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We compare various bank capital regulation regimes using a dynamic equilibrium model of relationship lending in which banks are unable to access the equity markets every period and the business cycle determines loans' probabilities of default. Banks hold endogenous capital buffers as a precaution against shocks that impair their future lending capacity. We find that Basel II is more procyclical than Basel I but makes banks safer, and it is generally superior in welfare terms. For high social costs of bank failure, the optimal capital requirements are higher but less cyclically varying, like those currently targeted by Basel III.

Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR-/-) and mice overexpressing C3a in the brain, we uncovered 2 opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR-/- mice; C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity, and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within a convenient time window holds translational promise to improve outcome after ischemic stroke.

Locally advanced rectal cancer is usually treated with preoperative chemoradiation. After chemoradiation and surgery, 15–27% of the patients have no residual viable tumour at pathological examination, a pathological complete response (pCR). This study established whether patients with pCR have better long-term outcome than do those without pCR. In PubMed, Medline, and Embase we identified 27 articles, based on 17 different datasets, for long-term outcome of patients with and without pCR. 14 investigators agreed to provide individual patient data. All patients underwent chemoradiation and total mesorectal excision. Primary outcome was 5-year disease-free survival. Kaplan-Meier survival functions were computed and hazard ratios (HRs) calculated, with the Cox proportional hazards model. Subgroup analyses were done to test for effect modification by other predicting factors. Interstudy heterogeneity was assessed for disease-free survival and overall survival with forest plots and the Q test. 484 of 3105 included patients had a pCR. Median follow-up for all patients was 48 months (range 0–277). 5-year crude disease-free survival was 83·3% (95% CI 78·8–87·0) for patients with pCR (61/419 patients had disease recurrence) and 65·6% (63·6–68·0) for those without pCR (747/2263; HR 0·44, 95% CI 0·34–0·57; p<0·0001). The Q test and forest plots did not suggest significant interstudy variation. The adjusted HR for pCR for failure was 0·54 (95% CI 0·40–0·73), indicating that patients with pCR had a significantly increased probability of disease-free survival. The adjusted HR for disease-free survival for administration of adjuvant chemotherapy was 0·91 (95% CI 0·73–1·12). The effect of pCR on disease-free survival was not modified by other prognostic factors. Patients with pCR after chemoradiation have better long-term outcome than do those without pCR. pCR might be indicative of a prognostically favourable biological tumour profile with less propensity for local or distant recurrence and improved survival. None.

Background Both Alzheimer’s disease (AD) and type 2 diabetes (T2D) share common pathological features including inflammation, insulin signaling alterations, or vascular damage. AD has no successful treatment, and the close relationship between both diseases supports the study of antidiabetic drugs to limit or slow down brain pathology in AD. Empagliflozin (EMP) is a sodium-glucose co-transporter 2 inhibitor, the newest class of antidiabetic agents. EMP controls hyperglycemia and reduces cardiovascular comorbidities and deaths associated to T2D. Therefore, we have analyzed the role of EMP at the central level in a complex mouse model of AD-T2D. Methods We have treated AD-T2D mice (APP/PS1xdb/db mice) with EMP 10 mg/kg for 22 weeks. Glucose, insulin, and body weight were monthly assessed. We analyzed learning and memory in the Morris water maze and the new object discrimination test. Postmortem brain assessment was conducted to measure brain atrophy, senile plaques, and amyloid-β levels. Tau phosphorylation, hemorrhage burden, and microglia were also measured in the brain after EMP treatment. Results EMP treatment helped to maintain insulin levels in diabetic mice. At the central level, EMP limited cortical thinning and reduced neuronal loss in treated mice. Hemorrhage and microglia burdens were also reduced in EMP-treated mice. Senile plaque burden was lower, and these effects were accompanied by an amelioration of cognitive deficits in APP/PS1xdb/db mice. Conclusions Altogether, our data support a feasible role for EMP to reduce brain complications associated to AD and T2D, including classical pathological features and vascular disease, and supporting further assessment of EMP at the central level.

The firing of dopaminergic midbrain neurons is thought to reflect prediction errors (PE) that depend on the difference between the value of expected and received rewards. However, recent work has demonstrated that unexpected changes in value-neutral outcome features, such as identity, can evoke similar responses. It remains unclear whether the magnitude of these identity PEs scales with the perceptual dissimilarity of expected and received rewards, or whether they are independent of perceptual similarity. We used a Pavlovian transreinforcer reversal task to elicit identity PEs for value-matched food odor rewards, drawn from two perceptual categories (sweet, savory). Replicating previous findings, identity PEs were correlated with fMRI activity in midbrain, OFC, piriform cortex, and amygdala. However, the magnitude of identity PE responses was independent of the perceptual distance between expected and received outcomes, suggesting that identity comparisons underlying sensory PEs may occur in an abstract state space independent of straightforward sensory percepts.

The NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) is a critical intracellular inflammasome sensor and an important clinical target against inflammation-driven human diseases. Recent studies have elucidated its transition from a closed cage to an activated disk-like inflammasome, but the intermediate activation mechanism remains elusive. Here we report the cryo-electron microscopy structure of NLRP3, which forms an open octamer and undergoes a ~ 90° hinge rotation at the NACHT domain. Mutations on open octamer’s interfaces reduce IL-1β signaling, highlighting its essential role in NLRP3 activation/inflammasome assembly. The centrosomal NIMA-related kinase 7 (NEK7) disrupts large NLRP3 oligomers and forms NEK7/NLRP3 monomers/dimers which is a critical step preceding the assembly of the disk-like inflammasome. These data demonstrate an oligomeric cooperative activation of NLRP3 and provide insight into its inflammasome assembly mechanism. NLRP3 is a critical intracellular inflammasome sensor and an important clinical target against inflammation-driven human diseases. Here, the authors determined Cryo-EM structures of human NLRP3 in its closed and open states, elucidating the mechanism of NLRP3 inflammasome activation.

This paper explores how motivating an incumbent CEO to undertake actions that improve the effectiveness of his management interacts with the firm's policy on CEO replacement. Such policy depends on the presence and the size of severance pay in the CEO's compensation package and on the CEO's influence on the board of directors regarding his own replacement (i.e., entrenchment). We explain when and why the combination of some degree of entrenchment and a sizeable severance package is desirable. The analysis offers predictions about the correlation between entrenchment, severance pay, and incentive compensation.

Social contacts help to find jobs, but not necessarily in the occupations where workers are most productive. Hence social contacts can generate mismatch between workers' occupational choices and their productive advantage. Accordingly, social networks can lead to low labour force quality, low returns to firms' investment and depressed aggregate productivity. We analyse surveys from both the US and Europe including information on job finding through contacts. Consistent with our predictions, contacts reduce unemployment duration by 1–3 months on average, but they are associated with wage discounts of at least 2.5%. We also find some evidence of negative externalities on aggregate productivity.

In surveillance and monitoring systems, the use of mobile vehicles or unmanned aerial vehicles (UAVs), like the drone type, provides advantages in terms of access to the environment with enhanced range, maneuverability, and safety due to the ability to move omnidirectionally to explore, identify, and perform some security tasks. These activities must be performed autonomously by capturing data from the environment; usually, the data present errors and uncertainties that impact the recognition and resolution in the detection and identification of objects. The resolution in the acquisition of data can be improved by integrating data sensor fusion systems to measure the same physical phenomenon from two or more sensors by retrieving information simultaneously. This paper uses the constant turn and rate velocity (CTRV) kinematic model of a drone but includes the angular velocity not considered in previous works as a complementary alternative in Lidar and Radar data sensor fusion retrieved using UAVs and applying the extended Kalman filter (EKF) for the detection of moving targets. The performance of the EKF is evaluated by using a dataset that jointly includes position data captured from a LiDAR and a Radar sensor for an object in movement following a trajectory with sudden changes. Additive white Gaussian noise is then introduced into the data to degrade the data. Then, the root mean square error (RMSE) versus the increase in noise power is evaluated, and the results show an improvement of 0.4 for object detection over other conventional kinematic models that do not consider significant trajectory changes.

Computational chemistry predicts that atomic motions on the femtosecond timescale are coupled to transition-state formation (barrier-crossing) in human purine nucleoside phosphorylase (PNP). The prediction is experimentally supported by slowed catalytic site chemistry in isotopically labeled PNP (13C,15N, and ²H). However, other explanations are possible, including altered volume or bond polarization from carbon-deuterium bonds or propagation of the femtosecond bond motions into slower (nanoseconds to milliseconds) motions of the larger protein architecture to alter catalytic site chemistry. We address these possibilities by analysis of chemistry rates in isotope-specific labeled PNPs. Catalytic site chemistry was slowed for both [²H]PNP and [13C,15N]PNP in proportion to their altered protein masses. Secondary effects emanating from carbon–deuterium bond properties can therefore be eliminated. Heavy-enzyme mass effects were probed for local or global contributions to catalytic site chemistry by generating [15N, ²H]His₈-PNP. Of the eight His per subunit, three participate in contacts to the bound reactants and five are remote from the catalytic sites. [15N, ²H]His₈-PNP had reduced catalytic site chemistry larger than proportional to the enzymatic mass difference. Altered barrier crossing when only His are heavy supports local catalytic site femtosecond perturbations coupled to transitionstate formation. Isotope-specific and amino acid specific labels extend the use of heavy enzyme methods to distinguish global from local isotope effects.