Miracle-dz/UniFAR-FTUs huggingface dataset:
Myocardial MMP-2 contributes to SERCA2a proteolysis during cardiac ischemia-reperfusion injury.

AIMS Matrix metalloproteinase-2 (MMP-2) is a zinc dependent protease which contributes to cardiac contractile dysfunction when activated during myocardial ischemia-reperfusion (IR) injury. MMP-2 is localized to several subcellular sites inside cardiac myocytes, however, its role in the sarcoplasmic reticulum (SR) is unknown. The Ca2+ ATPase SERCA2a, which pumps cytosolic Ca2+ into the SR to facilitate muscle relaxation, is degraded in cardiac IR injury, however, the protease responsible for this is unclear. We hypothesized that MMP-2 contributes to cardiac contractile dysfunction by proteolyzing SERCA2a, thereby impairing its activity in IR injury. METHODS AND RESULTS Isolated rat hearts were subjected to IR injury in the presence or absence of the selective MMP inhibitor ARP-100, or perfused aerobically as a control. Inhibition of MMP activity with ARP-100 significantly improved the recovery of cardiac mechanical function and prevented the increase of a 70 kDa SERCA2a degradation fragment following IR injury, although 110 kDa SERCA2a and phospholamban levels appeared unchanged. Electrophoresis of IR heart samples followed by LC-MS/MS confirmed the presence of a SERCA2a fragment of ∼70 kDa. MMP-2 activity co-purified with SR enriched microsomes prepared from the isolated rat hearts. Endogenous SERCA2a in SR enriched microsomes was proteolyzed to ∼70 kDa products when incubated in vitro with exogenous MMP-2. MMP-2 also cleaved purified porcine SERCA2a in vitro. SERCA activity in SR enriched microsomes was decreased by IR injury, however, this was not prevented with ARP-100. CONCLUSIONS This study shows that MMP-2 activity is found in SR enriched microsomes from heart muscle and that SERCA2a is proteolyzed by MMP-2. The cardioprotective actions of MMP inhibition in myocardial IR injury may include the prevention of SERCA2a degradation.
Dynamic multilevel graph layout and visualisation

This thesis addresses the issue of efficient dynamic graph drawing for large scale connected graphs with around 10,000 vertices. It contains three main contributions. Firstly, an efficient method for approximating the n-body calculations used in Force Directed Placement (FDP) is described, exploiting use of a multilevel scheme to approximate distance between groups of vertices much like the Barnes Hut Octree. The method suggests better representation of the graphs underlying relationships. In experiments this algorithm, referred to as Multilevel Global Force (MGF), reduces running time by an average of 40% compared to the popular Barnes Hut Octree approximation method. Secondly, optimisation methods used in static graph drawing (such as multilevel and approximation schemes) are adapted for use in dynamic graph drawing, simultaneously improving the quality of layouts produced and reducing the complexity such that large graphs with thousands of vertices can be drawn in interactive time. Thirdly, several techniques are introduced for incorporating graph changes into the dynamic graph drawing to differing extents, allowing the viewer to decide whether the ongoing layout should preserve the original layout or prioritise the graph changes. The works are combined to form an efficient multilevel dynamic graph drawing algorithm.
Reduced arterial compliance along the cerebrovascular tree predicts cognitive slowing in multiple sclerosis: Evidence for a neurovascular uncoupling hypothesis

Background: Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases following neural activity, is essential for efficient cognition. Loss of vascular compliance along the cerebrovascular tree would result in suboptimal vasodilation, neurovascular uncoupling, and cognitive slowing. Objective: To assess vascular compliance along the cerebrovascular tree and its relationship to MS-related cognition. Methods: We tested vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested layers. MS patients and healthy controls were scanned using a dual-echo functional magnetic resonance imaging (fMRI) sequence while they periodically inhaled room air and hypercapnic gas mixture. Cerebrovascular reactivity was calculated from both cerebral blood flow (arterial) and blood-oxygen-level-dependent signal (venous) increases per unit increase in end-tidal CO2. Results: Arterial cerebrovascular reactivity changes along the cerebrovascular tree were reduced in cognitively slow MS compared to cognitively normal MS and healthy controls. These changes were fit to exponential functions, the decay constant (arterial compliance index; ACI) of which was associated with individual subjects’ reaction time and predicted reaction time after controlling for disease processes. Conclusion: Such associations suggest prospects for utility of ACI in predicting future cognitive disturbances, monitoring cognitive deficiencies and therapeutic responses, and implicates neurovascular uncoupling as a mechanism of cognitive slowing in MS.
Sex differences in limbic network and risk‐taking propensity in healthy individuals

