vivo. Unlike roles of these signalling molecules in other bacteria, these signal to two separate motility systems, gliding and flagellar, which are essential for completion of the bacterial predation cycle and prey exit by B. bacteriovorus.
The epidemiology of head injuries at 2019 Rugby Union World Cup

ABSTRACT Introduction The sequelae of concussion are of growing concern within Rugby. World Rugby has introduced rule changes to improve player welfare and reduce head injury frequency. We aimed to report the incidence of head injuries and head injury assessment (HIA) at the 2019 Rugby World Cup (RWC). Methods We reviewed all 45 tournament matches and recorded the number of head injuries, the injured player’s position, and the mechanism of injury; whether the player had an HIA; and if they returned to play following injury. We compared these findings with previous RWCs. Results We recorded 68 head injuries (1.33/game). Thirty-six players (52.9%) were removed from the field of play for an HIA. Of these, 23 (63.9%) failed and therefore considered to have concussion. The head injury rate in 2019 was 37.8 per 1000 player hours, which increased from previous tournaments (22.0 in 2015, 14.6 in 2011, and 4.7 in 2007). The concussion rate was 23 per 1000 player hours in 2019, which was lower than 29 in 2015. In 2019, 63.9% of HIAs were failed compared to 48.7% in 2015. We identified 17 cases where medical staff did not attend to a player suffering a head injury on-field. Of these, four players underwent an HIA after the match doctor reviewed the incident. Conclusion We recorded a higher rate of head injuries, and a player was more likely to fail their HIA than in previous tournaments. These findings may represent a greater awareness from medical staff and the benefits of education. However, 25% of head injuries not receiving an initial on-field assessment provide room for improvement.
Association between thoracic epidural block and major complications after pleurectomy/decortication for malignant pleural mesothelioma under general anesthesia

Introduction A curative-intent surgical procedure, pleurectomy/decortication, for malignant pleural mesothelioma is accompanied by a high incidence of major postoperative complications. Although epidural block, which suppresses nociception during and after surgery, reportedly has both benefits and disadvantages in terms of outcomes after thoracic surgery for other diseases, the effects of epidural block on major complications after pleurectomy/decortication have not been evaluated. The aim of this study was to evaluate the association between epidural block and major postoperative complications following pleurectomy/decortication. Methods In a single-institutional observational study, consecutive adult patients undergoing pleurectomy/decortication under general anesthesia were enrolled from March 2019 to December 2021. Multivariable logistic regression analysis was performed to determine the association between perioperative variables and major complications. Next, patients were divided into two groups: general anesthesia with and without epidural block. Incidences of major postoperative complications, defined as Clavien-Dindo grades≥III, were compared between groups. Results In all patients enrolled with American Society of Anesthesiologists (ASA) physical status II or III (n=99), general anesthesia without epidural block was identified as a sole risk factor for major complications among perioperative variables. The incidence of major complications was 32.3% (95% CI 19.1% to 49.2%) in patients with epidural block (n=34), which was significantly lower than 63.1% (95% CI 50.9% to 73.8%) in patients without epidural block (n=65). In sensitivity analysis in patients with ASA physical status II alone, the same results were obtained. Conclusion Epidural block is likely associated with reduction of the incidence of major complications after pleurectomy/decortication for malignant pleural mesothelioma under general anesthesia.
Neuropeptide regulation of hormone secretion from the anterior pituitary gland of the ewe

The actions of LHRH, CRH and NPY on the activity of the reproductive axis and, in particular, the LHRH pulse generator were investigated in vivo. A model was developed to allow direct administration of neuro¬ peptides, antagonists and antibodies into the third cerebral ventricle of conscious, free-moving and unstressed sheep, giving access to hypo¬ thalamic periventricular structures involved in the control of the anterior pituitary gland. Plasma levels of LH were used as a measure of LHRH pulsatility. Three major questions were addressed: 1 (1) Does hypothalamic LHRH autoregulate its own release? Injection of LHRH (2.1-21 pmol) into the third ventricle caused a specific, doserelated and receptor-mediated inhibition of LH secretion. It is therefore suggested that the intrinsic communication between LHRH neurones may be inhibitory and may provide a mechanism to affect the timing of the pulsatile release of LHRH. However, as central injection of LHRH also caused a rapid 4-5-fold rise in plasma Cortisol levels, prior to and correlated with the reduction in LH secretion, this inhibitory commun¬ ication may be indirect. (2) Does CRH act as a central neurotransmitter to mediate the inhibitory effects of stress on LHRH release? In contrast to other species, central injection of CRH (0.12-1.2 nmol) caused a dose-related stimulation of LH secretion, due to a significant increase in LH pulse frequency. CRH also caused a marked and dose-related stimulation of prolactin and Cortisol secretion, two hormones known to be released under conditions of stress. Endogenous opioid peptides were shown to mediate the central effect of CRH on the release of prolactin, but not on LH or Cortisol. The effect on LH may reflect a species difference, or alternatively may be similar to the increase in LH secretion reported in rats and monkeys subjected to short-term handling or restraint stress. These data provide evidence that CRH acts as a central neurotransmitter; i.e., distinct from its action as a secretagogue for ACTH. (3) Does central NPY interact with LHRH and/or CRH to modulate the reproductive axis? In contrast to the rat, central injection of NPY (0.151.5 nmol) had no effect on LH levels in ovariectomized ewes with or
Investigation of the effect of IFN-γ/TNF-α-treated mesenchymal stem cells on Th9- and Treg cell-related parameters in a mouse model of ovalbumin-induced allergic asthma

