Miracle-dz/UniFAR-FTUs huggingface dataset:
Aldehyde inactivation of the RicR regulon sensitizes Mycobacterium tuberculosis to copper

Mycobacterium tuberculosis is a major human pathogen and the causative agent of tuberculosis disease. While M. tuberculosis can persist in the presence of host-derived antimicrobials like nitric oxide and copper, bacteria defective for proteasome activity are highly sensitive to these molecules, making the proteasome an attractive target for drug development. Previous work linked nitric oxide susceptibility with the accumulation of at least one aldehyde in an M. tuberculosis mutant lacking proteasomal degradation. In this study, we show that this aldehyde accumulation is also responsible for copper sensitivity in this strain. Furthermore, we show the exogenous addition of aldehydes to wild-type M. tuberculosis cultures sensitizes bacteria to copper. We determined that aldehydes directly affect the activity of two members of the RicR (regulated in copper repressor) regulon, resulting in the reduced production and function of critical copper-responsive proteins. This study is the first to mechanistically describe how aldehydes can render M. tuberculosis susceptible to an existing host defense, and could support a broader role for aldehydes in controlling M. tuberculosis infections. IMPORTANCE M. tuberculosis is a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine for M. tuberculosis infections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can control M. tuberculosis infections for decades. For these reasons, a clear understanding of how mammalian immunity inhibits mycobacterial growth is warranted. In this study, we show aldehydes can increase M. tuberculosis susceptibility to copper. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes target critical bacterial survival pathways, making aldehydes a previously unappreciated antimicrobial defense.
On Solutions to a Class of Functional Differential Equations with Time-Dependent Coefficients

In this paper, we study initial boundary value problems that involve functional (nonlocal) partial di ﬀ erential equations with variable coe ﬃ cients. These problems arise in cell growth models with symmetric and asymmetric modes of division. We determine the general solution to the symmetric cell division problem for a certain class of coe ﬃ cients and establish the convergence of solutions to a large time asymptotic solution. The existence of a steady size distribution (SSD) solution for an asymmetric cell division problem is established and is shown to be the large time-attracting solution for a certain class of coe ﬃ cients. The rate of convergence of solutions towards the SSD solution is a ﬀ ected by the choice of coe ﬃ cients and remains una ﬀ ected by the asymmetry in cell division. The uniqueness of solutions to the initial boundary value problem is also established.
Barriers and facilitators of physical activity in children with bronchiectasis: Perspectives from children and parents

Background Current bronchiectasis management guidelines recommend regular physical activity but a large proportion of children with bronchiectasis do not meet public health recommendations which call for 60 min or more of moderate-to-vigorous intensity physical activity daily. Knowing the factors that influence physical activity in children with bronchiectasis is necessary for the development of effective interventions to increase physical activity in this patient group. The objective of this study was to identify facilitators and barriers to physical activity in children with bronchiectasis unrelated to cystic fibrosis (CF) from the perspectives of children and their parents. Materials and methods This was a qualitative study informed by the theoretical domains framework (TDF). Children aged 7–15 years (8.8 years, 8.4–11.0) (median, interquartile range) and parents (45.8 years, 39.7–48.3) completed separate, semi-structured interviews (n = 21). Recordings were transcribed verbatim, and barriers and facilitators related to each TDF domain deductively coded. Emergent themes were inductively derived via consensus moderation. Results From the perspectives of children, fun with friends, organized sport and activities, and family co-participation in physical activity emerged as facilitators. Inability to keep up with their peers and time on technology emerged as barriers. From the perspectives of parents, instrumental and logistic support for physical activity and supportive social and physical activity environments emerged as facilitators, while management of symptoms associated with bronchiectasis emerged as a barrier. Conclusion Programs to increase physical activity in children with bronchiectasis should be fun, accessible, provide opportunities for social interaction and address barriers related to exercise tolerance, perceived competence, and presence of respiratory symptoms.
Influence of arginine vasopressin on the ultradian dynamics of Hypothalamic-Pituitary-Adrenal axis

