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Context: Land use history of urban forests impacts present-day soil structure, vegetation, and ecosystem function, yet is rarely documented in a way accessible to planners and land managers. Objectives: To (1) summarize historical land cover of present-day forest patches in Baltimore, MD, USA across land ownership categories and (2) determine whether social-ecological characteristics vary by historical land cover trajectory. Methods: Using land cover classification derived from 1927 and 1953 aerial imagery, we summarized present-day forest cover by three land cover sequence classes: (1) Persistent forest that has remained forested since 1927, (2) Successional forest previously cleared for non-forest vegetation (including agriculture) that has since reforested, or (3) Converted forest that has regrown on previously developed areas. We then assessed present-day ownership and average canopy height of forest patches by land cover sequence class. Results: More than half of Baltimore City’s forest has persisted since at least 1927, 72% since 1953. About 30% has succeeded from non-forest vegetation during the past century, while 15% has reverted from previous development. A large proportion of forest converted from previous development is currently privately owned, whereas persistent and successional forest are more likely municipally-owned. Successional forest occurred on larger average parcels with the fewest number of distinct property owners per patch. Average tree canopy height was significantly greater in patches of persistent forest (mean = 18.1 m) compared to canopy height in successional and converted forest patches (16.6 m and 16.9 m, respectively). Conclusions: Historical context is often absent from urban landscape ecology but provides information that can inform management approaches and conservation priorities with limited resources for sustaining urban natural resources. Using historical landscape analysis, urban forest patches could be further prioritized for protection by their age class and associated ecosystem characteristics. [ABSTRACT FROM AUTHOR]

DPANN archaea are a diverse group of microorganisms characterised by small cells and reduced genomes. To date, all cultivated DPANN archaea are ectosymbionts that require direct cell contact with an archaeal host species for growth and survival. However, these interactions and their impact on the host species are poorly understood. Here, we show that a DPANN archaeon (Candidatus Nanohaloarchaeum antarcticus) engages in parasitic interactions with its host (Halorubrum lacusprofundi) that result in host cell lysis. During these interactions, the nanohaloarchaeon appears to enter, or be engulfed by, the host cell. Our results provide experimental evidence for a predatory-like lifestyle of an archaeon, suggesting that at least some DPANN archaea may have roles in controlling host populations and their ecology. DPANN archaea are a group of microorganisms that require direct cell contact with other archaeal host species for growth. Here, Hamm et al. show that a DPANN archaeon engages in parasitic interactions with its host leading to host cell lysis, thus providing experimental evidence of a predatory-like lifestyle for an archaeon. [ABSTRACT FROM AUTHOR]

The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients. [ABSTRACT FROM AUTHOR]

Baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) has been widely used as a bioinsecticide and a protein expression vector. Despite their importance, very little is known about the structure of most baculovirus proteins. Here, we show a 3.2 Å resolution structure of helical cylindrical body of the AcMNPV nucleocapsid, composed of VP39, as well as 4.3 Å resolution structures of both the head and the base of the nucleocapsid composed of over 100 protein subunits. AcMNPV VP39 demonstrates some features of the HK97-like fold and utilizes disulfide-bonds and a set of interactions at its C-termini to mediate nucleocapsid assembly and stability. At both ends of the nucleocapsid, the VP39 cylinder is constricted by an outer shell ring composed of proteins AC104, AC142 and AC109. AC101(BV/ODV-C42) and AC144(ODV-EC27) form a C14 symmetric inner layer at both capsid head and base. In the base, these proteins interact with a 7-fold symmetric capsid plug, while a portal-like structure is seen in the central portion of head. Additionally, we propose an application of AlphaFold2 for model building in intermediate resolution density. Baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is used as a bioinsecticide and a protein expression vector. Here, the authors report structures of cylindrical body of the AcMNPV nucleocapsid, as well as of both the nucleocapsid head and base. [ABSTRACT FROM AUTHOR]

