Cost-effectiveness of erosion mitigation to meet water clarity targets in the Manawatu-Whanganui Region of New Zealand.

Soil erosion is a significant environmental issue worldwide. It affects water quality, biodiversity, and land productivity. New Zealand government agencies and regional councils work to mitigate soil erosion through policies, management programmes, and funding for soil conservation projects. Information about cost-effectiveness is crucial for planning, targeting, and implementing erosion mitigation to achieve improvements in sediment-related water quality. While there is a good understanding of the costs of erosion mitigation measures, there is a dearth of literature on their cost-effectiveness in reducing sediment loads and improving water quality at the catchment level. In this study, we estimate the cost-effectiveness of erosion mitigation measures in meeting visual water clarity targets. The analysis utilizes the spatially explicit SedNetNZ erosion process and sediment budget modelling in the Manawatu-Whanganui Region and region-specific mitigation costs. The erosion mitigation measures considered in the analysis include afforestation, bush retirement, riparian retirement, space-planted trees, and gully tree planting. We modelled two scenarios with on-farm erosion mitigation implemented across the region from 2021 to 2100, resulting in a 48% and 60% reduction of total sediment load. We estimate the marginal costs to achieve the visual national bottom line for water clarity, as assessed by the length of waterways that meet the clarity targets. We also estimate the marginal costs of improving average water clarity, which can be linked with non-market valuation studies when conducting a cost-benefit analysis. We find that gully tree planting and space-planted trees are the most cost-effective mitigation measures and that riparian retirement is the least cost-effective. Moreover, cost-effectiveness is highly dependent on current land use and the biophysical features of the landscape. Our estimates can be used in cost-benefit analysis to plan and prioritize soil erosion mitigation at the catchment and regional levels.

Infrared nanoimaging of neuronal ultrastructure and nanoparticle interaction with cells.

Here we introduce scattering-type scanning near-field optical microscopy (s-SNOM) as a novel tool for nanoscale chemical-imaging of sub-cellular organelles, nanomaterials and of the interactions between them. Our setup uses a tuneable mid-infrared laser and a sharp scanning probe to image at a resolution substantially surpassing the diffraction limit. The laser can be tuned to excite vibrational modes of functional groups in biomolecules, (e.g. amide moieties), in a way that enables direct chemical mapping without the need for labelling. We, for the first time, chemically image neuronal ultrastructure, identify neuronal organelles and sub-organelle structures as small as 10 nm and validate our findings using transmission electron microscopy (TEM). We produce chemical and morphological maps of neurons treated with gold nanospheres and characterize nanoparticle size and intracellular location, and their interaction with the plasma membrane. Our results show that the label-free nature of s-SNOM means it has a 'true' chemical resolution of up to 20 nm which can be further improved. We argue that it offers significant potential in nanomedicine for nanoscale chemical imaging of cell ultrastructure and the subcellular distribution of nanomaterials within tissues.

Striatal dopamine contributions to skilled motor learning.

Coordinated multi-joint limb and digit movements - "manual dexterity" - underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's Disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that cortico-striatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release as mice learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In dorsolateral striatum, dopamine dynamics are faster than in dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

Performance of a novel spectroscopy-based tool for adjuvant therapy decision-making in hormone receptor-positive breast cancer: a validation study.

PURPOSE: Digistain Index (DI), measured using an inexpensive mid-infrared spectrometer, reflects the level of aneuploidy in unstained tissue sections and correlates with tumor grade. We investigated whether incorporating DI with other clinicopathological variables could predict outcomes in patients with early breast cancer. METHODS: DI was calculated in 801 patients with hormone receptor-positive, HER2-negative primary breast cancer and ≤ 3 positive lymph nodes. All patients were treated with systemic endocrine therapy and no chemotherapy. Multivariable proportional hazards modeling was used to incorporate DI with clinicopathological variables to generate the Digistain Prognostic Score (DPS). DPS was assessed for prediction of 5- and 10-year outcomes (recurrence, recurrence-free survival [RFS] and overall survival [OS]) using receiver operating characteristics and Cox proportional hazards regression models. Kaplan-Meier analysis evaluated the ability of DPS to stratify risk. RESULTS: DPS was consistently highly accurate and had negative predictive values for all three outcomes, ranging from 0.96 to 0.99 at 5 years and 0.84 to 0.95 at 10 years. DPS demonstrated statistically significant prognostic ability with significant hazard ratios (95% CI) for low- versus high-risk classification for RFS, recurrence and OS (1.80 [CI 1.31-2.48], 1.83 [1.32-2.52] and 1.77 [1.28-2.43], respectively; all P < 0.001). CONCLUSION: DPS showed high accuracy and predictive performance, was able to stratify patients into low or high-risk, and considering its cost and rapidity, has the potential to offer clinical utility.