Abstract Objective Th9- and regulatory T (Treg) cells exert pro- and anti-allergic activity, respectively. Mesenchymal stem cell (MSC)-related immunomodulatory impacts can be enhanced by inflammatory cytokines. Here, the modulatory effects of IFN-γ/TNF-α-induced MSCs on Th9- and Treg cell-related parameters were investigated using an asthma model. Methods Allergic asthma was induced in BALB/c mice using sensitized and challenging with ovalbumin (OVA). The asthmatic groups were treated intraperitoneally with PBS, MSCs, IFN-γ-induced MSCs, TNF-α-induced MSCs and ‘IFN-γ + TNF-α’-induced MSCs before the challenge phase. The mice were sacrificed 24 h after challenge. The serum IL-9 and IL-35 levels, as well as gene expression of IL-9, PU.1, IL-35-EBI3, and FOXP3 in the lung tissues were assessed using ELISA and real time-PCR, respectively. Results The differences of Th9 and Treg-related parameters were not significant between untreated asthmatic mice and those treated with non-induced MSCs. In comparison with untreated asthmatic group, treatment with IFN-γ-induced MSCs significantly reduced serum IL-9 levels, reduced lung expression of IL-9 and PU.1, while increasing serum IL-35 levels as well as lung expression of FOXP3; treatment with TNF-α-induced MSCs significantly reduced serum IL-9 levels as well as lung expression of IL-9, and treatment with ‘IFN-γ + TNF-α’-induced MSCs, significantly modulated all investigated Th9 and Treg-related parameters. In comparison to mice treated with non-induced MSCs, serum IL-9 levels were remarkably decreased in mice treated with IFN-γ-induced and ‘IFN-γ + TNF-α’-induced MSCs. Conclusions IFN-γ-and ‘IFN-γ + TNF-α’ treated MSCs exerted almost comparable impacts, but were more efficient than TNF-α-exposed MSCs. Thus, IFN-γ alone can be sufficient to promote immunomodulatory effects of MSCs.
Pharmaceutical agents for contractile-metabolic dysfunction after volumetric muscle loss.

Volumetric muscle loss (VML) injuries represent a majority of military servicemember casualties and are common in civilian populations following blunt and/or penetrating traumas. Characterized as a skeletal muscle injury with permanent functional impairments, there are currently no standards for rehabilitation, leading to life-long disability. Toward developing rehabilitative strategies, previous research demonstrates that the remaining muscle after a VML injury lacks similar levels of plasticity or adaptability as healthy, uninjured skeletal muscle. This may be due in part to impaired innervation and vascularization of the remaining muscle as well as disrupted molecular signaling cascades commonly associated with muscle adaptation. The primary objective of this study was to assess the ability of four pharmacological agents with a strong record of modulating muscle contractile and metabolic function to improve functional deficits in a murine model of VML injury. Male C57BL/6 mice underwent a 15% multi-muscle VML injury of the posterior hindlimb and were randomized into drug treatment groups (formoterol, AICAR, pioglitazone, or sildenafil) or untreated VML group. At the end of 60 days, the injury model was first validated by comparison to age-matched injury naïve mice. Untreated VML mice had 22% less gastrocnemius muscle mass, 36% less peak-isometric torque, and 27% less maximal mitochondrial oxygen consumption rate compared to uninjured mice (p<0.01). Experimental drug groups were, then, compared to VML untreated, and there was minimal evidence of efficacy for AICAR, pioglitazone, or sildenafil in improving contractile and metabolic functional outcomes. However, formoterol-treated VML mice had 18% greater peak-isometric torque (p<0.01) and permeabilized muscle fibers had 36% greater State III mitochondrial oxygen consumption rate (p<0.01) compared to VML untreated, suggesting an overall improvement in muscle condition. There was minimal evidence that these benefits came from greater mitochondrial biogenesis and/or mitochondrial complex protein content, but could be due to greater enzyme activities levels for complex I and complex II. These findings suggest that formoterol treatment is candidate to pair with a rehabilitative approach to maximize functional improvements in VML-injured muscle.
A computational approach to investigate constitutive activation of NF‐κB