Background: A rapid, low-cost blood test that can be applied to reliably detect multiple different cancer types would be transformational. Methods: In this large-scale discovery study (n = 2092 patients) we applied the Dxcover® Cancer Liquid Biopsy to examine eight different cancers. The test uses Fourier transform infrared (FTIR) spectroscopy and machine-learning algorithms to detect cancer. Results: Area under the receiver operating characteristic curve (ROC) values were calculated for eight cancer types versus symptomatic non-cancer controls: brain (0.90), breast (0.76), colorectal (0.91), kidney (0.91), lung (0.91), ovarian (0.86), pancreatic (0.84) and prostate (0.86). We assessed the test performance when all eight cancer types were pooled to classify 'any cancer' against non-cancer patients. The cancer versus asymptomatic non-cancer classification detected 64% of Stage I cancers when specificity was 99% (overall sensitivity 57%). When tuned for higher sensitivity, this model identified 99% of Stage I cancers (with specificity 59%). Conclusions: This spectroscopic blood test can effectively detect early-stage disease and can be fine-tuned to maximise either sensitivity or specificity depending on the requirements from different healthcare systems and cancer diagnostic pathways. This low-cost strategy could facilitate the requisite earlier diagnosis, when cancer treatment can be more effective, or less toxic. Statement of translational relevance: The earlier diagnosis of cancer is of paramount importance to improve patient survival. Current liquid biopsies are mainly focused on single tumour-derived biomarkers, which limits test sensitivity, especially for early-stage cancers that do not shed enough genetic material. This pan-omic liquid biopsy analyses the full complement of tumour and immune-derived markers present within blood derivatives and could facilitate the earlier detection of multiple cancer types. There is a low barrier to integrating this blood test into existing diagnostic pathways since the technology is rapid, simple to use, only minute sample volumes are required, and sample preparation is minimal. In addition, the spectroscopic liquid biopsy described in this study has the potential to be combined with other orthogonal tests, such as cell-free DNA, which could provide an efficient route to diagnosis. Cancer treatment can be more effective when given earlier, and this low-cost strategy has the potential to improve patient prognosis. [ABSTRACT FROM AUTHOR]

Context: Previous studies developed distance-weighted regression to describe how land use effects on aquatic systems attenuate with arrangement of source areas within catchments. Objectives: We clarify and extend the conceptual foundations of this approach, enhance the spatial and statistical methods, and provide new tools to interpret the results. Methods: We derive the framework from first principles to resolve conceptual issues with how weighting is applied to source area versus total area, and we formalize the requirements for an ideal weighting function. We quantify the spatial distributions of land areas in a way that integrates with model fitting. We adapt non-linear optimization to simultaneously fit regression and weighting parameters. We quantify the spatial distribution of source effects with arrangement and document how different weighting functions alter that distribution. Results: To verify their utility, we applied these methods to a published analysis relating polychlorinated biphenyls in fish to developed land use in catchments. We identified a stronger distance-weighted model and more completely characterized the effects of weighting on where aquatic impacts originate. Conclusions: Our methods enable more comprehensive analyses of the effects of spatial arrangement to better inform a wide range of scientific investigations and applications. Our methods can relate almost any spatially distributed source or driver to an integrated response at a point or along a boundary; and alternate hypotheses about the effects of pattern or proximity on processes can be tested with alternative weighting functions. New applications will generate additional weighting functions that enhance the general approach. [ABSTRACT FROM AUTHOR]

The external globus pallidus (GPe) coordinates action-selection through GABAergic projections throughout the basal ganglia. GPe arkypallidal (arky) neurons project exclusively to the dorsal striatum, which regulates goal-directed and habitual seeking. However, the role of GPe arky neurons in reward-seeking remains unknown. Here, we identified that a majority of arky neurons target the dorsolateral striatum (DLS). Using fiber photometry, we found that arky activities were higher during random interval (RI; habit) compared to random ratio (RR; goal) operant conditioning. Support vector machine analysis demonstrated that arky neuron activities have sufficient information to distinguish between RR and RI behavior. Genetic ablation of this arkyGPe→DLS circuit facilitated a shift from goal-directed to habitual behavior. Conversely, chemogenetic activation globally reduced seeking behaviors, which was blocked by systemic D1R agonism. Our findings reveal a role of this arkyGPe→DLS circuit in constraining habitual seeking in male mice, which is relevant to addictive behaviors and other compulsive disorders. The external part of the globus pallidus is involved in action-selection. Here, the authors investigate the function of an arkypallidal neuronal circuit to the dorsolateral striatum in goal-directed and habitual-seeking behaviors in male mice. [ABSTRACT FROM AUTHOR]

Key Message: Terrestrial laser scanning data can be converted to reliable woody aboveground biomass estimates, but estimation quality is influenced by growing environment, leaf condition, and variation in tree density affecting volume to mass conversion. Both rural and urban forests play an important role in terrestrial carbon cycling. Forest carbon stocks are typically estimated from models predicting the aboveground biomass (AGB) of trees. However, such models are often limited by insufficient data on tree mass, which generally requires felling and weighing parts of trees. In this study, thirty-one trees of both deciduous and evergreen species were destructively sampled in rural and urban forest conditions. Prior to felling, terrestrial laser scanning (TLS) data were used to estimate tree biomass based on volume estimates from quantitative structure models, combined with tree basic density estimates from disks sampled from stems and branches after scanning and felling trees, but also in combination with published basic density values. Reference woody AGB, main stem, and branch biomass were computed from destructive sampling. Trees were scanned in leaf-off conditions, except evergreen and some deciduous trees, to assess effects of a leaf-separation algorithm on TLS-based woody biomass estimates. We found strong agreement between TLS-based and reference woody AGB, main stem, and branch biomass values, using both measured and published basic densities to convert TLS-based volume to biomass, but use of published densities reduced accuracy. Correlations between TLS-based and reference branch biomass were stronger for urban trees, while correlations with stem mass were stronger for rural trees. TLS-based biomass estimates from leaf-off and leaf-removed point clouds strongly agreed with reference biomass data, showing the utility of the leaf-removal algorithm for enhancing AGB estimation. [ABSTRACT FROM AUTHOR]

