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Differential sensing attempts to mimic the mammalian senses of smell and taste to identify analytes and complex mixtures. In place of hundreds of complex, membrane-bound G-protein coupled receptors, differential sensors employ arrays of small molecules. Here we show that arrays of computationally designed de novo peptides provide alternative synthetic receptors for differential sensing. We use self-assembling α-helical barrels (αHBs) with central channels that can be altered predictably to vary their sizes, shapes and chemistries. The channels accommodate environment-sensitive dyes that fluoresce upon binding. Challenging arrays of dye-loaded barrels with analytes causes differential fluorophore displacement. The resulting fluorimetric fingerprints are used to train machine-learning models that relate the patterns to the analytes. We show that this system discriminates between a range of biomolecules, drink, and diagnostically relevant biological samples. As αHBs are robust and chemically diverse, the system has potential to sense many analytes in various settings. Differential sensing aims to mimic senses such as taste and smell through the use of synthetic receptors. Here, the authors show that arrays of de novo designed peptide assemblies can be used as sensor components to distinguish various analytes and complex mixtures.

Synaptic dysfunction is one of the primary hallmarks of both Alzheimer’s and Parkinson’s disease, leading to cognitive and behavioural decline. While alpha-synuclein, beta-amyloid, and tau are involved in the physiological functioning of synapses, their pathological aggregation has been linked to synaptic dysfunction. However, the methodology for studying the small (sub-diffraction limit) and soluble aggregates -often called oligomers, formed by these proteins is limited. Here we describe SynPull, a novel method combining single-molecule pulldown, super-resolution microscopy, and advanced computational analyses, in order to reliably study the quantity and morphology of the oligomeric alpha-synuclein, beta-amyloid, and AT8-positive tau aggregates in synaptosomes harvested from post-mortem human brain samples and mouse models. Using SynPull, we show that AT8-positive tau is the predominant aggregate type in AD, with significantly more aggregates compared to the control samples, yet the aggregate size does not differ between disease and control samples. Meanwhile, the relatively smaller amount of alpha-synuclein and beta-amyloid aggregates found in the synapses are larger than the extra-synaptic ones. Collectively, these results show the utility of SynPull to study pathological aggregates in dementia, which can help further understand the disease mechanisms causing synaptic dysfunction. Human post-mortem orbitofrontal cortex samples from subjects with neuropathological diagnosis of Alzheimer’s and Parkinson’s disease, as well as age-matched controls cut into ∼300 mg sections, and MI2, APPNL-G-F, P301S, and C57Bl/6J mouse brains were first homogenised in synaptosome buffer using a Dounce homogeniser and then filtered and centrifuged to separate nuclei and organelles from the synaptic fragments. Then, the isolated synaptosomes were incubated on the SiMPull surface with anti-neurexin antibody overnight, followed by fixation and permeabilisation. Imaging antibodies against beta-amyloid, alpha-synuclein, and AT8-positive tau were added to the samples and dSTORM imaging was performed to super-resolve the aggregates.

This article reports Australia's first confirmed ancient underwater archaeological sites from the continental shelf, located off the Murujuga coastline in north-western Australia. Details on two underwater sites are reported: Cape Bruguieres, comprising > 260 recorded lithic artefacts at depths down to -2.4 m below sea level, and Flying Foam Passage where the find spot is associated with a submerged freshwater spring at -14 m. The sites were discovered through a purposeful research strategy designed to identify underwater targets, using an iterative process incorporating a variety of aerial and underwater remote sensing techniques and diver investigation within a predictive framework to map the submerged landscape within a depth range of 0-20 m. The condition and context of the lithic artefacts are analysed in order to unravel their depositional and taphonomic history and to corroborate their in situ position on a pre-inundation land surface, taking account of known geomorphological and climatic processes including cyclone activity that could have caused displacement and transportation from adjacent coasts. Geomorphological data and radiometric dates establish the chronological limits of the sites and demonstrate that they cannot be later than 7000 cal BP and 8500 cal BP respectively, based on the dates when they were finally submerged by sea-level rise. Comparison of underwater and onshore lithic assemblages shows differences that are consistent with this chronological interpretation. This article sets a foundation for the research strategies and technologies needed to identify archaeological targets at greater depth on the Australian continental shelf and elsewhere, building on the results presented. Emphasis is also placed on the need for legislation to better protect and manage underwater cultural heritage on the 2 million square kilometres of drowned landscapes that were once available for occupation in Australia, and where a major part of its human history must lie waiting to be discovered.

