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One aspirational goal of computational chemistry is to predict potent and drug-like binders for any protein, such that only those that bind are synthesized. In this Roadmap, we describe the launch of Critical Assessment of Computational Hit-finding Experiments (CACHE), a public benchmarking project to compare and improve small molecule hit-finding algorithms through cycles of prediction and experimental testing. Participants will predict small molecule binders for new and biologically relevant protein targets representing different prediction scenarios. Predicted compounds will be tested rigorously in an experimental hub, and all predicted binders as well as all experimental screening data, including the chemical structures of experimentally tested compounds, will be made publicly available, and not subject to any intellectual property restrictions. The ability of a range of computational approaches to find novel binders will be evaluated, compared, and openly published. CACHE will launch 3 new benchmarking exercises every year. The outcomes will be better prediction methods, new small molecule binders for target proteins of importance for fundamental biology or drug discovery, and a major technological step towards achieving the goal of Target 2035, a global initiative to identify pharmacological probes for all human proteins.

Strong inhibitory synaptic gating of dentate gyrus granule cells (GCs), attributed largely to fast-spiking parvalbumin interneurons (PV-INs), is essential to maintain sparse network activity needed for dentate dependent behaviors. However, the contribution of PV-INs to basal and input-driven sustained synaptic inhibition in GCs and semilunar granule cells (SGCs), a sparse morphologically distinct dentate projection neuron subtype, is currently unknown. In studies conducted in hippocampal slices from mice, we find that although basal IPSCs are more frequent in SGCs and optical activation of PV-INs reliably elicited IPSCs in both GCs and SGCs, optical suppression of PV-INs failed to reduce IPSC frequency in either cell type. Amplitude and kinetics of IPSCs evoked by perforant path (PP) activation were not different between GCs and SGCs. However, the robust increase in sustained polysynaptic IPSCs elicited by paired afferent stimulation was lower in SGCs than in simultaneously recorded GCs. Optical suppression of PV-IN selectively reduced sustained IPSCs in SGCs but not in GCs. These results demonstrate that PV-INs, while contributing minimally to basal synaptic inhibition in both GCs and SGCs in slices, mediate sustained feedback inhibition selectively in SGCs. The temporally selective blunting of activity-driven sustained inhibitory gating of SGCs could support their preferential and persistent recruitment during behavioral tasks.SIGNIFICANCE STATEMENT Our study identifies that feedback inhibitory regulation of dentate semilunar granule cells (SGCs), a sparse and functionally distinct class of projection neurons, differs from that of the classical projection neurons, GCs. Notably, we demonstrate relatively lower activity-dependent increase in sustained feedback inhibitory synaptic inputs to SGCs when compared with GCs which would facilitate their persistent activity and preferential recruitment as part of memory ensembles. Since dentate GC activity levels during memory processing are heavily shaped by basal and feedback inhibition, the fundamental differences in basal and evoked sustained inhibition between SGCs and GCs characterized here provide a framework to reorganize current understanding of the dentate circuit processing.

IntroductionTo address the need for remote assessments of cognitive decline and dementia, we developed and administered electronic versions of the Clinical Dementia Rating (CDR®) and the Financial Capacity Instrument-Short Form (FCI-SF) (F-CAP®), called the eCDR and eFCI, respectively.MethodsThe CDR and FCI-SF were adapted for remote, unsupervised, online use based on item response analysis of the standard instruments. Participants completed the eCDR and eFCI first in clinic, and then at home within 2 weeks.ResultsOf the 243 enrolled participants, 179 (73%) cognitively unimpaired (CU), 50 (21%) with mild cognitive impairment (MCI) or dementia, and 14 (6%) with an unknown diagnosis, 84% and 85% of them successfully completed the eCDR and eFCI, respectively, at home.DiscussionThese results show initial feasibility in developing and administering online instruments to remotely assess and monitor cognitive decline along the CU to MCI/very mild dementia continuum. Validation is an important next step.

Sorghum, a cereal grain rich in nutrients, is a major source of phenolic compounds that can be altered by different processes, thereby modulating their phenolic content and antioxidant properties. Previous studies have characterised phenolic compounds from pigmented and non-pigmented varieties. However, the impact of processing via the cooking and fermentation of these varieties remains unknown. Wholegrain flour samples of Liberty (WhiteLi1 and WhiteLi2), Bazley (RedBa1 and RedBa2), Buster (RedBu1 and RedBu2), Shawaya black (BlackSb), and Shawaya short black 1 (BlackSs) were cooked, fermented, or both then extracted using acidified acetone. The polyphenol profiles were analysed using a UHPLC-Online ABTS and QTOF LC-MS system. The results demonstrated that combining the fermentation and cooking of the BlackSs and BlackSb varieties led to a significant increase (p < 0.05) in total phenolic content (TPC) and antioxidant activities, as determined through DPPH, FRAP, and ABTS assays. The 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity of WhiteLi1, BlackSb, RedBu2, and BlackSs increased by 46%, 32%, 25%, and 10%, respectively, post fermentation and cooking. Conversely, fermentation only or cooking generally resulted in lower phenolic content and antioxidant levels than when samples were fully processed compared to raw. Notably, most of the detected antioxidant peaks (53 phenolic compounds) were only detected in fermented and cooked black and red pericarp varieties. The phenolic compounds with the highest antioxidant activities in pigmented sorghum included 3-aminobenzoic acid, 4-acetylburtyic acid, malic acid, caffeic acid, and luteolin derivative. Furthermore, the growing location of Bellata, NSW, showed more detectable phenolic compounds following processing compared to Croppa Creek, NSW. This study demonstrates that sorghum processing releases previously inaccessible polyphenols, making them available for human consumption and potentially providing added health-promoting properties.