Cardiolipin is a hallmark phospholipid of mitochondrial membranes. Despite established significance of cardiolipin in supporting respiratory supercomplex organization, a mechanistic understanding of this lipid-protein interaction is still lacking. To address the essential role of cardiolipin in supercomplex organization, we report cryo-EM structures of a wild type supercomplex (IV1III2IV1) and a supercomplex (III2IV1) isolated from a cardiolipin-lacking Saccharomyces cerevisiae mutant at 3.2-Å and 3.3-Å resolution, respectively, and demonstrate that phosphatidylglycerol in III2IV1 occupies similar positions as cardiolipin in IV1III2IV1. Lipid-protein interactions within these complexes differ, which conceivably underlies the reduced level of IV1III2IV1 and high levels of III2IV1 and free III2 and IV in mutant mitochondria. Here we show that anionic phospholipids interact with positive amino acids and appear to nucleate a phospholipid domain at the interface between the individual complexes, which dampen charge repulsion and further stabilize interaction, respectively, between individual complexes. Whether anionic phospholipids required for respiratory supercomplex (SC) formation is unclear. Here authors resolve SCs from a wild type and cardiolipin-deficient yeast strain at 3.2- 3.3 Å resolution to show that cardiolipin can be replaced by phosphatidylglycerol. [ABSTRACT FROM AUTHOR]

This dataset contains ligand conformations and docking scores for 1.4 billion molecules docked against 6 structural targets from SARS-CoV2, representing 5 unique proteins: MPro, NSP15, PLPro, RDRP, and the Spike protein. Docking was carried out using the AutoDock-GPU platform on the Summit supercomputer and Google Cloud. The docking procedure employed the Solis Wets search method to generate 20 independent ligand binding poses per compound. Each compound geometry was scored using the AutoDock free energy estimate, and rescored using RFScore v3 and DUD-E machine-learned rescoring models. Input protein structures are included, suitable for use by AutoDock-GPU and other docking programs. As the result of an exceptionally large docking campaign, this dataset represents a valuable resource for discovering trends across small molecule and protein binding sites, training AI models, and comparing to inhibitor compounds targeting SARS-CoV-2. The work also gives an example of how to organize and process data from ultra-large docking screens. Measurement(s) equilibrium association constant (KA) Technology Type(s) molecular docking by scoring function Factor Type(s) Chemical formula and connectivity Sample Characteristic - Organism Severe acute respiratory syndrome-related coronavirus Sample Characteristic - Environment in-silico [ABSTRACT FROM AUTHOR]

Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are clinical syndromes that commonly have underlying Alzheimer's disease (AD), although non-AD pathologies have also been reported. PET imaging allows for identification of beta-amyloid (Aβ) and tau in AD, so we aimed to assess these in a large cohort to identify patients that do not have evidence for biomarker-defined AD. Eight-one patients, 47 PCA and 34 LPA, underwent extensive neurological and neuropsychological testing, [11C] Pittsburgh compound B, [18F] flortaucipir and [18F] fluorodeoxyglucose PETs. Global Aβ and tau-PET standardized uptake value ratios (SUVRs) were plotted for all patients and outliers, and patients with abnormally low SUVRs compared to the biomarker-classic cohort were identified. Six (7.4%) biomarker-outlier cases were identified, and three patterns were observed: (i) negative/borderline Aβ-PET and striking widespread tau-PET uptake (two LPA); (ii) negative/borderline Aβ-PET and low tau-PET uptake (three PCA) and (iii) elevated Aβ-PET uptake but mild focal tau-PET uptake (one LPA). Among the unusual patients in group ii, two patients showed no abnormal tau uptake suggesting non-AD pathology, with one developing features of cortico-basal syndrome and the other dementia with Lewy bodies. The remaining patient showed very mild focal tau uptake. This study demonstrates that a small minority (~ 8%) of PCA and LPA patients do not show the typical striking patterns of Aβ and tau PET uptake, with only 2% showing absence of both proteins. These findings will help inform the use of molecular PET in clinical treatment trials that include patients with atypical phenotypes of AD. [ABSTRACT FROM AUTHOR]