Little is known about the structural neural substrates that may contribute to sex differences in risk‐taking propensity (RTP). A close association between risk‐seeking behavior and the emotional‐regulation network led us to hypothesize that the sex differences in RTP would be associated with sex differences in brain morphometry of the limbic network (LN). We collected RTP scores using the bubble sheet version of the evaluation of risk (EVAR) scale and neuroanatomical data from 57 healthy individuals (29 males). The EVAR scale included sub‐scales measuring recklessness/impulsivity, self‐confidence, and need for control (NFC). We observed significant sex differences in NFC showing greater desire for control and dominance in males than females (multivariate analysis of covariance, MANCOVAN: p = .01). Morphometry analysis showed that it was only the right LN, which showed significant sex differences in normalized surface area, normalized cortical volume, and adjusted mean curvature index (females > males) at p < . 01 (MANCOVAN, corrected for multiple comparisons). Correlation analysis showed that greater curvature of the right LN was significantly associated with lower desire for control in high‐risk events (r = −.31, p = .02 at 95% CI of [−0.53, –0.05]). Our findings suggest that the normalized cortical measures could indicate specific sex differences in brain morphometry, particularly within the LN. The curvature index was the only differentiating factor for greater/lower propensity for risk‐taking behavior in overall sample. Therefore, the LN and the curvature measures could be key biomarkers, which play an important role in predicting risk‐taking behavior.
Potential Impact of Construction Noise on Selected Zoo Animals

Simple Summary Animals in zoos can adapt to many noises they hear on a regular basis. However, construction noise that is intense or occurs unpredictably may negatively impact the welfare state of some animals and induce a chronic stress response. This study aimed to understand the behavioral response to construction noise of selected species in an urban zoo in order to guide mitigating actions in advance of, and during, a planned construction project. The behavior of elephants, giraffes, emus and alligators was recorded during 90-min exposures to different sound environments including ambient sound, and four construction sound treatments. A non-invasive measure of physiological stress response was also measured in emus. All species appeared to respond to the recorded noise, with giraffes, elephants and emu, demonstrating behavioral changes potentially indicative of agitation or stress. This study has implications for the trade-offs that occur when zoos seek to improve long-term animal welfare through enclosure refurbishment and short-term impacts on animals exposed to construction noise. Abstract In anticipation of a major construction project in an urban New Zealand zoo, a study was initiated to assess the response to construction noise of selected animal species (elephant, giraffe, emu and alligator) previously observed to be sensitive to this kind of noise. The overall aim was to detect any signs of aversive responses to this noise to enable keepers to recognize these and take any necessary mitigating actions during the construction period. The experimental approach involved the creation of acoustic maps of each focal animal enclosure, a series of 90-min video recordings of the animals’ behavior in response to ambient noise (control) and amplified broadcast of pre-recorded continuous and intermittent construction noise. Concentration of fecal corticosterone metabolites was also measured for the emus. Key findings were that giraffes, elephants and emus appeared to show an increase in behaviors that could indicate stress or agitation including vigilance and locomotion and may prefer quieter regions of their enclosure during sound exposure. Giraffes also increased close contact with conspecifics when exposed to construction noise. While alligators did not show clear evidence of noise-related stress, our findings indicated that all focal species showed some behavioral responses to recorded construction noise.
A mid-level organization of the ventral stream