Nuclear factor kappa B (NF‐κB) signaling is the master regulator of inflammatory pathways; therefore, its regulation has been the subject of investigation since last two decades. Multiple models have been published that describes the dynamics of NF‐κB activity by stimulated activation and feedback loops. However, there is also paramount evidence of the critical role of posttranslational modifications (PTMs) in the regulation of NF‐κB pathway. With the premise that PTMs present alternate routes for activation or repression of the NF‐κB pathway, we have developed a model including all PTMs known so far describing the system behavior. We present a pathway network model consisting of 171 proteins forming 315 molecular species and consisting of 482 reactions that describe the NF‐κB activity regulation in totality. The overexpression or knockdown of interacting molecular partners that regulate NF‐κB transcriptional activity by PTMs is used to infer the dynamics of NF‐κB activity and offers qualitative agreement between model predictions and the experimental results heuristically. Finally, we have demonstrated an instance of NF‐κB constitutive activation through positive upregulation of cytokines (the stimuli) and IKK complex (NF‐κB activator), the characteristic features in several cancer types and metabolic disorders, and its reversal by employing combinatorial activation of PPARG, PIAS3, and P50‐homodimer. For the first time, we have presented a NF‐κB model that includes transcriptional regulation by PTMs and presented a theoretical strategy for the reversal of NF‐κB constitutive activation. The presented model would be important in understanding the NF‐κB system, and the described method can be used for other pathways as well.
Higher-order olfactory neurons in the lateral horn support odor valence and odor identity coding in Drosophila

Understanding neuronal representations of odor-evoked activities and their progressive transformation from the sensory level to higher brain centers features one of the major aims in olfactory neuroscience. Here, we investigated how odor information is transformed and represented in higher-order neurons of the lateral horn, one of the higher olfactory centers implicated in determining innate behavior, using Drosophila melanogaster. We focused on a subset of third-order glutamatergic lateral horn neurons (LHNs) and characterized their odor coding properties in relation to their presynaptic partner neurons, the projection neurons (PNs) by two-photon functional imaging. We found that odors evoke reproducible, stereotypic and odor-specific response patterns in LHNs. Notably, odor-evoked responses in these neurons are valence-specific in a way that their response amplitude is positively correlated with innate odor preferences. We postulate that this valence-specific activity is the result of integrating inputs from multiple olfactory channels through second-order neurons. GRASP and micro-lesioning experiments provide evidence that glutamatergic LHNs obtain their major excitatory input from uniglomerular PNs, while they receive an odor-specific inhibition through inhibitory multiglomerular PNs. In summary, our study indicates that odor representations in glutamatergic LHNs encode hedonic valence and odor identity and primarily retain the odor coding properties of second-order neurons.
Higher intensive care unit consultations for COVID‐19 patients living with HIV compared to those without HIV coinfection in Uganda

Coronavirus disease‐2019 (COVID‐19) is the leading cause of death worldwide from a single infectious agent. Whether or not HIV infection affects clinical outcomes in patients with COVID‐19 remains inconclusive. This study aimed to compare the clinical outcomes of people living with HIV (PLWH) and non‐HIV‐infected patients hospitalized during the second wave of the COVID‐19 pandemic in Uganda. We retrospectively retrieved data on patients with COVID‐19 who were admitted to the Mulago National Referral Hospital in Uganda between April 2021 and mid‐July 2021. We performed propensity‐score‐matching of 1:5 to compare outcomes in COVID‐19 patients living with and those without HIV coinfection (controls). We included 31 PLWH and 155 non‐HIV controls. The baseline characteristics were similar across groups (all p values > 0.05). PLWH had close to threefold higher odds of having ICU consultation compared to controls (odds ratio [OR]: 2.9, 95% CI: 1.2–6.9, p = 0.015). There was a trend toward having a severe or critical COVID‐19 illness among PLWHIH compared to controls (OR: 1.9, 95% CI: 0.8–4.7, p = 0.164). Length of hospitalization was not significantly different between PLWH and non‐HIV controls (6 days vs. 7 days, p = 0.184). Seven‐day survival was 63% (95% CI: 42%–78%) among PLWH and 72% (95% CI: 61%–82%) among controls while 14‐day survival was 50% (95% CI: 28%–69%) among PLWH and 65% (95% CI: 55%–73%) among controls (p = 0.280). There was another trend toward having 1.7‐fold higher odds of mortality among PLWH compared to controls (OR: 1.7, 95% CI: 0.8–3.8, p = 0.181). Our data suggest that PLWH may be at an increased risk of severe or critical COVID‐19 illness requiring ICU consultation. Further studies with larger sample sizes are recommended.