Fragment approaches are long-established in target-based ligand discovery yet their full transformative potential lies dormant, because progressing hits to potency remains underserved by methodological work. The only credible progression paradigm is multiple cycles of costly conventional design-make-test-analyse (DMTA) medicinal chemistry, necessitating picking winners early and discarding others. It is effective to cheaply parallelize large numbers of non-uniform multi-step reactions, because, even without compound purification, a high-quality readout of binding is available, viz.
View Article and Find Full Text PDFChildren and adolescents with neurodevelopmental disorders demonstrate extensive cognitive heterogeneity that is not adequately captured by traditional diagnostic systems, emphasizing the need for alternative assessment and classification techniques. Using a transdiagnostic approach, a retrospective cohort study of cognitive functioning was conducted using a large heterogenous sample ( = 1529) of children and adolescents 7 to 18 years of age with neurodevelopmental disorders. Measures of short-term memory, verbal ability, and reasoning were administered to participants with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), comorbid ADHD/ASD, and participants without neurodevelopmental disorders (non-NDD) using a 12-task, web-based neurocognitive testing battery.
View Article and Find Full Text PDFMaintaining cognitive capacity through adulthood has been the target of many recent studies that have examined the influence of lifestyle choices such as exercise, diet, and sleeping habits. Many of these studies have focused on a single factor (e.g.
View Article and Find Full Text PDFThe ventral visual stream is shaped during development by innate proto-organization within the visual system, such as the strong input from the fovea to the fusiform face area. In adults, category-selective regions have distinct signatures of connectivity to brain regions beyond the visual system, likely reflecting cross-modal and motoric associations. We tested if this long-range connectivity is part of the innate proto-organization, or if it develops with postnatal experience, by using diffusion-weighted imaging to characterize the connectivity of anatomical correlates of category-selective regions in neonates (N = 445), 1-9 month old infants (N = 11), and adults (N = 14).
View Article and Find Full Text PDFAs COVID-19 cases exceed hundreds of millions globally, many survivors face cognitive challenges and prolonged symptoms. However, important questions about the cognitive effects of COVID-19 remain unresolved. In this cross-sectional online study, 478 adult volunteers who self-reported a positive test for COVID-19 (mean = 30 days since most recent test) perform significantly worse than pre-pandemic norms on cognitive measures of processing speed, reasoning, verbal, and overall performance, but not short-term memory, suggesting domain-specific deficits.
View Article and Find Full Text PDFPolyomaviruses are a family of ubiquitous double-stranded DNA viruses many of which are human pathogens. These include BK polyomavirus which causes severe urinary tract infection in immunocompromised patients and Merkel cell polyomavirus associated with aggressive cancers. The small genome of polyomaviruses lacks conventional drug targets, and no specific drugs are available at present.
View Article and Find Full Text PDFSpeech is often degraded by environmental noise or hearing impairment. People can compensate for degradation, but this requires cognitive effort. Previous research has identified frontotemporal networks involved in effortful perception, but materials in these works were also less intelligible, and so it is not clear whether activity reflected effort or intelligibility differences.
View Article and Find Full Text PDFBackground: Abnormalities in cognitive function are almost universal in patients receiving hemodialysis (HD) and are associated with worse quality of life, impaired decision making, increased healthcare utilization and mortality. While cognitive impairment in the HD population is increasingly recognized, it is unclear how quickly it develops after starting HD.
Methods: This was a cross-sectional study of a cohort of low dialysis vintage HD patients (<12 months).
In fragment-based drug discovery, hundreds or often thousands of compounds smaller than ~300 Da are tested against the protein of interest to identify chemical entities that can be developed into potent drug candidates. Since the compounds are small, interactions are weak, and the screening method must therefore be highly sensitive; moreover, structural information tends to be crucial for elaborating these hits into lead-like compounds. Therefore, protein crystallography has always been a gold-standard technique, yet historically too challenging to find widespread use as a primary screen.
