There are several index insurance methodologies. Most of them rely on linear piece-wise methods. Recently, there has been studies promoting the potential of data-driven methodologies in construction ...index insurance models due to their ability to capture intricate non-linear structures. However, these types of frameworks have mainly been implemented in high-income countries due to the large amounts of data and high-frequency requirements. This paper adapts a data-driven methodology based on high-frequency satellite-based climate indices to explain flood risk and agricultural losses in the Antioquia area (Colombia). We used flood records as a proxy of crop losses, while satellite data comprises run-off, soil moisture, and precipitation variables. We analyse the period between 3 June 2000 and 31 December 2021. We used a logistic regression model as a reference point to assess the performance of a deep neural network. The results show that a neural network performs better than traditional logistic regression models for the available loss event data on the selected performance metrics. Additionally, we obtained a utility measure to derive the costs associated for both parts involved including the policyholder and the insurance provider. When using neural networks, costs associated with the policyholder are lower for the majority of the range of cut-off values. This approach contributes to the future construction of weather insurance indexes for the region where a decrease in the base risk would be expected, thus, resulting in a reduction in insurance costs.
Hepatitis C virus (HCV) enters into human hepatocytes via tetraspanin hCD81. HCV glycoprotein E2 recognizes the “head” subdomain of the large extracellular loop (LEL) of CD81 (hCD81LEL), but the ...precise mechanism of virus cell attachment and entry remains elusive. Here, by combining the structural analysis of a conspicuous number of crystallized CD81LEL molecules with molecular dynamics simulations, we show that the conformational plasticity of the hCD81LEL head subdomain is a molecular property of the receptor. The observed closed, intermediate, and open conformations of the head subdomain provide distinct binding platforms. Simulations at pH 7.4 and 4.0 indicate that this dynamism is pH modulated. The crystallized double conformation of the disulfide bridge C157-C175 at the base of the head subdomain identifies this bond as the molecular zipper of the plasticity of hCD81LEL. We propose that this conformational dependence of hCD81LEL, which is finely tuned by pH and redox conditions, enables the virus-receptor interactions to diversely re-engage at endosomal conditions.
Display omitted
•CD81LEL crystal structures cluster in closed, intermediate, and open conformations•CD81LEL crystallographic conformers are visited in molecular dynamics simulations•Molecular dynamics simulations show a CD81LEL conformational pH dependence•CD81LEL conformational pH dependence is foreseen to have a major role in HCV entry
CD81 is one of the cellular receptors of hepatitis C virus. Here, combining crystallographic and molecular dynamics studies of CD81LEL long-extracellular-loop, Cunha et al. show that its flexibility is an inherent molecular property likely to be tuned by variation in pH and redox conditions. This tuning mechanism would explain the priming role ascribed to CD81LEL in rendering the virus-receptor complex fusogenic during cell entry.
Objective
The current coronavirus disease 2019 (COVID‐19 outbreak) demands an increased need for hospitalizations in emergency departments (EDs) and critical care units. Owing to refractory ...hypoxemia, prone position ventilation has been used more frequently and patients will need repeated hemodynamic assessments. Our main objective was to show the feasibility of obtaining images to measure multiple parameters with transthoracic echocardiography during the prone position ventilation.
Methods
We enrolled 15 consecutive mechanically ventilated patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection that required prone position ventilation as a rescue maneuver for refractory hypoxemia. The studies were performed by 2 operators with training in critical care echocardiography. Measurements were done outside the patient's room and the analysis of the images was performed by 3 cardiologists with training in echocardiography.
Results
Adequate image acquisition of the left ventricle was possible in all cases; we were not able to visualize the right ventricular free wall only in 1 patient. The mean tricuspid annular plane systolic excursion was 17.8 mm, tricuspid peak systolic S wave tissue Doppler velocity 11.5 cm/s, and the right ventricular basal diameter 36.6 mm; left ventricle qualitative function was reduced in 6 patients; pericardial effusion or valvular abnormalities were not observed.
Conclusion
We showed that echocardiographic images can be obtained to measure multiple parameters during the prone position ventilation. This technique has special value in situations where there is sudden hemodynamic deterioration and it is not possible to return the patient in the supine position.
Human DNA polymerase δ is essential for DNA replication and acts in conjunction with the processivity factor proliferating cell nuclear antigen (PCNA). In addition to its catalytic subunit (p125), ...pol δ comprises three regulatory subunits (p50, p68, and p12). PCNA interacts with all of these subunits, but only the interaction with p68 has been structurally characterized. Here, we report solution NMR–, isothermal calorimetry–, and X-ray crystallography–based analyses of the p12–PCNA interaction, which takes part in the modulation of the rate and fidelity of DNA synthesis by pol δ. We show that p12 binds with micromolar affinity to the classical PIP-binding pocket of PCNA via a highly atypical PIP box located at the p12 N terminus. Unlike the canonical PIP box of p68, the PIP box of p12 lacks the conserved glutamine; binds through a 2-fork plug made of an isoleucine and a tyrosine residue at +3 and +8 positions, respectively; and is stabilized by an aspartate at +6 position, which creates a network of intramolecular hydrogen bonds. These findings add to growing evidence that PCNA can bind a diverse range of protein sequences that may be broadly grouped as PIP-like motifs as has been previously suggested.