Human object-selective cortex shows a large-scale organization characterized by the high-level properties of both animacy and object-size. To what extent are these neural responses explained by primitive perceptual features that distinguish animals from objects and big objects from small objects? To address this question, we used a texture synthesis algorithm to create a novel class of stimuli—texforms—which preserve some mid-level texture and form information from objects while rendering them unrecognizable. We found that unrecognizable texforms were sufficient to elicit the large-scale organizations of object-selective cortex along the entire ventral pathway. Further, the structure in the neural patterns elicited by texforms was well predicted by curvature features and by intermediate layers of a deep convolutional neural network, supporting the mid-level nature of the representations. These results provide clear evidence that a substantial portion of ventral stream organization can be accounted for by coarse texture and form information, without requiring explicit recognition of intact objects. SIGNIFICANCE STATEMENT While neural responses to object categories are remarkably systematic across human visual cortex, the nature of these responses been hotly debated for the past 20 years. In this paper, a new class of stimuli (“texforms”) is used to examine how mid-level features contribute to the large-scale organization of the ventral visual stream. Despite their relatively primitive visual appearance, these unrecognizable texforms elicited the entire large-scale organizations of the ventral stream by animacy and object size. This work demonstrates that much of ventral stream organization can be explained by relatively primitive mid-level features, without requiring explicit recognition of the objects themselves.
Different factors underlie recurrent and de novo organ involvement in immunoglobulin G4-related disease.

OBJECTIVES In IgG4-related disease (IgG4-RD), relapse including recurrent organ involvement (ROI) and de novo organ involvement (DNOI) occurs frequently during the clinical course. This study aimed to clarify the differences between the risk factors underlying ROI and DNOI in IgG4-RD. METHODS We retrospectively investigated factors related to ROI and DNOI in 86 IgG4-RD patients. For assessment of factors related to ROI and DNOI, we performed uni- and multivariate Cox regression analyses. On stepwise multivariate analysis, we applied the variables with P < 0.1 in the univariate analysis and the predictors of relapse suggested in past reports. RESULTS During the mean follow-up period of 63.1 months, ROI was detected at 1.0-120 months after diagnosis in 20 patients, 4 of whom were not receiving glucocorticoid (GC) at the time of ROI. In contrast, DNOI was detected at 5.0-120 months after diagnosis in 15 patients, 8 of whom were not receiving GC at the time of DNOI. In the multivariate analysis, blood eosinophil counts at diagnosis [per 100/μl; hazard ratio (HR) 1.072 (95% CI 1.018, 1.129)] and continuation of GC [vs discontinuation or observation without GC; HR 0.245 (95% CI 0.076, 0.793)] had a significant impact on the time to DNOI, whereas age [HR 0.942 (95% CI 0.899, 0.986)] and ANA positivity [vs negativity; HR 6.632 (95% CI 1.892, 23.255)] had a significant impact on the time to ROI. CONCLUSION The present study suggests that the risk factors of ROI and DNOI are different in IgG4-RD, highlighting the need for different preventative strategies.
Are drought resistance strategies associated with life history strategy? A commentary on: 'Arabidopsis species deploy distinct strategies to cope with drought stress'.

This article comments on: M. Bouzid, F. He, G. Schmitz, R. E. Häusler, A. P. M. Weber, T. Mettler-Altmann and J. de Meaux. 2019. Arabidopsis species deploy distinct strategies to cope with drought stress. Annals of Botany 124(1): 27–40.
Dilated cardiomyopathy mutation (R174W) in troponin T attenuates the length-mediated increase in crossbridge recruitment and myofilament Ca2+ sensitivity.

Alterations in length-dependent activation (LDA) may constitute a mechanism by which cardiomyopathy mutations lead to deleterious phenotypes and compromised heart function because LDA underlies the molecular basis by which the heart tunes myocardial force production on a beat-to-beat basis (Frank-Starling mechanism). In this study, we investigated the effect of DCM-linked mutation (R173W) in human cardiac troponin T (TnT) on myofilament LDA. R173W mutation is associated with left ventricular dilatation and systolic dysfunction, and is found in multiple families. R173W mutation is in the central region (residues 80-180) of TnT, which is known to be important for myofilament cooperativity and crossbridge (XB) recruitment. Steady-state and dynamic contractile parameters were measured in detergent-skinned guinea pig left ventricular muscle fibers reconstituted with recombinant guinea pig wild-type TnT (TnTWT) or mutant TnT (TnTR174W; guinea pig analog of human R173W mutation) at two different sarcomere lengths (SL): short (1.9 µm) and long (2.3 µm). TnTR174W decreased pCa50 (-log [Ca2+]free required for half-maximal activation) to a greater extent at long than at short SL; for example, pCa50 decreased by 0.12 pCa units at long SL and by 0.06 pCa units at short SL. Differential changes in pCa50 at short and long SL attenuated the SL-dependent increase in myofilament Ca2+ sensitivity (ΔpCa50) in TnTR174W fibers; ΔpCa50 was 0.10 units in TnTWT fibers but only 0.04 units in TnTR174W fibers. Furthermore, TnTR174W blunted the SL-dependent increase in the magnitude of XB recruitment. Our observations suggest that the R173W mutation in human cardiac TnT may impair Frank-Starling mechanism.
Decreased Sensitivity of the Serological Detection of Feline Immunodeficiency Virus Infection Potentially Due to Imported Genetic Variants