Intracellular compartments are functional units that support the metabolism within living cells, through spatiotemporal regulation of chemical reactions and biological processes. Consequently, as a step forward in the bottom-up creation of artificial cells, building analogous intracellular architectures is essential for the expansion of cell-mimicking functionality. Herein, we report the development of a droplet laboratory platform to engineer complex emulsion-based, multicompartment artificial cells, using microfluidics and acoustic levitation. Such levitated models provide free-standing, dynamic, definable droplet networks for the compartmentalisation of chemical species. Equally, they can be remotely operated with pneumatic, heating, and magnetic elements for post-processing, including the incorporation of membrane proteins; alpha-hemolysin; and mechanosensitive channel of large-conductance. The assembly of droplet networks is three-dimensionally patterned with fluidic input configurations determining droplet contents and connectivity, whilst acoustic manipulation can be harnessed to reconfigure the droplet network in situ. The mechanosensitive channel can be repeatedly activated and deactivated in the levitated artificial cell by the application of acoustic and magnetic fields to modulate membrane tension on demand. This offers possibilities beyond one-time chemically mediated activation to provide repeated, non-contact, control of membrane protein function. Collectively, this expands our growing capability to program and operate increasingly sophisticated artificial cells as life-like materials. Engineering micro-emulsion plays a key role in the creation of bottom-up synthetic cells. Here, authors demonstrate a droplet laboratory platform to control membrane protein gating in functional artificial cell using microfluidics and acoustic levitation. [ABSTRACT FROM AUTHOR]

Developing prediction models for emerging infectious diseases from relatively small numbers of cases is a critical need for improving pandemic preparedness. Using COVID-19 as an exemplar, we propose a transfer learning methodology for developing predictive models from multi-modal electronic healthcare records by leveraging information from more prevalent diseases with shared clinical characteristics. Our novel hierarchical, multi-modal model ( T R A N S MED ) integrates baseline risk factors from the natural language processing of clinical notes at admission, time-series measurements of biomarkers obtained from laboratory tests, and discrete diagnostic, procedure and drug codes. We demonstrate the alignment of T R A N S MED 's predictions with well-established clinical knowledge about COVID-19 through univariate and multivariate risk factor driven sub-cohort analysis. T R A N S MED 's superior performance over state-of-the-art methods shows that leveraging patient data across modalities and transferring prior knowledge from similar disorders is critical for accurate prediction of patient outcomes, and this approach may serve as an important tool in the early response to future pandemics. [ABSTRACT FROM AUTHOR]

Bacterial type IV secretion systems (T4SSs) are largely responsible for the proliferation of multi-drug resistance. We solved the structure of the outer-membrane core complex (OMCCF) of a T4SS encoded by a conjugative F plasmid at <3.0 Å resolution by cryoelectron microscopy. The OMCCF consists of a 13-fold symmetrical outer ring complex (ORC) built from 26 copies of TraK and TraV C-terminal domains, and a 17-fold symmetrical central cone (CC) composed of 17 copies of TraB β-barrels. Domains of TraV and TraB also bind the CC and ORC substructures, establishing that these proteins undergo an intraprotein symmetry alteration to accommodate the C13:C17 symmetry mismatch. We present evidence that other pED208-encoded factors stabilize the C13:C17 architecture and define the importance of TraK, TraV and TraB domains to T4SSF function. This work identifies OMCCF structural motifs of proposed importance for structural transitions associated with F plasmid dissemination and F pilus biogenesis. Bacteria conjugatively transfer DNA through type IV secretion systems (T4SSs). Here, the authors report the structure of a T4SS outer-membrane core complex (OMCC), revealing how a distinct C13:C17 symmetry mismatch exhibited by peripheral ring and central cone substructures is accommodated. [ABSTRACT FROM AUTHOR]

Learning to anticipate potentially dangerous contexts is an adaptive behavioral response to coping with stressors. An animal's stress coping style (e.g. proactive–reactive axis) is known to influence how it encodes salient events. However, the neural and molecular mechanisms underlying these stress coping style differences in learning are unknown. Further, while a number of neuroplasticity-related genes have been associated with alternative stress coping styles, it is unclear if these genes may bias the development of conditioned behavioral responses to stressful stimuli, and if so, which brain regions are involved. Here, we trained adult zebrafish to associate a naturally aversive olfactory cue with a given context. Next, we investigated if expression of two neural plasticity and neurotransmission-related genes (npas4a and gabbr1a) were associated with the contextual fear conditioning differences between proactive and reactive stress coping styles. Reactive zebrafish developed a stronger conditioned fear response and showed significantly higher npas4a expression in the medial and lateral zones of the dorsal telencephalon (Dm, Dl), and the supracommissural nucleus of the ventral telencephalon (Vs). Our findings suggest that the expression of activity-dependent genes like npas4a may be differentially expressed across several interconnected forebrain regions in response to fearful stimuli and promote biases in fear learning among different stress coping styles. [ABSTRACT FROM AUTHOR]

Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment. Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome of multiple etiologies which affects spoken communication. Here, the authors characterized the molecular pathology, biochemistry, genetics and longitudinal neuroimaging of 32 autopsy-confirmed patients with PAOS who were followed over 10 years. [ABSTRACT FROM AUTHOR]