Numerous studies on humans and animals have indicated that the corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) stimulate both individually and synergistically secretion of adrenocorticotropic hormone (ACTH) by corticotropic cells in anterior pituitary. With aim to characterize and better comprehend the mechanisms underlying the effects of AVP on Hypothalamic-Pituitary-Adrenal (HPA) axis ultradian dynamics, AVP is here incorporated into our previously proposed stoichiometric model of HPA axis in humans. This extended nonlinear network reaction model took into account AVP by: reaction steps associated with two separate inflows of AVP into pituitary portal system, that is synthesized and released from hypothalamic parvocellular and magnocellular neuronal populations, as well as summarized reaction steps related to its individual and synergistic action with CRH on corticotropic cells. To explore the properties of extended model and its capacity to emulate the effects of AVP, nonlinear dynamical systems theory and bifurcation analyses based on numerical simulations were utilized to determine the dependence of ultradian oscillations on rate constants of the inflows of CRH and AVP from parvocellular neuronal populations, the conditions under which dynamical transitions occur due to their synergistic action and, moreover, the types of these transitions. The results show that under certain conditions, HPA system could enter into oscillatory dynamic states from stable steady state and vice versa under the influence of synergy reaction rate constant. Transitions between these dynamical states were always through supercritical Andronov-Hopf bifurcation point. Also, results revealed the conditions under which amplitudes of ultradian oscillations could increase several-fold due to CRH and AVP synergistic stimulation of ACTH secretion in accordance with results reported in the literature. Moreover, results showed experimentally observed superiority of CRH as a stimulator of ACTH secretion compared to AVP in humans. The proposed model can be very useful in studies related to the role of AVP and its synergistic action with CRH in life-threatening circumstances such as acute homeostasis dynamic crisis, autoimmune inflammations or severe hypovolemia requiring instant or several-days sustained corticosteroid excess levels. Moreover, the model can be helpful for investigations of indirect AVP-induced HPA activity by exogenously administered AVP used in therapeutic treatment.
Analgesic efficacy and risk of low-to-medium dose intrathecal morphine in patients undergoing cardiac surgery: An updated meta-analysis

Background To evaluate the analgesic efficacy and risk of low-to-medium dose intrathecal morphine (ITM) (i.e., ≤0.5 mg) following cardiac surgery. Methods Medline, Cochrane Library, Google scholar and EMBASE databases were searched from inception to February 2022. The primary outcome was pain intensity at postoperative 24 h, while the secondary outcomes included intravenous morphine consumption (IMC), extubation time, hospital/intensive care unit (ICU) length of stay (LOS), and ITM-associated side effects (e.g., respiratory depression). Subgroup analysis was performed on ITM dosage (low: <0.3 mg vs. medium: 0.3–0.5 mg). Results Fifteen RCTs involving 683 patients published from 1988 to 2021 were included. Pooled results showed significantly lower postoperative 24-h pain scores [mean difference (MD) = −1.61, 95% confidence interval: −1.98 to −1.24, p < 0.00001; trial sequential analysis: sufficient evidence; certainty of evidence: moderate] in the ITM group compared to the controls. Similar positive findings were noted at 12 (MD = −2.1) and 48 h (MD = −1.88). Use of ITM was also associated with lower IMC at 24 and 48 h (MD: −13.69 and −14.57 mg, respectively; all p < 0.05) and early tracheal extubation (i.e., 48.08 min). No difference was noted in hospital/ICU LOS, and nausea/vomiting in both groups, but patients receiving ITM had higher risk of pruritus (relative risk = 2.88, p = 0.008). There was no subgroup difference in IMC except a lower pain score with 0.3–0.5 mg than <0.3 mg at postoperative 24 h. Respiratory depression events were not noted in the ITM group. Conclusion Our results validated the analgesic efficacy of low-to-medium dose ITM for patients receiving cardiac surgery without increasing the risk of respiratory depression.
Association between the LACE+ index and unplanned 30-day hospital readmissions in hospitalized patients with stroke