Research activity among physicians in the United Kingdom: results from the Royal College of Physicians Census 2022.

We present the results of the 2022 Census of the Federation of Royal Colleges of Physicians of Edinburgh, Glasgow and London on whether physicians undertake research and the barriers they have encountered. 40% of physicians reported that they undertook research alongside their clinical work. Multivariate analysis of the responses showed that men were 1.6 times more likely to say they undertake research than women. The main barriers to undertaking research were having enough time, organisational factors and a lack of confidence. In this opinion piece we discuss some of the challenges and how they could be addressed.

Cryo-EM structure determination of small therapeutic protein targets at 3 Å-resolution using a rigid imaging scaffold.

Cryoelectron microscopy (Cryo-EM) has enabled structural determination of proteins larger than about 50 kDa, including many intractable by any other method, but it has largely failed for smaller proteins. Here, we obtain structures of small proteins by binding them to a rigid molecular scaffold based on a designed protein cage, revealing atomic details at resolutions reaching 2.9 Å. We apply this system to the key cancer signaling protein KRAS (19 kDa in size), obtaining four structures of oncogenic mutational variants by cryo-EM. Importantly, a structure for the key G12C mutant bound to an inhibitor drug (AMG510) reveals significant conformational differences compared to prior data in the crystalline state. The findings highlight the promise of cryo-EM scaffolds for advancing the design of drug molecules against small therapeutic protein targets in cancer and other human diseases.

Label-free nanoscale mapping of intracellular organelle chemistry.

The ability to image cell chemistry at the nanoscale is key for understanding cell biology, but many optical microscopies are restricted by the ~(200-250)nm diffraction limit. Electron microscopy and super-resolution fluorescence techniques beat this limit, but rely on staining and specialised labelling to generate image contrast. It is challenging, therefore, to obtain information about the functional chemistry of intracellular components. Here we demonstrate a technique for intracellular label-free chemical mapping with nanoscale (~30 nm) resolution. We use a probe-based optical microscope illuminated with a mid-infrared laser whose wavelengths excite vibrational modes of functional groups occurring within biological molecules. As a demonstration, we chemically map intracellular structures in human multiple myeloma cells and compare the morphologies with electron micrographs of the same cell line. We also demonstrate label-free mapping at wavelengths chosen to target the chemical signatures of proteins and nucleic acids, in a way that can be used to identify biochemical markers in the study of disease and pharmacology.

A systematic review of potential screening biomarkers for active TB disease.

INTRODUCTION: The standard TB Four Symptom Screen does not meet the World Health Organization (WHO) ideal screening criteria for having greater than 90% sensitivity to identify active TB disease, regardless of HIV status. To identify novel screening biomarkers for active TB, we performed a systematic review of any cohort or case-control study reporting associations between screening biomarkers and active TB disease. METHODS: We searched PubMed and Embase for articles published before October 10, 2021. We included studies from high or medium tuberculosis burden countries. We excluded articles focusing on C-reactive protein and lipoarabinomannan. For all included biomarkers, we calculated sensitivity, specificity and 95% confidence intervals, and assessed study quality using a tool adapted from the QUADAS-2 risk of bias. RESULTS: From 8,062 abstracts screened, we included 79 articles. The articles described 302 unique biomarkers, including host antibodies, host proteins, TB antigens, microRNAs, whole blood gene PCRs, and combinations of biomarkers. Of these, 23 biomarkers had sensitivity greater than 90% and specificity greater than 70%, meeting WHO criteria for an ideal screening test. Among the eleven biomarkers described in people living with HIV, only one had a sensitivity greater than 90% and specificity greater than 70% for active TB. CONCLUSION: Further evaluation of biomarkers of active TB should be pursued to accelerate identification of TB disease.

Cryo-EM: The Resolution Revolution and Drug Discovery.

Single-particle cryogenic electron microscopy (cryo-EM) has been elevated to the mainstream of structural biology propelled by technological advancements in numerous fronts, including imaging analysis and the development of direct electron detectors. The drug discovery field has watched with (initial) skepticism and wonder at the progression of the technique and how it revolutionized the molecular understanding of previously intractable targets. This article critically assesses how cryo-EM has impacted drug discovery in diverse therapeutic areas. Targets that have been brought into the realm of structure-based drug design by cryo-EM and are thus reviewed here include membrane proteins like the GABAA receptor, several TRP channels, and G protein-coupled receptors, and multiprotein complexes like the ribosomes, the proteasome, and eIF2B. We will describe these studies highlighting the achievements, challenges, and caveats.