Hunter-gatherer societies are characterized by decentralized decision making and shared access to resources. Goods are distributed via reciprocal exchange, sharing, and gift-giving, in the end resulting in relatively equal distribution. Work effort, however, is not distributed equally; the best hunters exert a disproportionate share of productive effort. We argue that these features of the hunter-gatherer economy are interrelated, and are consistent with the view that customary gift-giving and sharing arrangements manage usage of open-access resources. In particular, sharing rules can induce optimal hunting effort, while gift-giving can serve to elicit information about hunter productivity. [ABSTRACT FROM AUTHOR]

The influence of climate on the dynamics of Arctic gadids is of increasing interest, particularly as research and survey effort expands in the Pacific Arctic. Understanding species-specific thermal tolerance may inform models of species distribution and projections of available habitat and also clarify implications of warming for ecological communities. Analyzing shifts in species distribution in warm and cold periods, this study considers the effects of a warming climate on the distribution of two keystone Arctic gadids (polar cod, saffron cod) and two commercially important sub-Arctic gadids (walleye pollock, Pacific cod). Shifts in distribution were used to derive temperature tolerance thresholds and to project how these species might react to a warming Arctic. Significant shifts were noted in comparisons of warm (2002–2005, 2014–2016, 2017–2018) and cold (2006–2013) periods. Sub-Arctic species expanded and contracted their range as environmental conditions shifted. In contrast, Arctic species appeared constrained, such that population densities increased or decreased within the same core geographic area. Additionally, species with a demersal life history were able to tolerate a wider range of thermal conditions. These results provide important insights on relative thermal tolerance of each species, differential influence of temperature on pelagic versus demersal life histories, and depth as thermal refuge. This study demonstrates both the need to understand the spatial response of fish to changing ocean conditions in polar regions and the utility of distributional analyses to inform that effort. [ABSTRACT FROM AUTHOR]

Recent research with classic psychedelics suggests significant therapeutic potential, particularly for neuropsychiatric disorders. A mediating influence behind symptom resolution is thought to be the personal insight – at times, bordering on the mystical – one acquires during the acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between the acute subjective effects (ASE) under the influence of psychedelics and their enduring therapeutic properties. However, with potential barriers to widespread clinical implementation, including the healthcare resource-intensive nature of psychedelic sessions and the exclusion of certain at-risk patient groups, there is an active search to determine whether ASE elimination can be accompanied by the retention of persisting therapeutic benefits of these class of compounds. Recognizing the aberrant underlying neural circuitry that characterizes a range of neuropsychiatric disorders, and that classic psychedelics promote neuroplastic changes that may correct abnormal circuitry, investigators are rushing to design and discover compounds with psychoplastogenic, but not hallucinogenic (i.e., ASE), therapeutic potential. These efforts have paved the discovery of ‘non-psychedelic/subjective psychedelics’, or compounds that lack hallucinogenic activity but with therapeutic efficacy in preclinical models. This review aims to distill the current evidence – both clinical and preclinical – surrounding the question: can the ASE of classic psychedelics be dissociated from their sustained therapeutic properties? Several plausible clinical scenarios are then proposed to offer clarity on and potentially answer this question. [ABSTRACT FROM AUTHOR]

Type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) is the predominant Ca2+-release channel in neurons. IP3R1 mediates Ca2+ release from the endoplasmic reticulum into the cytosol and thereby is involved in many physiological processes. Here, we present the cryo-EM structures of full-length rat IP3R1 reconstituted in lipid nanodisc and detergent solubilized in the presence of phosphatidylcholine determined in ligand-free, closed states by single-particle electron cryo-microscopy. Notably, both structures exhibit the well-established IP3R1 protein fold and reveal a nearly complete representation of lipids with similar locations of ordered lipids bound to the transmembrane domains. The lipid-bound structures show improved features that enabled us to unambiguously build atomic models of IP3R1 including two membrane associated helices that were not previously resolved in the TM region. Our findings suggest conserved locations of protein-bound lipids among homotetrameric ion channels that are critical for their structural and functional integrity despite the diversity of structural mechanisms for their gating. 3D structure of full-length rat type 1 inositol 1,4,5-trisphosphate receptor reconstituted in lipid nanodisc is determined using single-particle cryo-electron microscopy. The study suggests conserved locations of protein-bound lipids among structurally diverse, homo-tetrameric ion channels. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10–5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden. [ABSTRACT FROM AUTHOR]

Nature Biotechnology asks a selection of faculty about the most exciting frontier in their field and the most needed technologies for advancing knowledge and applications. [ABSTRACT FROM AUTHOR]

Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca2+ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants. Individuals with malignant hyperthermia susceptibility (MHS) suffer from lifethreatening responses to heat. Here the authors demonstrate that adaptive thermogenesis from brown adipose tissue contributes to this heat sensitivity in a preclinical mouse model of MHS [ABSTRACT FROM AUTHOR]