Feline immunodeficiency virus (FIV) is a lentivirus of domestic cats worldwide. Diagnosis usually relies on antibody screening by point-of-care tests (POCT), e.g., by enzyme-linked immunosorbent assays (ELISA), and confirmation using Western blot (WB). We increasingly observed ELISA-negative, WB-positive samples and aimed to substantiate these observations using 1194 serum/plasma samples collected from 1998 to 2019 primarily from FIV-suspect cats. While 441 samples tested positive and 375 tested negative by ELISA and WB, 81 samples had discordant results: 70 were false ELISA-negative (WB-positive) and 11 were false ELISA-positive (WB-negative); 297 ambiguous results were not analyzed further. The diagnostic sensitivity and specificity of the ELISA (82% and 91%, respectively) were lower than those reported in 1995 (98% and 97%, respectively). The diagnostic efficiency was reduced from 97% to 86%. False ELISA-negative samples originated mainly (54%) from Switzerland (1995: 0%). Sixty-four false ELISA-negative samples were available for POCT (SNAPTM/WITNESSR): five were POCT-positive. FIV RT-PCR was positive for two of these samples and was weakly positive for two ELISA- and POCT-negative samples. Low viral loads prohibited sequencing. Our results suggest that FIV diagnosis has become more challenging, probably due to increasing travel by cats and the introduction of new FIV isolates not recognized by screening assays.
Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration

Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with intravitreal bevacizumab, ranibizumab, and aflibercept has been conducted. Moreover, the factors that can influence the vitreous pharmacokinetics of these drugs, as well as the methods that were used in the studies for analytical determination, have been exposed. These anti-VEGF drugs present different charge and molecular weights, which play an important role in vitreous distribution and elimination. The pharmacokinetic parameters that were collected differ depending on the species that were involved in the studies and on physiological and pathological conditions, such as vitrectomy and lensectomy. Knowledge of the intravitreal pharmacokinetics of the anti-VEGF drugs that were used in clinical practice is of vital importance.
POF Smart Carpet: A Multiplexed Polymer Optical Fiber-Embedded Smart Carpet for Gait Analysis

This paper presents the development of a smart carpet based on polymer optical fiber (POF) for ground reaction force (GRF) and spatio-temporal gait parameter assessment. The proposed carpet has 20 intensity variation-based sensors on one fiber with two photodetectors for acquisition, each one for the response of 10 closer sensors. The used multiplexing technique is based on side-coupling between the light sources and POF lateral sections in which one light-emitting diode (LED) is activated at a time, sequentially. Three tests were performed, two for sensor characterization and one for validation of the smart carpet, where the first test consisted of the application of calibrated weights on the top of each sensor for force characterization. In the second test, the foot was positioned on predefined points distributed on the carpet, where a mean relative error of 2.9% was obtained. Results of the walking tests on the proposed POF-embedded smart carpet showed the possibility of estimating the GRF and spatio-temporal gait parameters (step and stride lengths, cadence, and stance duration). The obtained results make possible the identification of gait events (stance and swing phases) as well as the stance duration and double support periods. The proposed carpet is a low-cost and reliable tool for gait analysis in different applications.
Synthesis and Characterization of Bodipy-FL-Cyclosporine A as a Substrate for Multidrug Resistance-Linked P-Glycoprotein (ABCB1)

