Brain Potentials Reflect Behavioral Differences in True and False Recognition

People often falsely recognize nonstudied lures that are semantically similar to previously studied words. Behavioral research suggests that such false recognition is based on high semantic overlap between studied items and lures that yield a feeling of familiarity, whereas true recognition is more often associated with the recollection of details. Despite this behavioral evidence for differences between true and false recognition, research measuring brain activity (PET, fMRI, ERP) has not clearly differentiated corresponding differences in brain activity. A median split was used to separate subjects into Good and Poor performers based on their discrimination of studied targets from similar lures. Only Good performers showed late (1000-1500 msec), right frontal event-related brain potentials (ERPs) that were more positive for targets and lures compared with new items. The right frontal differences are interpreted as reflecting postretrieval evaluation processes that were more likely to be engaged by Good than Poor performers. Both Good and Poor performers showed a parietal ERP old/new effect (400-800 msec), but only Poor performers showed a parietal old/lure difference. These results are consistent with the view that the parietal and frontal ERP old/new effects reflect dissociable processes related to recollection.Psycholog

Screening a protein kinase inhibitor library against <i>Plasmodium falciparum</i>

Abstract Background Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interest to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets. Results As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described. Discussion This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation. Conclusions Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library

Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC50 = 2 nM) and T. brucei (EC50 = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.</p

Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi. Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the β5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the β4 and β5 proteasome subunits. This induced pocket exploits β4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.</p

2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease

Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.</p

Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity:Initial SAR and Assessment of In Vivo Activity

Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26,000 - 65,000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration between the Drugs for Neglected Diseases initiative (DNDi), GlaxoSmithKline (GSK) and the University of Dundee. An 8-hydroxynaphthyridine was identified as a start point and an early compound demonstrated weak efficacy in a mouse model of VL but was hampered by glucuronidation. Efforts to address this led to the development of compounds with improved in vitro profiles, but these were poorly tolerated in vivo. Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.</p

Development of a 2,4-diaminothiazole series for the treatment of human African trypanosomiasis highlights the importance of static-cidal screening of analogues

While treatment options for human African trypanosomiasis (HAT) have improved significantly, there is still a need for new drugs with eradication now a realistic possibility. Here, we report the development of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei, the causative agent of HAT. Using phenotypic screening to guide structure-activity relationships, potent drug-like inhibitors were developed. Proof of concept was established in an animal model of the hemolymphatic stage of HAT. To treat the meningoencephalitic stage of infection, compounds were optimized for pharmacokinetic properties, including blood-brain barrier penetration. However, in vivo efficacy was not achieved, in part due to compounds evolving from a cytocidal to a cytostatic mechanism of action. Subsequent studies identified a nonessential kinase involved in the inositol biosynthesis pathway as the molecular target of these cytostatic compounds. These studies highlight the need for cytocidal drugs for the treatment of HAT and the importance of static-cidal screening of analogues

Operationalizing marketable blue carbon

The global carbon sequestration and avoided emissions potentially achieved via blue carbon is high (∼3% of annual global greenhouse gas emissions); however, it is limited by multidisciplinary and interacting uncertainties spanning the social, governance, financial, and technological dimensions. We compiled a transdisciplinary team of experts to elucidate these challenges and identify a way forward. Key actions to enhance blue carbon as a natural climate solution include improving policy and legal arrangements to ensure equitable sharing of benefits; improving stewardship by incorporating indigenous knowledge and values; clarifying property rights; improving financial approaches and accounting tools to incorporate co-benefits; developing technological solutions for measuring blue carbon sequestration at low cost; and resolving knowledge gaps regarding blue carbon cycles. Implementing these actions and operationalizing blue carbon will achieve measurable changes to atmospheric greenhouse gas concentrations, provide multiple co-benefits, and address national obligations associated with international agreements

Population-based interventions for preventing falls and fall-related injuries in older people.