Background: Some weight regain is expected after bariatric surgery; however, this concept is not well defined. A favorable weight loss response has commonly been defined as 50% excess weight loss (EWL). The medical literature uses %total weight loss (%TWL), which has recently been adopted in some surgical literature. Objective: To demonstrate variability in bariatric surgery outcomes based on the definition applied and propose a standardized definition. Methods: A retrospective review of patients who underwent bariatric surgery from 2001 to 2016 with ≥ 1 year follow-up was completed. Several previously proposed definitions of weight regain were analyzed. Results: One thousand five hundred seventy-four patients met inclusion criteria. Preoperative mean body mass index (BMI) was 47.6 ± 6.4 kg/m2. Increased preoperative BMI was associated with increased mean %TWL at 2 years postoperative (29.3 ± 9.1% for BMI < 40, vs. 37.5 ± 9.5% for BMI > 60; P < 0.001). Based on %EWL, 93% of patients experienced ≥ 50% EWL by 1–2 years, and 61.8% maintained ≥ 50% EWL through the 10-year follow-up period. Similarly, 97% experienced ≥ 20% TWL by 1–2 years and 70.3% maintained ≥ 20% TWL through the 10-year follow-up period. Over 50% of patients maintained their weight based on several proposed definitions through 5 years follow-up. Conclusions: A high percentage (> 90%) of patients achieve ≥ 20% TWL and ≥ 50% EWL. Increased preoperative BMI was associated with increased %TWL and decreased %EWL at 2 years postoperative. The incidence of weight regain varies depending on the definition. We propose a standardized definition for identifying good responders following bariatric surgery to be ≥ 20% TWL, as this measure is least influenced by preoperative BMI. [ABSTRACT FROM AUTHOR]

Machine learning (ML) is a form of artificial intelligence which is placed to transform the twenty-first century. Rapid, recent progress in its underlying architecture and algorithms and growth in the size of datasets have led to increasing computer competence across a range of fields. These include driving a vehicle, language translation, chatbots and beyond human performance at complex board games such as Go. Here, we review the fundamentals and algorithms behind machine learning and highlight specific approaches to learning and optimisation. We then summarise the applications of ML to medicine. In particular, we showcase recent diagnostic performances, and caveats, in the fields of dermatology, radiology, pathology and general microscopy. [ABSTRACT FROM AUTHOR]

TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0-VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with "typical" TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-β). We compared pathological, genetic (APOE4, TMEM106B and GRN variants), neuroimaging and clinical data between types, as well as compared neuroimaging between types and a group of TDP-43 negative cases (n = 309). Two-hundred forty-one cases were classified as TDP type-α (n = 131, 54%) or TDP type-β (n = 110, 46%). Type-α cases were older than type-β at death (median 89 years vs. 87 years; p = 0.02). Hippocampal sclerosis was present in 78 (60%) type-α cases and 16 (15%) type-β cases (p < 0.001). Type-α cases showed a pattern of widespread TDP-43 deposition commonly extending into temporal, frontal and brainstem regions (84% TDP-43 stage 4-6) while in type-β cases deposition was predominantly limbic, located in amygdala, entorhinal cortex and subiculum of the hippocampus (84% TDP-43 stages 1-3) (p < 0.001). There was a difference in the frequency of TMEM106B protective (GG) and risk (CC) haplotypes (SNP rs3173615 encoding p.T185S) in type-α cases compared to type-β cases (GG/CG/CC: 8%/42%/50% vs. 24%/49%/27%; p = 0.01). Type-α cases had smaller amygdala (− 10.6% [− 17.6%, − 3.5%]; p = 0.003) and hippocampal (− 14.4% [− 21.6%, − 7.3%]; p < 0.001) volumes on MRI at death compared to type-β cases, although both types had smaller amygdala and hippocampal volumes compared to TDP-43 negative cases (− 7.77%, − 21.6%; p < 0.001). These findings demonstrate that there is distinct heterogeneity of TDP-43 deposition in non-FTLD brains. [ABSTRACT FROM AUTHOR]

Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer. Therapeutic T cells bearing ligands engineered to optimize adhesion and transmigration through the blood-brain barrier can be targeted to brain tumours. [ABSTRACT FROM AUTHOR]

The bacterial flagellum is a large extracellular protein organelle that extrudes from the cell surface. The flagellar filament is assembled from tens of thousands of flagellin subunits that are exported through the flagellar type III secretion system. Here, we measure the growth of Escherichia coli flagella in real time and find that, although the growth rate displays large variations at similar lengths, it decays on average as flagella lengthen. By tracking single flagella, we show that the large variations in growth rate occur as a result of frequent pauses. Furthermore, different flagella on the same cell show variable growth rates with correlation. Our observations are consistent with an injection-diffusion model, and we propose that an insufficient cytoplasmic flagellin supply is responsible for the pauses in flagellar growth in E. coli. [ABSTRACT FROM AUTHOR]