Background The LACE+ index is used to predict unplanned 30-day hospital readmissions, but its utility to predict 30-day readmission in hospitalized patients with stroke is unknown. Methods We retrospectively analyzed 1,657 consecutive patients presenting with ischemic or hemorrhagic strokes, included in an institutional stroke registry between January 2018 and August 2020. The primary outcome of interest was unplanned 30-day readmission for any reason after index hospitalization for stroke. The 30-day readmission risk was categorized by LACE+ index to high risk (≥78), medium-to-high risk (59–77), medium risk (29–58), and low risk (≤ 28). Kaplan-Meier analysis, Log rank test, and multivariable Cox regression analysis (with backward elimination) were used to determine whether the LACE+ score was an independent predictor for 30-day unplanned readmission. Results The overall 30-day unplanned readmission rate was 11.7% (194/1,657). The median LACE+ score was higher in the 30-day readmission group compared to subjects that had no unplanned 30-day readmission [74 (IQR 67–79) vs. 70 (IQR 62–75); p < 0.001]. On Kaplan-Meier analysis, the high-risk group had the shortest 30-day readmission free survival time as compared to medium and medium-to-high risk groups (p < 0.01, each; statistically significant). On fully adjusted multivariable Cox-regression, the highest LACE+ risk category was independently associated with the unplanned 30-day readmission risk (per point: HR 1.67 95%CI 1.23–2.26, p = 0.001). Conclusion Subjects in the high LACE+ index category had a significantly greater unplanned 30-day readmission risk after stroke as compared to lower LACE+ risk groups. This supports the validity of the LACE+ scoring system for predicting unplanned readmission in subjects with stroke. Future studies are warranted to determine whether LACE+ score-based risk stratification can be used to devise early interventions to mitigate the risk for unplanned readmission.
Predictors and neurological consequences of periprocedural cerebrovascular events following transcatheter aortic valve implantation with self-expanding valves

Aims To evaluate the patient- and procedure-related predictors of transcatheter aortic-valve implantation (TAVI)-associated ischemic brain lesions and to assess the effect of silent cerebral ischemic lesions (SCIL) on neurocognitive function. Methods and results We investigated 113 consecutive patients with severe aortic stenosis who underwent brain magnetic resonance imaging (MRI) within a week following TAVI. To assess periprocedural cerebral ischemic lesions, diffusion-weighted MRI was utilized. We used multivariate linear regression to identify the independent predictors of TAVI-related ischemic lesion volume (ILV) and periprocedural stroke. Neurocognitive evaluation was performed before and following TAVI at 6-month and one-year follow-up. Following TAVI, a total of 944 new cerebral ischemic lesions were detected in 104 patients (92%). The median ILV was 257 μl (interquartile range [IQR]:97.1–718.8μl) with a median lesion number of 6/patient [IQR:2–10]. The majority of ischemic lesions were clinically silent (95%), while 5% of the lesions induced a stroke, which was confirmed by MRI. Predilatation (β = 1.13[95%CI:0.32–1.93], p = 0.01) and the number of valve positioning attempts during implantation (β = 0.28[95%CI:0.06–0.50], p = 0.02) increased the log-transformed total ILV. Predilatation (OR = 12.04[95%CI:1.46–99.07], p = 0.02) and alternative access routes (OR = 7.84[95%CI:1.01–61.07], p = 0.02) were associated with stroke after adjustments for comorbidities and periprocedural factors. The presence of SCILs were not associated with a change in neurocognitive function that remained stable during the one-year follow-up. Conclusion While periprocedural ischemic lesions are frequent, most of them are clinically silent and might not impact the patients' neurocognitive function. The number of valve positioning attempts, predilatation, and alternative access routes should be taken into consideration during TAVI to reduce the ILV and risk for stroke.
Recovering groundwater for wetlands from an anthropogenic aquifer