View Article and Find Full Text PDFMaintaining cognitive health across the lifespan has been the focus of a multi-billion-dollar industry. In order to guide treatment and interventions, a clear understanding of the way that proficiency in different cognitive domains develops and declines in both sexes across the lifespan is necessary. Additionally, there are sex differences in a range of other factors, including psychiatric illnesses such as anxiety, depression, and substance use, that are also known to affect cognition, although the scale of this interaction is unknown.
View Article and Find Full Text PDFComprehension of degraded speech requires higher-order expectations informed by prior knowledge. Accurate top-down expectations of incoming degraded speech cause a subjective semantic 'pop-out' or conscious breakthrough experience. Indeed, the same stimulus can be perceived as meaningless when no expectations are made in advance.
View Article and Find Full Text PDFCOVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication.
View Article and Find Full Text PDFThe foundational tenet of brain training is that general cognitive functioning can be enhanced by completing computerized games, a notion that is both intuitive and appealing. Moreover, there is strong incentive to improve our cognitive abilities, so much so that it has driven a billion-dollar industry. However, whether brain training can really produce these desired outcomes continues to be debated.
View Article and Find Full Text PDFWhether acquiring a second language affords any general advantages to executive function has been a matter of fierce scientific debate for decades. If being bilingual does have benefits over and above the broader social, employment, and lifestyle gains that are available to speakers of a second language, then it should manifest as a cognitive advantage in the general population of bilinguals. We assessed 11,041 participants on a broad battery of 12 executive tasks whose functional and neural properties have been well described.
View Article and Find Full Text PDFObjective: We investigated the long-term cognitive effects of concussion in 19,261 members of the general population and a cohort of varsity American football players with a history of frequent head impacts, using tests that are known to be sensitive to small changes in performance.
Methods: We asked 19,261 participants to complete a demographic questionnaire and 12 cognitive tests measuring aspects of executive function, including inhibitory control. We compared the performance of those reporting a history of concussion (post-concussion) to those reporting no history of concussion (non-concussed) on the cognitive battery and four non-cognitive variables.
Group differences in touch and pain thresholds-and their neural correlates-were studied in women with provoked vestibulodynia (PVD; N = 15), a common subtype of vulvodynia (chronic vulvar pain), and pain-free control women (N = 15). Results from quantitative sensory testing and self-report measures indicated that, as compared with control participants, women with PVD exhibited allodynia (ie, pain in response to a normally nonpainful stimulus) and hyperalgesia (ie, an increased response to a normally painful stimulus) at vulvar and nonvulvar sites. In addition, brain imaging analyses demonstrated reduced difference scores between touch and pain in the S2 area in women with PVD compared with control participants, supporting previous findings of allodynia in women with PVD.
View Article and Find Full Text PDFPurpose: To assess the feasibility of using a widely validated, web-based neurocognitive test battery (Cambridge Brain Sciences, CBS) in a cohort of critical illness survivors.
Methods: We conducted a prospective observational study in two intensive care units (ICUs) at two tertiary care hospitals. Twenty non-delirious ICU patients who were mechanically ventilated for a minimum of 24 hours underwent cognitive testing using the CBS battery.
Most people will at some point experience not getting enough sleep over a period of days, weeks, or months. However, the effects of this kind of everyday sleep restriction on high-level cognitive abilities-such as the ability to store and recall information in memory, solve problems, and communicate-remain poorly understood. In a global sample of over 10000 people, we demonstrated that cognitive performance, measured using a set of 12 well-established tests, is impaired in people who reported typically sleeping less, or more, than 7-8 hours per night-which was roughly half the sample.
View Article and Find Full Text PDFFrom their second year, infants typically begin to show rapid acquisition of receptive and expressive language. Here, we ask why these language skills do not begin to develop earlier. One evolutionary hypothesis is that infants are born when many brains systems are immature and not yet functioning, including those critical to language, because human infants have large have a large head and their mother's pelvis size is limited, necessitating an early birth.
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