WelQrate: Defining the Gold Standard in Small Molecule Drug Discovery Benchmarking.

While deep learning has revolutionized computer-aided drug discovery, the AI community has predominantly focused on model innovation and placed less emphasis on establishing best benchmarking practices. We posit that without a sound model evaluation framework, the AI community's efforts cannot reach their full potential, thereby slowing the progress and transfer of innovation into real-world drug discovery. Thus, in this paper, we seek to establish a new gold standard for small molecule drug discovery benchmarking, .

"Sounding Black": Speech Stereotypicality Activates Racial Stereotypes and Expectations About Appearance.

Black Americans who are perceived as more racially phenotypical-that is, who possess more physical traits that are closely associated with their race-are more often associated with racial stereotypes. These stereotypes, including assumptions about criminality, can influence how Black Americans are treated by the legal system. However, it is unclear whether other forms of racial stereotypicality, such as a person's way of speaking, also activate stereotypes about Black Americans.

Challenges in the Discovery and Optimization of mGlu Heterodimer Positive Allosteric Modulators.

Background: This article describes the challenges in the discovery and optimization of mGlu2/4 heterodimer Positive Allosteric Modulators (PAMs).

Methods: Initial forays based on VU0155041, a PAM of both the mGlu4 homodimer and the mGlu2/4 heterodimer, led to flat, intractable SAR that precluded advancement. Screening of a collection of 1,152 FDA approved drugs led to the discovery that febuxostat, an approved xanthine oxidase inhibitor, was a moderately potent PAM of the mGlu heterodimer (EC = 3.

Regulation of Diabetes: a Therapeutic Strategy for Alzheimer's Disease?

Accumulated evidence suggests that sporadic cases of Alzheimer's disease (AD) make up more than 95% of total AD patients, and diabetes has been implicated as a strong risk factor for the development of AD. Diabetes shares pathological features of AD, such as impaired insulin signaling, increased oxidative stress, increased amyloid-beta (Aβ) production, tauopathy and cerebrovascular complication. Due to shared pathologies between the two diseases, anti-diabetic drugs may be a suitable therapeutic option for AD treatment.

Labeling and Imaging of Amyloid Plaques in Brain Tissue Using the Natural Polyphenol Curcumin.

Deposition of amyloid beta protein (Aβ) in extra- and intracellular spaces is one of the hallmark pathologies of Alzheimer's disease (AD). Therefore, detection of the presence of Aβ in AD brain tissue is a valuable tool for developing new treatments to prevent the progression of AD. Several classical amyloid binding dyes, fluorochrome, imaging probes, and Aβ-specific antibodies have been used to detect Aβ histochemically in AD brain tissue.

VU0810464, a non-urea G protein-gated inwardly rectifying K (K 3/GIRK) channel activator, exhibits enhanced selectivity for neuronal K 3 channels and reduces stress-induced hyperthermia in mice.

Background And Purpose: G protein-gated inwardly rectifying K (K 3) channels moderate the activity of excitable cells and have been implicated in neurological disorders and cardiac arrhythmias. Most neuronal K 3 channels consist of K 3.1 and K 3.

Radiation resistant PIDECα cell using photon intermediate direct energy conversion and a Po source.

Radiation damage is a significant concern with both alphavoltaic and betavoltaic cells because their performance degrades, especially with high-energy - (>200keV) beta and alpha particles. Indirect excitation methods, such as the Photon Intermediate Direct Energy Conversion (PIDEC) framework, can protect the transducer from radiation. A nuclear battery using a Sr beta source was constructed by the author's research group, which demonstrated the radiation resistance of a PIDEC cell driven by beta particles (PIDECβ cell).

Expression of Alzheimer-Type Neurofibrillary Epitopes in Primary Rat Cortical Neurons Following Infection with Enterococcus faecalis.

The neurofibrillary tau pathology and amyloid deposits seen in Alzheimer's disease (AD) also have been seen in bacteria-infected brains. However, few studies have examined the role of these bacteria in the generation of tau pathology. One suggested link between infection and AD is edentulism, the complete loss of teeth.

Inhibition of p53 attenuates ischemic stress-induced activation of astrocytes.

In cerebral ischemia, studies of cell death have focused primarily on neurons, but recent work indicates that ischemia also causes damage to astrocytes. Activation of astrocytes is a typical brain response to stress stimuli and is evidenced by changes in cellular function and morphology, as well as upregulation of glial fibrillary acidic protein. The tumor-suppressor transcription factor p53 has recently been implicated as a mediator of ischemia-induced neuronal death, but very little is known about its role in the activation or the death of astrocytes.

Correlates of the multidimensional construct of hypnotizability: paranormal belief, fantasy proneness, magical ideation, and dissociation.

Hypnotizability is a multifaceted construct that may relate to multiple aspects of personality and beliefs. This study sought to address 4 known correlates of hypnotizability to aid in its understanding. Eighty undergraduates completed the Magical Ideation Scale (MIS), the Creative Experiences Questionnaire (CEQ), the Australian Sheep-Goat Scale (ASGS), and the Dissociative Experiences Scale (DES) and then were administered the Creative Imagination Scale (CIS).

Hypnotizability, not suggestion, influences false memory development.