Freshwater wetlands are groundwater-dependent ecosystems that require groundwater for saturation, for wetland plants and creatures, for maintenance of wetland soils, and thermal buffering. With worldwide wetland area in decline for decades if not centuries, finding and restoring wetlands provides enormous ecosystem and public benefits, yet so often these projects fail to yield self-sustaining wetland ecosystems. One reason is that restored wetlands are often built in places that are neither wet enough nor possess the underlying geology to sustain them, and they dry out or require continual (expensive! ) water inputs. Massachusetts is making the best of a challenging situation for the declining cranberry farming industry: while competition from less expensive land and more productive varietals shifts cranberry production to other locations, everything under historic cranberry farms is ripe for resilient wetland restoration projects. These low-lying water-rich areas are underlain by glacial geology (peats and clays) that are ideal for holding water, they possess historic seed banks of wetland plants and large accumulations of organic and hydric soils, and are currently sought-after by a statewide restoration program, for which these results provide critical information for restoration design, enabling practitioners to maximize the capture and residence time of groundwater inputs to sustain the future wetland. In this paper, we investigate the human legacy of cranberry farming on the surface of a wetland as it has created a unique hydrogeologic unit: the anthropogenic aquifer. Water moves through an anthropogenically constructed aquifer in specific and predictable ways that were engineered to favor a monoculture of cranberry plants on the surface of what once was a peatland. In order to restore this landscape to a functioning freshwater wetland, every property of the anthropogenic aquifer must be reversed. We detail observational, thermal, hydrologic, geologic and isotopic evidence for the location of groundwater inflows to Foothills Preserve in southeastern Massachusetts. The specific properties of the Anthropogenic aquifer, and the location and magnitude of groundwater discharge at this location provide crucial information for practitioners when designing plans for a self-sustaining, resilient restored freshwater wetland on this and future sites.
On sums of eigenvalues of elliptic operators on manifolds

We use the averaged variational principle introduced in a recent article on graph spectra [7] to obtain upper bounds for sums of eigenvalues of several partial differential operators of interest in geometric analysis, which are analogues of Kr{\"o}ger 's bound for Neumann spectra of Laplacians on Euclidean domains [12]. Among the operators we consider are the Laplace-Beltrami operator on compact subdomains of manifolds. These estimates become more explicit and asymptotically sharp when the manifold is conformal to homogeneous spaces (here extending a result of Strichartz [21] with a simplified proof). In addition we obtain results for the Witten Laplacian on the same sorts of domains and for Schr{\"o}dinger operators with confining potentials on infinite Euclidean domains. Our bounds have the sharp asymptotic form expected from the Weyl law or classical phase-space analysis. Similarly sharp bounds for the trace of the heat kernel follow as corollaries.
Autonomous robotic exploration with simultaneous environment and traversability models learning

In this study, we address generalized autonomous mobile robot exploration of unknown environments where a robotic agent learns a traversability model and builds a spatial model of the environment. The agent can benefit from the model learned online in distinguishing what terrains are easy to traverse and which should be avoided. The proposed solution enables the learning of multiple traversability models, each associated with a particular locomotion gait, a walking pattern of a multi-legged walking robot. We propose to address the simultaneous learning of the environment and traversability models by a decoupled approach. Thus, navigation waypoints are generated using the current spatial and traversability models to gain the information necessary to improve the particular model during the robot’s motion in the environment. From the set of possible waypoints, the decision on where to navigate next is made based on the solution of the generalized traveling salesman problem that allows taking into account a planning horizon longer than a single myopic decision. The proposed approach has been verified in simulated scenarios and experimental deployments with a real hexapod walking robot with two locomotion gaits, suitable for different terrains. Based on the achieved results, the proposed method exploits the online learned traversability models and further supports the selection of the most appropriate locomotion gait for the particular terrain types.
Feedlot growth performance and carcass characteristics of steers backgrounded on buffel grass or buffel–Desmanthus mixed pastures