Background: Golf is commonly considered a low-impact sport that carries little risk of injury to the knee and is generally allowed following total knee arthroplasty (TKA). Kinematic and kinetic studies of the golf swing have reported results relevant to the knee, but consensus as to the loads experienced during a swing and how the biomechanics of an individual's technique may expose the knee to risk of injury is lacking. Objectives: Our objective was to establish (1) the prevalence of knee injury resulting from participation in golf and (2) the risk factors for knee injury from a biomechanical perspective, based on an improved understanding of the internal loading conditions and kinematics that occur in the knee from the time of addressing the ball to the end of the follow-through. Methods: A systematic literature search was conducted to determine the injury rate, kinematic patterns, loading, and muscle activity of the knee during golf. Results: A knee injury prevalence of 3-18% was established among both professional and amateur players, with no clear dependence on skill level or sex; however, older players appear at greater risk of injury. Studies reporting kinematics indicate that the lead knee is exposed to a complex series of motions involving rapid extension and large magnitudes of tibial internal rotation, conditions that may pose risks to the structures of a natural knee or TKA. To date, the loads experienced by the lead knee during a golf swing have been reported inconsistently in the literature. Compressive loads ranging from 100 to 440% bodyweight have been calculated and measured using methods including inverse dynamics analysis and instrumented knee implants. Additionally, the magnitude of loading appears to be independent of the club used. Conclusions: This review is the first to highlight the lack of consensus regarding knee loading during the golf swing and the associated risks of injury. Results from the literature suggest the lead knee is subject to a higher magnitude of stress and more demanding motions than the trail knee. Therefore, recommendations regarding return to golf following knee injury or surgical intervention should carefully consider the laterality of the injury. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Since 1980, posttraumatic stress (PTS) disorder has been controversial because of its origin as a social construct, its discriminating trauma definition, and the Procrustean array of symptoms/clusters chosen for inclusion/exclusion. This review summarizes the history of trauma-related nosology and proposed changes, within current categorical models (trauma definitions, symptoms/clusters, subtypes/specifiers, disorders) and new models.Recent Findings: Considering that trauma is a risk factor for virtually all mental disorders (particularly depressive, anxiety, dissociative, personality), the multi-finality of trauma (some survivors are resilient, and some develop PTS and/or non-PTS symptoms), and the various symptoms that trauma survivors express (mood, cognitive, perceptual, somatic), it is difficult to classify PTS. Because the human mind best comprehends categories, reliable classification generally necessitates using a categorical nosology but PTS defies categories (internalizing and/or externalizing, fear-based and/or numbing symptoms), the authors conclude that PTS-like DSM-5's panic attacks specifier-is currently best conceptualized as a specifier for other mental disorders. [ABSTRACT FROM AUTHOR]

Two small swards of two grass species ( Agrostis stolonifera and Agrostis capillaris) previously unrecorded on Macquarie Island (54°30′S, 158°56′E) were found during the 2013-2014 austral summer. Their discovery leads to an assessment of their introduction status and invasive risk. Several evaluations were conducted on the plants regarding their extent, taxonomy, reproductive status and invasive potential. It is possible that the two species were accidentally introduced by human activities due to their proximity to human-frequented sites. No further occurrences were found, indicating that although the species were established, they were, respectively, restricted to two small swards of less than 1 m each. Observations of floral development in the field at the end of summer suggested that no sexually reproductive material was produced. Indoor cultivation of sampled specimens at the island station showed a faster development with mature flowers at the end of the summer but still no seeds. The bioclimatic niches of the two species were modeled with MaxEnt software. Biomodeling results indicate that reasonably favorable habitat is available on Macquarie Island for the successful colonization of both species. Agrostis stolonifera showed a higher invasion risk than A. capillaris. Our observations indicate that the two species are strong candidates for invading the island despite having phenological constraints. As a result, the two swards were removed by the island's management authority. Further introductions and establishment of non-native plant species are expected to occur on sub-Antarctic islands under current global change scenarios. [ABSTRACT FROM AUTHOR]

The ability to diagnose cancer rapidly with high sensitivity and specificity is essential to exploit advances in new treatments to lead significant reductions in mortality and morbidity. Current cancer diagnostic tests observing tissue architecture and specific protein expression for specific cancers suffer from inter-observer variability, poor detection rates and occur when the patient is symptomatic. A new method for the detection of cancer using 1 μl of human serum, attenuated total reflection-Fourier transform infrared spectroscopy and pattern recognition algorithms is reported using a 433 patient dataset (3897 spectra). To the best of our knowledge, we present the largest study on serum mid-infrared spectroscopy for cancer research. We achieve optimum sensitivities and specificities using a Radial Basis Function Support Vector Machine of between 80.0 and 100 % for all strata and identify the major spectral features, hence biochemical components, responsible for the discrimination within each stratum. We assess feature fed-SVM analysis for our cancer versus non-cancer model and achieve 91.5 and 83.0 % sensitivity and specificity respectively. We demonstrate the use of infrared light to provide a spectral signature from human serum to detect, for the first time, cancer versus non-cancer, metastatic cancer versus organ confined, brain cancer severity and the organ of origin of metastatic disease from the same sample enabling stratified diagnostics depending upon the clinical question asked. [ABSTRACT FROM AUTHOR]

