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Internationally, secure institutions face a range of challenges presented by detainees convicted or suspected of terrorism-related crimes and those interested or involved in groups that support ideologically justify violence (IJV). Currently, there is an apparent absence of a theoretically grounded but operationally focused paradigm (or conceptual lens) for understanding and preventing IJV within such settings. In response, this article presents such a paradigm, to inform and direct the implementation of coherent organizational policies and practices to address this issue. The paradigm, its theoretical basis, its implications for correctional policy and practice, and limitations are outlined and discussed.

Acute thrombotic thrombocytopenic purpura (TTP) is a life-threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality.To compare current practice in the United Kingdom (UK) against the standards set out in the 2012 British Society of Haematology guideline, and to better understand the issues affecting prompt initiation of PEX.The trainee research network HaemSTAR conducted a retrospective nationwide review of adults presenting to UK hospitals with a first episode of acute TTP.Data on 148 patients treated at 80 UK hospitals between 2014 and 2019 demonstrated that 64.8% of patients received PEX within 24 h. Diagnostic uncertainty was the most commonly cited reason for delayed treatment. Conversely, a shorter time to PEX occurred in patients who had red cell fragments or severe thrombocytopenia identified on their first complete blood count. Availability of on-site PEX was associated with a greater proportion of patients receiving PEX within 8 h compared to patients transferred, but by 24 h there was no difference between the two groups and two-thirds of all patients had received their first PEX. The mortality rate for patients that received PEX was 9.2%, with 27.8% of deaths linked to delayed treatment initiation.This is the first multi-center evaluation of treatment delays in acute TTP and it will inform targeted pathways to improve prompt access to life-saving intervention.

1. The open-source programming language ‘R’ has become a standard tool in the palaeobiologist’s toolkit. Its popularity within the palaeobiology community continues to grow, with published articles increasingly citing the usage of R and R packages. However, there are currently a lack of agreed standards for data preparation and available frameworks to support implementation of such standards. Consequently, data preparation workflows are often unclear and not reproducible, even when code is provided. Moreover, due to a lack of code accessibility and documentation, palaeobiologists are often forced to ‘reinvent the wheel’ to find solutions to issues already solved by other members of the community.2. Here, we introduce palaeoverse, a community-driven R package to aid data preparation and exploration for quantitative palaeobiological research. The package is freely available and has three core principles: (1) streamline data preparation and analyses; (2) enhance code readability; and (3) improve reproducibility of results. To develop these aims, we assessed the analytical needs of the broader palaeobiological community using an online survey, in addition to incorporating our own experiences.3. In this work, we first report the findings of the survey which shaped the development of the package. Subsequently, we describe and demonstrate the functionality available in palaeoverse and provide usage examples. Finally, we discuss the resources we have made available for the community and the future plans for the broader palaeoverse project.4. palaeoverse is the first community-driven R package in palaeobiology, developed with the intention of bringing palaeobiologists together to establish agreed standards for high-quality quantitative research. The package provides a user-friendly platform for preparing data for analysis with well-documented open-source code to enhance transparency. The functionality available in palaeoverse improves code reproducibility and accessibility, which is beneficial for both the review process and future research.

International audience; The Bayesian statistical approach considers teeth as forming a developmental module, as opposed to a tooth-by-tooth analysis. This approach has been employed to analyze Upper Pleistocene hominins, including Neandertals and some anatomically modern humans, but never earlier populations. Here we show its application on five hominins from the TD6.2 level of the Gran Dolina site (Homo antecessor, Early Pleistocene) and the Sima de los Huesos site (Middle Pleistocene) of the Sierra de Atapuerca (Burgos, northern Spain). Our results show an advanced development of the third molars in both populations with respect to modern Homo sapiens. In addition, the Sima de los Huesos hominins differ from H. sapiens and H. antecessor in the relatively advanced development of their second molar. The relative mineralization of I1/M1 in H. antecessor appears to be similar to that of modern humans, as opposed to that of Neandertals, which appear to be unique. These observations, combined with reduced enamel formation times and the advanced development of the third molars, appear to indicate a shorter ontogenetic period in the hominins from Gran Dolina and Sima de los Huesos in comparison to modern human average.