Evaluation of a custom GeneRead™ massively parallel sequencing assay with 210 ancestry informative SNPs using the Ion S5™ and MiSeq platforms.

A custom GeneRead DNAseq SNP panel with 210 markers was evaluated using the Ion S5 and MiSeq sequencing platforms. Sensitivity, PCR cycle number, and the use of half volume of reagents for target enrichment and library preparation were tested. Furthermore, genotype concordance between results obtained with the different sequencing platforms and with known profiles generated using other sequencing assays was analysed. The GeneRead DNASeq SNP assay gave reproducible results with an input of 200 pg DNA on both platforms. A total of 204 loci were successfully sequenced. Three loci failed completely in the PCR amplification, and three additional loci displayed frequent locus drop-outs due to low read depth or high heterozygote imbalance. Overall, the read depth across the loci was more well-balanced with the MiSeq, while the heterozygote balance was less variable with the Ion S5. Noise levels were low on both platforms (median< 0.2 %). Two simple criteria for genotyping were applied: A minimum threshold of 45 reads and an acceptable heterozygote balance range of 0.3-3.0. Complete concordance between platforms was observed except for three genotypes in one of the poorly performing loci, rs1470637. This locus had relatively low read depths on both platforms, skewed heterozygote balance, and frequent locus drop-outs. There was also full genotype concordance between the results from the GeneRead assay and known profiles generated with the QIAseq and Ion AmpliSeq assays. The few discordant results were either due to locus drop-outs in the poorly performing loci or allele drop-outs in the QIAseq assay. Profiles with a minimum of 179 SNPs were obtained from four challenging case work samples (blood swabs, bone, or blood from a corpse). Overall, the GeneRead DNASeq assay showed considerable potential and could provide a reliable method for SNP genotyping in cases involving identification of individuals, prediction of phenotypic traits, and ancestry inference.

Inferring Micro-Activities Using Wearable Sensing for ADL Recognition of Home-Care Patients.

In this study, we propose a novel, context-based, location-aware algorithm for identifying low-level micro-activities that can be used to derive complex activities of daily living (ADL) performed by home-care patients. This identification is achieved by gathering the location information of the target user by using a wearable beacon embedded with a magnetometer and inertial sensors. The shortcomings of beacon-signal stability and mismatch issues in magnetic-field sequences are overcome by adopting a hybrid, three-phase approach for deducing the locus of micro-activities and their associated zones in a smart home environment. The suggested approach is assessed in two different test environments, where the main intention is to map the location of a person performing an activity with pre-defined house landmarks and zones in the offline labeled database. In addition to the recognition of low-level activities, the proposed method also identifies the person's walking trajectory within the same zone or between different zones of the house. The experimental results demonstrate that it is possible to achieve centimeter-level accuracy for the recognition of micro-activities and to achieve the classification accuracy of 85% for trajectory prediction. These results are encouraging and imply that the collection of accurate low-level information for ADL recognition is possible using integration of inertial sensors, magnetic field and Bluetooth low energy (BLE) technologies from the wearable beacon without relying on other infrastructural sensors.

The low density and magnetization of a massive galaxy halo exposed by a fast radio burst.

Present-day galaxies are surrounded by cool and enriched halo gas extending for hundreds of kiloparsecs. This halo gas is thought to be the dominant reservoir of material available to fuel future star formation, but direct constraints on its mass and physical properties have been difficult to obtain. We report the detection of a fast radio burst (FRB 181112), localized with arcsecond precision, that passes through the halo of a foreground galaxy. Analysis of the burst shows that the halo gas has low net magnetization and turbulence. Our results imply predominantly diffuse gas in massive galactic halos, even those hosting active supermassive black holes, contrary to some previous results.

Cryo-EM in drug discovery.

The impact of structural biology on drug discovery is well documented, and the workhorse technique for the past 30 years or so has been X-ray crystallography. With the advent of several technological improvements, including direct electron detectors, automation, better microscope vacuums and lenses, phase plates and improvements in computing power enabled by GPUs, it is now possible to record and analyse images of protein structures containing high-resolution information. This review, from a pharmaceutical perspective, highlights some of the most relevant and interesting protein structures for the pharmaceutical industry and shows examples of how ligand-binding sites, membrane proteins, both big and small, pseudo symmetry and complexes are being addressed by this technique.

The Golden State Killer investigation and the nascent field of forensic genealogy.

The likely genetic analysis steps taken to identify suspect Joseph DeAngelo in the recently resolved Golden State Killer investigation are discussed. The consequences for the forensic genetics community of introducing much more detailed SNP analysis regimes, as used by the Golden State Killer investigators, are reviewed along with some of the limitations in accuracy and sensitivity that may be involved in such approaches.