Data Availability With permission from the Traditional Owners, the underlying data for the artefacts reported in this study [1] have now been provided as Supporting Information on this notice (S1 File) and additionally uploaded to a data repository and can be found at: https://doi.org/10.25451/flinders.21907413.v1 Within the underlying data folder, S4_table reports 483 terrestrial artefacts recorded from the Cape Bruguieres (CB) site. The same test was done for differences in artefact types, which also demonstrated a statistical significance (X2 (df = 6, N = 518) = 69.87, simulated p<0.001) with a moderate to strong effect size (V = 0.37). Additional Methodological Information Tidal data As stated in the subsection titled Aerial drone survey in the methodology section of [1], “A DJI Phantom 4 Pro and Mavic 2 were flown with automated flight planning software (Drone Deploy) and employed two survey strategies: single-line transects flown between 75–20 ft above the ground level (AGL); and large-area surveys flown at 82 ft AGL with a frontlap of 75% and a sidelap of 70% to produce a ground sample distance of 1 cm. The residual plot for the chi-squared test of artefact sizes from the Cape Bruguieres platform (land) and channel (submerged) assemblages is provided as S2_fig in S1 File.

RationaleThe voltage-insensitive, small-conductance calcium-activated potassium (SK) channel is a key regulator of neuronal depolarization and is implicated in the pathophysiology of depressive disorders.ObjectiveWe ascertained whether the SK channel is impaired in the chronic unpredictable stress (CUS) model and whether it can serve as a molecular target of antidepressant action.MethodsWe assessed the depressive-like behavioral phenotype of CUS-exposed rats and performed post-mortem SK channel binding and activity-dependent zif268 mRNA analyses on their brains. To begin an assessment of SK channel subtypes involved, we examined the effects of genetic and pharmacological inhibition of the SK3 channel using conditional knockout mice and selective SK3 channel negative allosteric modulators (NAMs).ResultsWe found that [125I]apamin binding to SK channels is increased in the prefrontal cortex and decreased in the hippocampus, an effect that was associated with reciprocal levels of zif268 mRNA transcripts indicating abnormal regional cell activity in this model. We found that genetic and pharmacological manipulations significantly decreased immobility in the forced swim test without altering general locomotor activity, a hallmark of antidepressant-like activity.ConclusionsTaken together, these findings link depression-related neural and behavioral pathophysiology with abnormal SK channel functioning and suggest that this can be reversed by the selective inhibition of SK3 channels.

BackgroundMedicinal plants (MPs) are widely accepted and used in most rural communities in sub-Saharan Africa and beyond to treat and control village chicken (VC) diseases and parasites. They are readily available, accessible and cheap. Moreover, they are nature friendly and have adapted to the local environment, making them easy to produce. Over and above, their use has health benefits for consumers. Little is known about the opportunities and challenges faced when commercialising these MPs.AimIt imperative to unpack the opportunities and challenges that are encountered while commercialising MPs used for treating VC diseases and controlling parasites. Despite these multiple benefits, the commercialisation of these plants seems to be under researched. In South Africa, different rural communities use various MPs in their locality. For instance, most rural families in South Africa are using Aloe ferox, Helichrysum petiolare, Tagetes minuta, Lippia javanica, Agave sisalana, Gunnera perpensa and Millettia grandis. Conspicuously, not much is known about the efforts made to commercialise these products.MethodThrough a systematic review of the literature, this paper unpacks the trends, opportunities and challenges faced in commercialising MPs used to treat VC disease and control parasites.ResultsResults have revealed that globally MPs for VC management are not widely recognised, despite their wide usage by local communities. If properly harnessed, they have the potential to strengthen local economic development through income generation. However, currently, little is derived from the sale of these products because of the presence of middlemen. Their commercialisation efforts are hampered by the lack of organised support systems and networks, lack of regularisation strategies and clear criteria for supporting quality, protection and presumed efficiency.ConclusionBy commercialising MPs, local farmers can exploit MPs beyond the village chickens to broiler and layer chickens, thus offering alternative chicken health and affordable medicinal options for the farmers.ContributionThe study contributes to understanding the available opportunities and challenges in commercialising MPs used for village chicken health management. It further demonstrates that MPs for village health can be used to transform the livelihoods of the custodians of these plants.