Around one-third of older adults aged 65 years or older who live in the community fall each year. Interventions to prevent falls can be designed to target the whole community, rather than selected individuals. These population-level interventions may be facilitated by different healthcare, social care, and community-level agencies. They aim to tackle the determinants that lead to risk of falling in older people, and include components such as community-wide polices for vitamin D supplementation for older adults, reducing fall hazards in the community or people's homes, or providing public health information or implementation of public health programmes that reduce fall risk (e.g. low-cost or free gym membership for older adults to encourage increased physical activity). To review and synthesise the current evidence on the effects of population-based interventions for preventing falls and fall-related injuries in older people. We defined population-based interventions as community-wide initiatives to change the underlying societal, cultural, or environmental conditions increasing the risk of falling. We searched CENTRAL, MEDLINE, Embase, three other databases, and two trials registers in December 2020, and conducted a top-up search of CENTRAL, MEDLINE, and Embase in January 2023. We included randomised controlled trials (RCTs), cluster RCTs, trials with stepped-wedge designs, and controlled non-randomised studies evaluating population-level interventions for preventing falls and fall-related injuries in adults ≥ 60 years of age. Population-based interventions target entire communities. We excluded studies only targeting people at high risk of falling or with specific comorbidities, or residents living in institutionalised settings. We used standard methodological procedures expected by Cochrane, and used GRADE to assess the certainty of the evidence. We prioritised seven outcomes: rate of falls, number of fallers, number of people experiencing one or more fall-related injuries, number of people experiencing one or more fall-related fracture, number of people requiring hospital admission for one or more falls, adverse events, and economic analysis of interventions. Other outcomes of interest were: number of people experiencing one or more falls requiring medical attention, health-related quality of life, fall-related mortality, and concerns about falling. We included nine studies: two cluster RCTs and seven non-randomised trials (of which five were controlled before-and-after studies (CBAs), and two were controlled interrupted time series (CITS)). The numbers of older adults in intervention and control regions ranged from 1200 to 137,000 older residents in seven studies. The other two studies reported only total population size rather than numbers of older adults (67,300 and 172,500 residents). Most studies used hospital record systems to collect outcome data, but three only used questionnaire data in a random sample of residents; one study used both methods of data collection. The studies lasted between 14 months and eight years. We used Prevention of Falls Network Europe (ProFaNE) taxonomy to classify the types of interventions. All studies evaluated multicomponent falls prevention interventions. One study (n = 4542) also included a medication and nutrition intervention. We did not pool data owing to lack of consistency in study designs. Medication or nutrition Older people in the intervention area were offered free-of-charge daily supplements of calcium carbonate and vitamin D . Although female residents exposed to this falls prevention programme had fewer fall-related hospital admissions (with no evidence of a difference for male residents) compared to a control area, we were unsure of this finding because the certainty of evidence was very low. This cluster RCT included high and unclear risks of bias in several domains, and we could not determine levels of imprecision in the effect estimate reported by study authors. Because this evidence is of very low certainty, we have not included quantitative results here. This study reported none of our other review outcomes. Multicomponent interventions Types of interventions included components of exercise, environment modification (home; community; public spaces), staff training, and knowledge and education. Studies included some or all of these components in their programme design. The effectiveness of multicomponent falls prevention interventions for all reported outcomes is uncertain. The two cluster RCTs included high or unclear risk of bias, and we had no reasons to upgrade the certainty of evidence from the non-randomised trial designs (which started as low-certainty evidence). We also noted possible imprecision in some effect estimates and inconsistent findings between studies. Given the very low-certainty evidence for all outcomes, we have not reported quantitative findings here. One cluster RCT reported lower rates of falls in the intervention area than the control area, with fewer people in the intervention area having one or more falls and fall-related injuries, but with little or no difference in the number of people having one or more fall-related fractures. In another cluster RCT (a multi-arm study), study authors reported no evidence of a difference in the number of female or male residents with falls leading to hospital admission after either a multicomponent intervention ("environmental and health programme") or a combination of this programme and the calcium and vitamin D programme (above). One CBA reported no difference in rate of falls between intervention and control group areas, and another CBA reported no difference in rate of falls inside or outside the home. Two CBAs found no evidence of a difference in the number of fallers, and another CBA found no evidence of a difference in fall-related injuries. One CITS found no evidence of a difference in the number of people having one or more fall-related fractures. No studies reported adverse events. Given the very low-certainty evidence, we are unsure whether population-based multicomponent or nutrition and medication interventions are effective at reducing falls and fall-related injuries in older adults. Methodologically robust cluster RCTs with sufficiently large communities and numbers of clusters are needed. Establishing a rate of sampling for population-based studies would help in determining the size of communities to include. Interventions should be described in detail to allow investigation of effectiveness of individual components of multicomponent interventions; using the ProFaNE taxonomy for this would improve consistency between studies. [Abstract copyright: Copyright © 2024 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage

BackgroundWe describe the genome of the western painted turtle, Chrysemys picta bellii, one of the most widespread, abundant, and well-studied turtles. We place the genome into a comparative evolutionary context, and focus on genomic features associated with tooth loss, immune function, longevity, sex differentiation and determination, and the species' physiological capacities to withstand extreme anoxia and tissue freezing.ResultsOur phylogenetic analyses confirm that turtles are the sister group to living archosaurs, and demonstrate an extraordinarily slow rate of sequence evolution in the painted turtle. The ability of the painted turtle to withstand complete anoxia and partial freezing appears to be associated with common vertebrate gene networks, and we identify candidate genes for future functional analyses. Tooth loss shares a common pattern of pseudogenization and degradation of tooth-specific genes with birds, although the rate of accumulation of mutations is much slower in the painted turtle. Genes associated with sex differentiation generally reflect phylogeny rather than convergence in sex determination functionality. Among gene families that demonstrate exceptional expansions or show signatures of strong natural selection, immune function and musculoskeletal patterning genes are consistently over-represented.ConclusionsOur comparative genomic analyses indicate that common vertebrate regulatory networks, some of which have analogs in human diseases, are often involved in the western painted turtle's extraordinary physiological capacities. As these regulatory pathways are analyzed at the functional level, the painted turtle may offer important insights into the management of a number of human health disorders