Bats play a key role as host for multiple microorganism and virus without showing clinical manifestations of disease. After recognition of a potential threat, innate immunity triggers acute phase ...response, a systemic reaction that contributes to restrain microbial and viral growth. APR is characterized by fever, leukocytosis, and production of acute phase proteins, but also by behavioral changes, including somnolence, lethargy, and anorexia. Deploying immune responses, such as acute phase response, represents an energetic cost for vertebrates. In bats, it has been suggested that higher metabolic rates reached during flight might subsidize any inherent cost of raising metabolism to activate an immune response. Therefore, a central question is whether immune response represents a significant cost to bats and, if so, how much is the metabolic cost of these responses. Here, we assess the resting metabolic rate of
Artibeus lituratus
in response to challenge with LPS. In addition, we assessed parameters of acute phase response including fever, body mass loss, and leukocytosis in this specie. We found that challenge with LPS leads to an increase of 40% in resting metabolic rate of
A. lituratus
, concomitant with body mass loss and an increase in body temperature of 1.5 °C.
Adaptor protein 4 (AP-4) is the most recently discovered and least well-characterized member of the family of heterotetrameric adaptor protein (AP) complexes that mediate sorting of transmembrane ...cargo in post-Golgi compartments. Herein, we report the interaction of an YKFFE sequence from the cytosolic tail of the Alzheimer's disease amyloid precursor protein (APP) with the k4 subunit of AP-4. Biochemical and X-ray crystallographic analyses reveal that the properties of the APP sequence and the location of the binding site on k4 are distinct from those of other signal-adaptor interactions. Disruption of the APP-AP-4 interaction decreases localization of APP to endosomes and enhances g-secretase-catalyzed cleavage of APP to the pathogenic amyloid-b peptide. These findings demonstrate that APP and AP-4 engage in a distinct type of signal-adaptor interaction that mediates transport of APP from the trans-Golgi network (TGN) to endosomes, thereby reducing amyloidogenic processing of the protein. Highlights - A sorting signal in the cytosolic tail of APP interacts with the k4 subunit of AP-4 X-ray crystallography reveals that the APP signal binds to a distinct site on k4 Disruption of the APP-AP-4 interaction decreases APP localization to endosomes Redistribution of APP enhances g-secretase-mediated cleavage to amyloid-b peptide
Endosomes undergo extensive spatiotemporal rearrangements as proteins and lipids flux through them in a series of fusion and fission events. These controlled changes enable the concentration of cargo ...for eventual degradation while ensuring the proper recycling of other components. A growing body of studies has now defined multiple recycling pathways from endosomes to the trans-Golgi network (TGN) which differ in their molecular machineries. The recycling process requires specific sets of lipids, coats, adaptors, and accessory proteins that coordinate cargo selection with membrane deformation and its association with the cytoskeleton. Specific tethering factors and SNARE (SNAP (Soluble NSF Attachment Protein) Receptor) complexes are then required for the docking and fusion with the acceptor membrane. Herein, we summarize some of the current knowledge of the machineries that govern the retrograde transport from endosomes to the TGN.
Resveratrol is growth-suppressive and pro-apoptotic in liver cancer cells. Methionine adenosyltransferase 2B (MAT2B) encodes for two dominant variants V1 and V2 that positively regulate growth, and ...V1 is anti-apoptotic when overexpressed. Interestingly, crystal structure analysis of MAT2B protein (MATβ) protomer revealed two resveratrol binding pockets, which raises the question of the role of MAT2B in resveratrol biological activities. We found that resveratrol induced the expression of MAT2BV1 and V2 in a time- and dose-dependent manner by increasing transcription, mRNA, and protein stabilization. Following resveratrol treatment, HuR expression increased first, followed by SIRT1 and MAT2B. SIRT1 induction contributes to increased MAT2B transcription whereas HuR induction increased MAT2B mRNA stability. MATβ interacts with HuR and SIRT1, and resveratrol treatment enhanced these interactions while reducing the interaction between MATβ and MATα2. Because MATβ lowers the Ki of MATα2 for S-adenosylmethionine (AdoMet), this allowed steady-state AdoMet level to rise. Interaction among MATβ, SIRT1, and HuR increased stability of these proteins. Induction of MAT2B is a compensatory response to resveratrol as knocking down MAT2BV1 potentiated the resveratrol pro-apoptotic and growth-suppressive effects, whereas the opposite occurred with V1 overexpression. The same effect on growth occurred with MAT2BV2. In conclusion, resveratrol induces HuR, SIRT1, and MAT2B expression; the last may represent a compensatory response against apoptosis and growth inhibition. However, MATβ induction also facilitates SIRT1 activation, as the interaction stabilizes SIRT1. This complex interplay among MATβ, HuR, and SIRT1 has not been previously reported and suggests that these proteins may regulate each other's signaling.
Background: Methionine adenosyltransferase 2B protein (MATβ) binds to resveratrol, but it exerts the opposite effects on growth and apoptosis.
Results: Resveratrol induces HuR, SIRT1, and MATβ expression. These proteins interact, which stabilizes them. MATβ induction blunts the resveratrol effect on growth and apoptosis.
Conclusion: MATβ-HuR-SIRT1 interaction impacts resveratrol actions.
Significance: This is the first demonstration of MATβ in SIRT1 signaling.
PDF