Feedlot performance and carcass characteristics of tropical beef steers backgrounded on buffel grass (Cenchrus ciliaris) only or buffel grass oversown with desmanthus (Desmanthus spp. ; 11.5% initial sward botanical composition) were evaluated. It was hypothesized that tropical beef cattle steers backgrounded on buffel grass only or buffel grass oversown with desmanthus with similar backgrounding growth performance will not differ in feedlot growth performance and carcass quality. Three hundred and twelve Bos indicus × Bos taurus tropical composite steers, 20–23 months old and weighing 413 ± 24 kg, previously backgrounded on buffel grass only or buffel-desmanthus mixed pastures for 147 days were finished on a concentrate diet in the feedlot for 110 days before slaughter. Buffel–desmanthus backgrounded steers had a slightly higher average daily gain (ADG; 1.8 kg/day) than the buffel grass backgrounded steers that had 1.7 kg/day ADG (p < 0.01). However, the final live weight and dry matter intake were not different (p ≥ 0.59). All the carcass traits measured were not different (p ≥ 0.18). Only 4% buffel grass and 8% buffel-desmanthus backgrounded steers fell short of the Meat Standards Australia (MSA) index, a level that is within the 4–9% reported for cattle produced in Queensland and slaughtered between July 2019 and June 2020. These findings indicate that desmanthus can be used to background beef cattle in northern Australia vertosol soil regions, where there is a paucity of adapted pasture legumes, with no negative impact on feedlot performance and carcass quality. The hypothesis that tropical beef cattle steers backgrounded on buffel grass only pastures or buffel grass oversown with desmanthus with similar backgrounding growth performance will have similar feedlot growth performance and carcass quality was accepted.
Metabolomics and random forests in patients with complex congenital heart disease

Introduction It is increasingly common to simultaneously determine a large number of metabolites in order to assess the metabolic state of, or clarify biochemical pathways in, an organism (“metabolomics”). This approach is increasingly used in the investigation of the development of heart failure. Recently, the first reports with respect to a metabolomic approach for the assessment of patients with complex congenital heart disease have been published. Classical statistical analysis of such data is challenging. Objective This study aims to present an alternative to classical statistics with respect to identifying relevant metabolites in a classification task and numerically estimating their relative impact. Methods Data from two metabolomic studies on 20 patients with complex congenital heart disease and Fontan circulation and 20 controls were reanalysed using random forest (RF) methodology. Results were compared to those of classical statistics. Results RF analysis required no elaborate data pre-processing. The ranking of the variables with respect to classification impact (subject diseased, or not) was remarkably similar irrespective of the evaluation method used, leading to identical clinical interpretation. Conclusion In metabolomic classification in adult patients with complex congenital heart disease, RF analysis as a one-step method delivers the most adequate results with minimum effort. RF may serve as an adjunct to traditional statistics also in this small but crucial-to-monitor patient group.
Modulation of the H+/ATP coupling ratio by ADP and ATP as a possible regulatory feature in the F-type ATP synthases

F-type ATP synthases are transmembrane enzymes, which play a central role in the metabolism of all aerobic and photosynthetic cells and organisms, being the major source of their ATP synthesis. Catalysis occurs via a rotary mechanism, in which the free energy of a transmembrane electrochemical ion gradient is converted into the free energy of ATP phosphorylation from ADP and Pi, and vice versa. An ADP, tightly bound to one of the three catalytic sites on the stator head, is associated with catalysis inhibition, which is relieved by the transmembrane proton gradient and by ATP. By preventing wasteful ATP hydrolysis in times of low osmotic energy and low ATP/ADP ratio, such inhibition constitutes a classical regulatory feedback effect, likely to be an integral component of in vivo regulation. The present miniview focuses on an additional putative regulatory phenomenon, which has drawn so far little attention, consisting in a substrate-induced tuning of the H+/ATP coupling ratio during catalysis, which might represent an additional key to energy homeostasis in the cell. Experimental pieces of evidence in support of such a phenomenon are reviewed.