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In the current study, eight college students were exposed to a successive matching-to-sample (S-MTS) procedure utilizing non-verbal auditory stimuli consisting of common sounds. During emergent relations tests, participants were asked to talk aloud, and their vocal-verbal statements were transcribed and categorized as class-consistent, class-inconsistent, or irrelevant. All participants met emergence criterion for symmetry and four did so for transitivity/equivalence. Analysis of vocal-verbal statements showed a positive correlation between class-consistent statements emitted by participants and correct selection responses during S-MTS tasks. Such results suggest possible verbal mediation during emergent relations tests.

Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a group of signaling molecules derived from unsaturated fatty acids. To better understand the basis of the substrate selectivity of MRP4, we used cryogenic-electron microscopy to determine six structures of nanodisc-reconstituted MRP4 at various stages throughout its transport cycle. Substrate-bound structures of MRP4 in complex with PGE1, PGE2 and the sulfonated-sterol DHEA-S reveal a common binding site that accommodates a diverse set of organic anions and suggest an allosteric mechanism for substrate-induced enhancement of MRP4 ATPase activity. Our structure of a catalytically compromised MRP4 mutant bound to ATP-Mg2+ is outward-occluded, a conformation previously unobserved in the MRP subfamily and consistent with an alternating-access transport mechanism. Our study provides insights into the endogenous function of this versatile efflux transporter and establishes a basis for MRP4-targeted drug design.

BackgroundKinetic modeling of 18F-florbetaben provides important quantification of brain amyloid deposition in research and clinical settings but its use is limited by the requirement of arterial blood data for quantitative PET. The total-body EXPLORER PET scanner supports the dynamic acquisition of a full human body simultaneously and permits noninvasive image-derived input functions (IDIFs) as an alternative to arterial blood sampling. This study quantified brain amyloid burden with kinetic modeling, leveraging dynamic 18F-florbetaben PET in aorta IDIFs and the brain in an elderly cohort.Methods18F-florbetaben dynamic PET imaging was performed on the EXPLORER system with tracer injection (300 MBq) in 3 individuals with Alzheimer's disease (AD), 3 with mild cognitive impairment, and 9 healthy controls. Image-derived input functions were extracted from the descending aorta with manual regions of interest based on the first 30 s after injection. Dynamic time-activity curves (TACs) for 110 min were fitted to the two-tissue compartment model (2TCM) using population-based metabolite corrected IDIFs to calculate total and specific distribution volumes (VT, Vs) in key brain regions with early amyloid accumulation. Non-displaceable binding potential ([Formula: see text] was also calculated from the multi-reference tissue model (MRTM).ResultsAmyloid-positive (AD) patients showed the highest VT and VS in anterior cingulate, posterior cingulate, and precuneus, consistent with [Formula: see text] analysis. [Formula: see text]and VT from kinetic models were correlated (r² = 0.46, P