During the Early to Middle Pleistocene, Java was inhabited by hominid taxa of great diversity. However, their seasonal dietary strategies have never been explored. We undertook geochemical analyses of orangutan (Pongo sp.), Homo erectus and other mammalian Pleistocene teeth from Sangiran. We reconstructed past dietary strategies at subweekly resolution and inferred seasonal ecological patterns. Histologically controlled spatially resolved elemental analyses by laser-based plasma mass spectrometry confirmed the preservation of authentic biogenic signals despite the effect of spatially restricted diagenetic overprint. The Sr/Ca record of faunal remains is in line with expected trophic positions, contextualizing fossil hominid diet. Pongo sp. displays marked seasonal cycles with ~3 month-long strongly elevated Sr/Ca peaks, reflecting contrasting plant food consumption presumably during the monsoon season, while lower Sr/Ca ratios suggest different food availability during the dry season. In contrast, omnivorous H. erectus shows low and less accentuated intra-annual Sr/Ca variability compared to Pongo sp., with δ13C data of one individual indicating a dietary shift from C4 to a mix of C3 and C4 plants. Our data suggest that H. erectus on Java was maximizing the resources available in more open mosaic habitats and was less dependent on variations in seasonal resource availability. While still influenced by seasonal food availability, we infer that H. erectus was affected to a lesser degree than Pongo sp., which inhabited monsoonal rain forests on Java. We suggest that H. erectus maintained a greater degree of nutritional independence by exploiting the regional diversity of food resources across the seasons.

This chapter, ‘Treatment planning’, covers the processes that are involved in the production of a patient specific treatment plan, ranging from simple single field palliative treatments through to complex radical treatments using volumetric modulated arc therapy (VMAT). The step-wise methodology for creating planning target volumes (PTVs) from gross tumour volumes (GTVs), taking into account uncertainties at each step is discussed as is the evaluation of treatment plans using isodose distributions and dose volume histograms. The processes of plan checking and patient specific checks for complex treatment plans are discussed. The basics of monitor unit calculations are described and sample calculations are presented. A new and relevant section in this edition of the book describes stereotactic treatments such as SRS (stereotactic radiosurgery) and SABR (stereotactic ablative body radiotherapy) and how evaluation of these plans differs from more conventional techniques. The chapter concludes with a short discussion on the more common dose calculation models (algorithms) implemented on treatment planning systems.

Electron transfer to and from metal oxide nanocrystals (NCs) modulates their infrared localized surface plasmon resonance (LSPR) absorption, revealing fundamental aspects of their photophysics and providing opportunities for sensing and dynamic window technologies. However, the achievable shift of the LSPR is diminished by the presence of a near-surface depletion layer with low electron concentration. The depletion layer also separates the plasmonic NC core from the surrounding environment with a deleterious effect on the near-field enhancement (NFE) of the electromagnetic field. Here, we synthesized a series of Sn-doped In2O3 NCs with dopants segregated either in the core or the shell region to tune the depletion layer and introduce a second region of band bending at the interface between doped and undoped regions. By chemically reducing these NCs, we investigated the influence of radial dopant segregation on LSPR modulation and NFE. We found that core-doped NCs show large LSPR shifts during chemical titration, enabling broadband modulation in LSPR energy of over 1000 cm−1 and of peak extinction over 300%. Simulations reveal that the evolution of the LSPR spectra during chemical reduction results from raising the surface potential and increasing the donor defect density in the shell region. Although the computationally predicted NFE is greater for shell-doped NCs as synthesized, the change in NFE when adding or removing electrons is larger for core-doped NCs. These results establish dopant segregation as a useful strategy for engineering the responsive properties of metal oxide NCs, highlighting opportunities for dynamic optical modulation in plasmonic semiconductor NC heterostructures that go beyond those accessible with conventional plasmonic metals.