Fluorescent conjugates of drugs can be used to study cellular functions and pharmacology. These compounds interact with proteins as substrates or inhibitors, helping in the development of unique fluorescence-based methods to study in vivo localization and molecular mechanisms. P-glycoprotein (P-gp, ABCB1) is an ATP-binding cassette (ABC) transporter that effluxes most anticancer drugs from cells, contributing to the development of drug resistance. To study the transport function of P-gp, we synthesized a Bodipy-labeled fluorescent conjugate of cyclosporine A (BD-CsA). After synthesis and characterization of its chemical purity, BD-CsA was compared with the commonly used 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-CsA probe. In flow cytometry assays, the fluorescence intensity of BD-CsA was almost 10 times greater than that of NBD-CsA, enabling us to use significantly lower concentrations of BD-CsA to achieve the same fluorescence levels. We found that BD-CsA is recognized as a transport substrate by both human and mouse P-gp. The rate of efflux of BD-CsA by human P-gp is comparable to that of NBD-CsA. The transport of BD-CsA was inhibited by tariquidar, with similar IC50 values to those for NBD-CsA. BD-CsA and NBD-CsA both partially inhibited the ATPase activity of P-gp with similar IC50 values. In silico docking of BD-CsA and NBD-CsA to the human P-gp structure indicates that they both bind in the drug-binding pocket with similar docking scores and possibly interact with similar residues. Thus, we demonstrate that BD-CsA is a sensitive fluorescent substrate of P-gp that can be used to efficiently study the transporter’s localization and function in vitro and in vivo. SIGNIFICANCE STATEMENT The goal of this study was to develop an effective probe to study drug transport by P-glycoprotein (P-gp). Fluorophore-conjugated substrates are useful to study the P-gp transport mechanism, structural characteristics, and development of its inhibitors. Cyclosporine A (CsA), a cyclic peptide comprising 11 amino acids, is a known substrate of P-gp. P-gp affects CsA pharmacokinetics and interactions with other coadministered drugs, especially during transplant surgeries and treatment of autoimmune disorders, when CsA is given as an immunosuppressive agent. We synthesized and characterized Bodipy-FL-CsA as an avid fluorescent substrate that can be used to study the function of P-gp both in vitro and in vivo. We demonstrate that Bodipy-FL-conjugation does not affect the properties of CsA as a P-gp substrate.
Hypoxia causes woodlice (Porcellio scaber) to select lower temperatures and impairs their thermal performance and heat tolerance

Environmental temperatures and oxygen availability are important for the balance between oxygen supply and demand. Terrestrial organisms are generally perceived to be less limited by access to oxygen than their aquatic counterparts. Nevertheless, even terrestrial environments can be deficient in oxygen, especially for organisms occurring in soil, litter, wood, rotten fruit or at high elevations. While isopods are the best adapted to a terrestrial lifestyle among crustaceans, many species, including woodlice, occupy environmental gradients of temperature and oxygen. To investigate whether mismatches between oxygen supply and demand can result in a loss of performance in a terrestrial organism, we studied the effects of atmospheric oxygen concentration on the thermal performance of the common rough woodlouse (Porcellio scaber). We compared the thermal preference, thermal sensitivity of running speed, and tolerance to extreme temperatures of woodlice exposed to one of two oxygen concentrations (21% - normoxia, 7% - hypoxia). Under hypoxia, P. scaber preferred microhabitats with temperatures that were on average 3°C lower than those preferred under normoxia. The running speed tended to reach its maximum at a lower temperature under hypoxia than under normoxia (25.13°C vs 28.87°C, respectively, although p was equal to 0.09), and normoxic woodlice ran approximately 1.5-fold faster than hypoxic woodlice at the point of maximum speed. Heat tolerance was significantly lower under hypoxia (38.9°C) than under normoxia (40.7°C), but there was no difference in cold tolerance (5.81°C under normoxia and 5.44°C under hypoxia). Overall, our results indicate that environmental gradients of temperature and oxygen may shape the physiological performance of terrestrial ectotherms, likely via their effects on the balance between oxygen supply and demand, which may have fitness consequences for these organisms in nature.