High-quality data from surveillance of vaccine-preventable disease (VPD) are critical for timely detection of and response to outbreaks. In 2019, the World Health Organization (WHO) Regional Office for Africa (AFRO) began a change from Epi Info, a statistical software package developed by the US Centers for Disease Control and Prevention (CDC), with limited capability to integrate with other information systems, affecting reporting timeliness and data use, to the District Health Information Software 2 (DHIS2), a free, open-source software platform for electronic aggregate Integrated Disease Surveillance and Response (IDSR) and case-based surveillance reporting. A national reporting system was introduced to allow countries to adopt this system. Regionally, the Epi Info database will be replaced by a DHIS2 regional data platform. This report describes phased implementation from 2019 to the present. Phase 1 (2019-2021) involved developing IDSR aggregate and case-based surveillance packages and pilot studies in Mali, Rwanda and Togo. Phase 2 (2022) included extending national implementation to 27 countries and establishing the WHO AFRO DHIS2 regional data platform. Phase 3 (from 2023 onwards) comprised building local capacity and support for national reporting to the regional platform. By February 2024, 8 of 47 AFRO countries had adopted both the aggregate IDSR and case-based surveillance packages, and 2 had successfully transferred VPD surveillance data to the AFRO regional platform. The challenges included limited human and financial resources, establishment of data-sharing and governance agreements, technical support for data transfer, and building local capacity to report to the regional platform. Transition to DHIS2 will ensure efficient data transmission to strengthen detection and response of VPD and public health emergencies through greater system integration and interoperability. Il est essentiel de disposer de donnees de surveillance de qualite sur les maladies a prevention vaccinale (MPV) pour detecter rapidement les flambees epidemiques et y riposter. En 2019, le Bureau regional de l'Organisation mondiale de la Sante (OMS) pour l'Afrique a commence a remplacer Epi Info, un progiciel statistique developpe par les Centers for Disease Control and Prevention (CDC) des Etats-Unis, s'adaptant difficilement a d'autres systemes d'information et ne permettant pas de bien tenir les delais ou de partager les donnees de maniere optimale, par le logiciel d'information sanitaire de district DHIS2 (District Health Information Software 2), une plateforme logicielle libre et gratuite pour les donnees de surveillance integree des maladies et la riposte et les donnees de surveillance basee sur l'identification des cas. Un systeme de notification au niveau national a ete mis en place, offrant aux pays la possibilite d'adopter ce nouveau systeme. Au niveau regional, la base de donnees Epi Info sera remplacee par une plateforme de donnees DHIS2 regionale. Le present rapport decrit la mise en oeuvre progressive de cette plateforme de 2019 a aujourd'hui. La phase 1 (2019-2021) a consiste a elaborer des modules pour les donnees agregees de surveillance integree des maladies et la riposte et de surveillance basee sur les cas; des essais pilotes ont ete menes au Mali, au Rwanda et au Togo. La phase 2 (2022) a vu l'extension de la mise en oeuvre au niveau national a 27 pays et la mise en place de la plateforme de donnees regionale DHIS2 du Bureau regional de l'OMS pour l'Afrique. Les activites de la phase 3 (a partir de 2023) ont porte sur le renforcement des capacites locales et l'appui aux pays pour la transmission des donnees nationales a la plateforme regionale. Les difficultes recensees concernaient le manque de ressources humaines et financieres, la necessite d'etablir des accords de partage et de gouvernance des donnees, l'appui technique pour le transfert des donnees et le renforcement des capacites locales pour la transmission des donnees a la plateforme regionale. En fevrier 2024, 8 pays parmi les 47 pays de la Region africaine de l'OMS avaient adopte les modules pour la surveillance integree des maladies et la riposte et pour la surveillance basee sur les cas, et 2 avaient transfere avec succes leurs donnees de surveillance sur les MPV vers la plateforme regionale. La transition vers la plateforme DHIS2 favorisera une transmission efficace des donnees pour renforcer la detection des MPV et des urgences de sante publique et la riposte a ces evenements grace a une meilleure integration et interoperabilite des systemes., Introduction VPD surveillance is critical to public health, as it provides data for timely detection of and response to VPD cases and outbreaks. High-quality, timely data are necessary to guide [...]

The urokinase-type plasminogen activator receptor (uPAR) is an essential regulator for cell signaling in tumor cell proliferation, adhesion, and metastasis. The ubiquitous nature of uPAR in many aggressive cancer types makes uPAR an attractive target for immunotherapy. Here, we present a rapid and successful workflow for developing cross-reactive anti-uPAR recombinant antibodies (rAbs) using high-throughput optofluidic screening of single B-cells from human uPAR-immunized mice. A total of 80 human and cynomolgus uPAR cross-reactive plasma cells were identified, and selected mouse VH/VL domains were linked to the trastuzumab (Herceptin®) constant domains for the expression of mouse-human chimeric antibodies. The resulting rAbs were characterized by their tumor-cell recognition, binding activity, and cell adhesion inhibition on triple-negative breast cancer cells. In addition, the rAbs were shown to enact antibody-dependent cellular cytotoxicity (ADCC) in the presence of either human natural killer cells or peripheral blood mononuclear cells, and were evaluated for the potential use of uPAR-targeting antibody-drug conjugates (ADCs). Three lead antibodies (11857, 8163, and 3159) were evaluated for their therapeutic efficacy in vivo and were shown to suppress tumor growth. Finally, the binding epitopes of the lead antibodies were characterized, providing information on their unique binding modes to uPAR. Altogether, the strategy identified unique cross-reactive antibodies with ADCC, ADC, and functional inhibitory effects by targeting cell-surface uPAR, that can be tested in safety studies and serve as potential immunotherapeutics.