Hypnotizability influences the development of false memories. In Experiment 1, participants heard a positive or negative suggestion regarding hypnosis and then listened to 8 Deese-Roediger-McDermott (DRM) false memory paradigm lists in a hypnotic state. Neither hypnosis nor prehypnotic suggestion affected memory.

Evaluating health interest profiles extracted from patient-generated data.

Patient-generated health data (PGHD) offers a promising resource for shaping patient care, self-management, population health, and health policy. Although emerging technologies bolster opportunities to extract PGHD and profile the needs and experiences of patients, few efforts examine the validity and use of such profiles from the patient's perspective. To address this gap, we explore health interest profiles built automatically from online community posts.

Identification of Small Molecule Inhibitors of Clostridium perfringens ε-Toxin Cytotoxicity Using a Cell-Based High-Throughput Screen.

The Clostridium perfringens epsilon toxin, a select agent, is responsible for a severe, often fatal enterotoxemia characterized by edema in the heart, lungs, kidney, and brain. The toxin is believed to be an oligomeric pore-forming toxin. Currently, there is no effective therapy for countering the cytotoxic activity of the toxin in exposed individuals.

Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4).

This Letter describes the synthesis and SAR of the novel positive allosteric modulator, VU0155041, a compound that has shown in vivo efficacy in rodent models of Parkinson's disease. The synthesis takes advantage of an iterative parallel synthesis approach to rapidly synthesize and evaluate a number of analogs of VU0155041.

A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduces seizures without impairing hippocampus-dependent learning.

Previous studies suggest that selective antagonists of specific subtypes of muscarinic acetylcholine receptors (mAChRs) may provide a novel approach for the treatment of certain central nervous system (CNS) disorders, including epileptic disorders, Parkinson's disease, and dystonia. Unfortunately, previously reported antagonists are not highly selective for specific mAChR subtypes, making it difficult to definitively establish the functional roles and therapeutic potential for individual subtypes of this receptor subfamily. The M(1) mAChR is of particular interest as a potential target for treatment of CNS disorders.

Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists.

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5.

The Medicare Modernization Act and reimbursement for outpatient chemotherapy: do patients perceive changes in access to care?

Background: The primary objectives were to measure and compare time to initiation of chemotherapy for patients undergoing treatment either before or after the enactment of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA), and to measure and compare the location of care for patients undergoing chemotherapy either before or after the enactment of the MMA.

Methods: A Web-based survey was conducted of a convenience sample of patients with cancer.

Results: A total of 1421 respondents completed the survey, 684 in the pre-MMA group and 737 in the post-MMA group.

Intracavitary chemotherapy (Gliadel) for recurrent esthesioneuroblastoma: case report and review of the literature.

Esthesioneuroblastoma is an uncommon malignancy of the nasal vault with a treatment regimen consisting of surgical resection followed by radiotherapy for primary lesions and addition of chemotherapy for patients with advanced, recurrent or metastatic lesions. We report a case of a 39-year-old female with a history of esthesioneuroblastoma, previously treated with resection, radiation and chemotherapy, presenting with a recurrent disease that was successfully treated with re-resection and placement of Gliadel) wafers in the surgical resection cavity. The novel option of controlled-release and local delivery of a chemotherapeutic agent for treatment of recurrent esthesioneuroblastoma should be recognized and considered.

Adjuvant docetaxel for node-positive breast cancer.

Background: We compared docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluorouracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy for operable node-positive breast cancer.

Methods: We randomly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. The primary end point was disease-free survival.

Consolidation-like effects in flashbulb memories: evidence from September 11, 2001.

After September 11, 2001, we distributed flashbulb memory questionnaires at 5 different dates: within 48 hr (T1) and at 1 week (T2), 1 month (T3), 3 months (T4), and 1 year (T5). We scored responses for self-reported memory (veracity unverified), memory accuracy (recollection-matched T1 response), and memory consistency (recollection-matched prior responses other than T1). Self-reported memory and subjective confidence remained near ceiling, although the accuracy declined.

Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes.

Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P+) versus placebo (P-) in nine subjects with type 2 diabetes (HbA(1c), 10.

Cerebrospinal fluid (vascular endothelial growth factor) and serologic (recoverin) tumor markers for malignant glioma.

Background: Clinically useful tumor markers have yet to be identified for malignant glioma. We report on two potential novel tumor markers, vascular endothelial growth factor (VEGF) and recoverin (protein A). VEGF is a highly specific endothelial cell activator that induces angiogenesis both in vivo and in vitro.

Happiness of Asian Americans.

Past surveys found a positive relation between job satisfaction and socioeconomic status, with Asian Americans scoring low and African Americans and Euro-Americans scoring higher. As job satisfaction is a component of happiness, the question arises whether this relationship holds for happiness in general. Responses of a sample of 499 Asian Americans, 24,432 Euro-Americans, and 2,828 African Americans were analyzed.

Processing similarity does not improve metamemory: evidence against transfer-appropriate monitoring.

The transfer-appropriate monitoring (TAM) hypothesis of metamemory predicts that judgment of learning (JOL) accuracy should improve when conditions during JOLs closely match conditions of the memory test. The authors devised 5 types of delayed JOLs for paired associates and varied them along with the type of memory test (cued recall or recognition). If the TAM hypothesis is correct, JOL and test type should interact to influence metamemory.