The Expanded Programme on Immunisation (EPI) provides an effective way of delivering intermittent preventive treatment for malaria (IPT) to infants. However, it is uncertain how IPT can be delivered most effectively to older children. Therefore, we have compared two approaches to the delivery of IPT to Gambian children: distribution by village health workers (VHWs) or through reproductive and child health (RCH) trekking teams. In rural areas, RCH trekking teams provide most of the health care to children under the age of 5 years in the Infant Welfare Clinic, and provide antenatal care for pregnant women. During the 2006 malaria transmission season, the catchment populations of 26 RCH trekking clinics in The Gambia, each with 400-500 children 6 years of age and under, were randomly allocated to receive IPT from an RCH trekking team or from a VHW. Treatment with a single dose of sulfadoxine pyrimethamine (SP) plus three doses of amodiaquine (AQ) were given at monthly intervals during the malaria transmission season. Morbidity from malaria was monitored passively throughout the malaria transmission season in all children, and a random sample of study children from each cluster was examined at the end of the malaria transmission season. The primary study endpoint was the incidence of malaria. Secondary endpoints included coverage of IPTc, mean haemoglobin (Hb) concentration, and the prevalence of asexual malaria parasitaemia at the end of malaria transmission period. Financial and economic costs associated with the two delivery strategies were collected and incremental cost and effects were compared. A nested case-control study was used to estimate efficacy of IPT treatment courses. Treatment with SP plus AQ was safe and well tolerated. There were 49 cases of malaria with parasitaemia above 5,000/µl in the areas where IPT was delivered through RCH clinics and 21 cases in the areas where IPT was delivered by VHWs, (incidence rates 2.8 and 1.2 per 1,000 child months, respectively, rate difference 1.6 [95% confidence interval (CI) -0.24 to 3.5]). Delivery through VHWs achieved a substantially higher coverage level of three courses of IPT than delivery by RCH trekking teams (74% versus 48%, a difference of 27% [95% CI 16%-38%]). For both methods of delivery, coverage was unrelated to indices of wealth, with similar coverage being achieved in the poorest and wealthiest groups. The prevalence of anaemia was low in both arms of the trial at the end of the transmission season. Efficacy of IPTc against malaria during the month after each treatment course was 87% (95% CI 54%-96%). Delivery of IPTc by VHWs was less costly in both economic and financial terms than delivery through RCH trekking teams, resulting in incremental savings of US$872 and US$1,244 respectively. The annual economic cost of delivering at least the first dose of each course of IPTc was US$3.47 and US$1.63 per child using trekking team and VHWs respectively. In this setting in The Gambia, delivery of IPTc to children 6 years of age and under by VHWs is more effective and less costly than delivery through RCH trekking clinics. ClinicalTrials.gov NCT00376155. Please see later in the article for the Editors' Summary.

Pastoral Note While everyone saw the need to change the times for weekend Masses, everyone also wanted to maintain the integrity of the three liturgical gatherings at each parish. Since during most weekends out of the year, we will have two priests to cover the Masses, all Masses will happen with a few changes to their start time.

We present the results of James Webb Space Telescope observations of the protostar ST6 in the Large Magellanic Cloud (LMC) with the Medium Resolution Spectrograph of the Mid-Infrared Instrument (4.9-27.9 \\(\\)m). Characterized by one-third to half-solar metallicity and strong UV radiation fields, the environment of the LMC allows us to study the physics and chemistry of star-forming regions under the conditions similar to those at earlier cosmological epochs. We detected five icy complex organic molecules (COMs): methanol (CH\\(_3\\)OH), acetaldehyde (CH\\(_3\\)CHO), ethanol (CH\\(_3\\)CH\\(_2\\)OH), methyl formate (HCOOCH\\(_3\\)), and acetic acid (CH\\(_3\\)COOH). This is the first conclusive detection of CH\\(_3\\)COOH ice in an astrophysical context, and CH\\(_3\\)CHO, CH\\(_3\\)CH\\(_2\\)OH, and HCOOCH\\(_3\\) ices are the first secure detections outside the Galaxy and in a low-metallicity environment. We address the presence of glycolaldehyde (HOCH\\(_2\\)CHO, a precursor of biomolecules), an isomer of HCOOCH\\(_3\\) and CH\\(_3\\)COOH, but its detection is inconclusive. ST6's spectrum is also rich in simple ices: H\\(_2\\)O, CO\\(_2\\), CH\\(_4\\), SO\\(_2\\), H\\(_2\\)CO, HCOOH, OCN\\(^-\\), HCOO\\(^-\\), NH\\(_3\\), and NH\\(_4^+\\). We obtain the composition and molecular abundances in the icy dust mantles by fitting the spectrum in the 6.8-8.4 \\(\\)m range with a large sample of laboratory ice spectra using the ENIIGMA fitting tool or the local continuum method. We found differences in the simple and COM ice abundances with respect to H\\(_2\\)O ice between ST6 and Galactic protostars that likely reflect differences in metallicity and UV flux. More laboratory ice spectra of COMs are needed to better reconstruct the observed infrared spectra of protostars.