Aggregation behavior provides bacteria protection from harsh environments and threats to survival. Two uncharacterized proteases, LapX and Lap, are important for Vibrio cholerae liquid-based aggregation. Here, we determined that LapX is a serine protease with a preference for cleavage after glutamate and glutamine residues in the P1 position, which processes a physiologically based peptide substrate with a catalytic efficiency of 180 ± 80 M-1s-1. The activity with a LapX substrate identified by a multiplex substrate profiling by mass spectrometry screen was 590 ± 20 M-1s-1. Lap shares high sequence identity with an aminopeptidase (termed VpAP) from Vibrio proteolyticus and contains an inhibitory bacterial prepeptidase C-terminal domain that, when eliminated, increases catalytic efficiency on leucine p-nitroanilide nearly four-fold from 5.4 ± 4.1 × 104 M-1s-1 to 20.3 ± 4.3 × 104 M-1s-1. We demonstrate that LapX processes Lap to its mature form and thus amplifies Lap activity. The increase is approximately eighteen-fold for full-length Lap (95.7 ± 5.6 × 104 M-1s-1) and six-fold for Lap lacking the prepeptidase C-terminal domain (11.3 ± 1.9 × 105 M-1s-1). In addition, substrate profiling reveals preferences for these two proteases that could inform in vivo function. Furthermore, purified LapX and Lap restore the timing of the V. cholerae aggregation program to a mutant lacking the lapX and lap genes. Both proteases must be present to restore WT timing, and thus they appear to act sequentially: LapX acts on Lap, and Lap acts on the substrate involved in aggregation.

New lead drugs to treat COVID-19 are beginning to emerge.

Large-scale data obtained from aggregation of already collected multi-site neuroimaging datasets has brought benefits such as higher statistical power, reliability, and robustness to the studies. Despite these promises from growth in sample size, substantial technical variability stemming from differences in scanner specifications exists in the aggregated data and could inadvertently bias any downstream analyses on it. Such a challenge calls for data normalization and/or harmonization frameworks, in addition to comprehensive criteria to estimate the scanner-related variability and evaluate the harmonization frameworks. In this study, we propose MISPEL (Multi-scanner Image harmonization via Structure Preserving Embedding Learning), a supervised multi-scanner harmonization method that is naturally extendable to more than two scanners. We also designed a set of criteria to investigate the scanner-related technical variability and evaluate the harmonization techniques. As an essential requirement of our criteria, we introduced a multi-scanner matched dataset of 3T T1 images across four scanners, which, to the best of our knowledge is one of the few datasets of this kind. We also investigated our evaluations using two popular segmentation frameworks: FSL and segmentation in statistical parametric mapping (SPM). Lastly, we compared MISPEL to popular methods of normalization and harmonization, namely White Stripe, RAVEL, and CALAMITI. MISPEL outperformed these methods and is promising for many other neuroimaging modalities.

Abstract A theoretical perspective on grandiose narcissism suggests four forms of it (sanctity, admiration, heroism, rivalry) and states that these forms conduce to different ways of thinking and acting. Guided by this perspective, we examined in a multinational and multicultural study (61 countries; N = 15,039) how narcissism forms are linked to cognitions and behaviors prompted by the COVID-19 pandemic. As expected, differences in cognitions and behaviors across narcissism forms emerged. For example, higher narcissistic rivalry predicted lower likelihood of enactment of COVID-19 prevention behaviors, but higher narcissistic sanctity predicted higher likelihood of enactment of COVID-19 prevention behaviors. Further, whereas the heroism, admiration, and rivalry narcissism forms acted in a typically antisocial manner, with high narcissism predicting greater endorsement of unfounded health beliefs, the sanctity form acted in a prosocial manner, with higher narcissism being linked to lower endorsement of unfounded COVID-19 health beliefs. Thus, the findings (a) support the idea of four narcissism forms acting differently, and (b) show that these differences reflect a double-edged sword, sometimes linking to an anti-social orientation, and sometimes linking to a pro-social orientation.

Antiviral therapeutics to treat SARS-CoV-2 are needed to diminish the morbidity of the ongoing COVID-19 pandemic. A well-precedented drug target is the main viral protease (MPro ), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure-based approach, we docked 1.2 billion non-covalent lead-like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 and 20 μM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of MPro inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like MPro versus other targets where it has been more successful, and versus other structure-based techniques against MPro itself.