We study smooth tropical plane quartic curves and show that they satisfy certain properties analogous to (but also different from) smooth plane quartics in algebraic geometry. For example, we show that every such curve admits either infinitely many or exactly 7 bitangent lines. We also prove that a smooth tropical plane quartic curve cannot be hyperelliptic. [ABSTRACT FROM AUTHOR]

Ground penetrating radar (GPR) can be used to image fractures and monitor fluid flow in the subsurface. Conventional GPR imaging uses single-polarization, co-polarized acquisition. We examine the use of cross-polarized GPR signals for imaging flow channeling in a discrete horizontal fracture. Numerical modeling (FDTD) demonstrates that when the fracture channel is oriented at an oblique angle to the survey line, depolarization of the GPR signal results in scattered energy along the cross-polarized components. When the channel is oriented parallel or orthogonal to the survey line, all scattered energy is captured by the co-polarized components and no signal is present in the cross-polarized orientation. Multipolarization, time-lapse 3D GPR field data were acquired at the Altona Flat Rock test site in New York State. The GPR surveys were conducted during background fresh fracture water conditions and during a natural gradient saline tracer test which was used to highlight flow channels along a sub-horizontal fracture. Amplitude analysis of the cross-polarized data reveals flow channeling that is in agreement with the co-polarized GPR images and with independent hydraulic tests. This investigation demonstrates that cross-polarized components of GPR signals can be used to enhance imaging of flow channels in fractured media. [ABSTRACT FROM AUTHOR]

The loss of chromosome 9 open reading frame 72 ( C9ORF72) expression, associated with C9ORF72 repeat expansions, has not been examined systematically. Three C9ORF72 transcript variants have been described thus far; the GGGGCC repeat is located between two non-coding exons (exon 1a and exon 1b) in the promoter region of transcript variant 2 (NM_018325.4) or in the first intron of variant 1 (NM_145005.6) and variant 3 (NM_001256054.2). We studied C9ORF72 expression in expansion carriers ( n = 56) for whom cerebellum and/or frontal cortex was available. Using quantitative real-time PCR and digital molecular barcoding techniques, we assessed total C9ORF72 transcripts, variant 1, variant 2, variant 3, and intron containing transcripts [upstream of the expansion (intron 1a) and downstream of the expansion (intron 1b)]; the latter were correlated with levels of poly(GP) and poly(GA) proteins aberrantly translated from the expansion as measured by immunoassay ( n = 50). We detected a decrease in expansion carriers as compared to controls for total C9ORF72 transcripts, variant 1, and variant 2: the strongest association was observed for variant 2 (quantitative real-time PCR cerebellum: median 43 %, p = 1.26e-06, and frontal cortex: median 58 %, p = 1.11e-05; digital molecular barcoding cerebellum: median 31 %, p = 5.23e-10, and frontal cortex: median 53 %, p = 5.07e-10). Importantly, we revealed that variant 1 levels greater than the 25th percentile conferred a survival advantage [digital molecular barcoding cerebellum: hazard ratio (HR) 0.31, p = 0.003, and frontal cortex: HR 0.23, p = 0.0001]. When focusing on intron containing transcripts, analysis of the frontal cortex revealed an increase of potentially truncated transcripts in expansion carriers as compared to controls [digital molecular barcoding frontal cortex (intron 1a): median 272 %, p = 0.003], with the highest levels in patients pathologically diagnosed with frontotemporal lobar degeneration. In the cerebellum, our analysis suggested that transcripts were less likely to be truncated and, excitingly, we discovered that intron containing transcripts were associated with poly(GP) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.33, p = 0.02, and (intron 1b): r = 0.49, p = 0.0004] and poly(GA) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.34, p = 0.02, and (intron 1b): r = 0.38, p = 0.007]. In summary, we report decreased expression of specific C9ORF72 transcripts and provide support for the presence of truncated transcripts as well as pre-mRNAs that may serve as templates for RAN translation. We further show that higher C9ORF72 levels may have beneficial effects, which warrants caution in the development of new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are ubiquitous ion channels responsible for cytosolic Ca2+ signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP3Rs, a mechanistic understanding of their structure-function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 Å) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP3R channel in its apo-state. At this resolution, we are able to trace unambiguously ∼85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca2+-conduction pathway is similar to other ion channels, including the closely related randiness receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed α-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals. [ABSTRACT FROM AUTHOR]