With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell invasion, and have generated analogues with improved potency. Here, we identify actin and profilin as putative targets of the MMV020291 series through resistance selection and whole genome sequencing of three MMV020291 resistant populations. This revealed three non-synonymous single nucleotide polymorphisms in two genes; two in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wildtype parasites which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade red blood cells. Additionally, the series inhibits the actin-1 dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro co-sedimentation experiments using recombinant P. falciparum actin-1 and profilin proteins indicate that potent MMV020291 analogues amplify the actin-monomer sequestering effect of profilin, thereby reducing the formation of filamentous actin. Altogether, this study identifies the first compound series targeting the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.

The objectives of this study were to quantify the variation in coincident stages of incisor, canine and molar eruption and tooth formation in modern humans and great apes and then to ask if any early fossil hominins showed a dental development pattern beyond the human range and/or clearly typical of great apes.Four stages of eruption and 18 stages of tooth development were defined and then scored for each developing tooth on radiographs of 159 once-free-living subadult great apes and on orthopantomographs of 4091 dental patients aged 1-23 years. From original observations, and from published images of eleven early fossil hominins, we then scored formation stages of permanent incisors when M1 was at root formation stage R¼-R½ and R¾-RC.Incisor and canine eruption/development was delayed in great apes relative to molar development when compared with humans but there was overlap in almost all anterior tooth stages observed. Molar crown initiation was generally advanced in great apes and delayed in humans but again, we observed overlap in all stages in both samples. Only two fossil hominin specimens (L.H.-3 from Laetoli, Tanzania and KNM-KP 34725 from Kanapoi, Kenya) showed delayed incisor development relative to M1 beyond any individuals observed in the human sample.For certain tooth types, the distribution of formation stages in our samples showed evidence of generally advanced or delayed development between taxa. However, it would rarely if ever be possible to allocate an individual to one taxon or another on this basis.

Palaeontological data provide a unique avenue to evaluate the impact of climatic, habitat and ecosystem change over longer temporal scales than typically examined in ecology and conservation, contributing critical data on extinction dynamics that can help contextualize the current biodiversity crisis. However, the fossil record is biased by a variety of factors. In particular, the issue of data absence causes a genuine concern when attempting to discern spatial patterns. Does the lack of a fossil occurrence indicate genuine absence or imperfect detection (i.e., pseudo-absence)? Failing to quantify, discern and mitigate both the main drivers and impacts of data absence will have major implications for any attempt to reconstruct past diversity dynamics, limiting the applicability of paleontological data for addressing questions pertaining to present-day biodiversity. Occupancy modelling, a technique commonly applied in the fields of ecology and conservation, provides a novel way to evaluate the impact of both spatial and temporal biases on the fossil record. By distinguishing between true (taxon genuinely absent) and false (taxon present, but not observed) absences, occupancy modelling produces independent and simultaneous probability estimates for both occupancy and detection. Here, we show how paleontological occurrences can be adapted for use alongside relevant modern and paleo covariate data in both single season models run using the R package ‘unmarked’ and dynamic occupancy models using a Bayesian framework. We additionally test the impact of varying spatial scale, as well as uneven numbers of repeated site visits, on model outcomes, and provide recommendations for conservation paleobiologists intending to run these models. Finally, we outline additional benefits of applying occupancy modelling within conservation paleobiology.

Annals of the New York Academy of Sciences 1516(1), 197-211 (2022). doi:10.1111/nyas.14865, In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway. Mutations in CLDN10 cause the rare autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia), in which patients display severe enamel wear. Here, we assess whether this enamel wear is caused by an innate fragility directly related to claudin-10 deficiency in addition to xerostomia. A third molar collected from a female HELIX patient was analyzed by a combination of microanatomical and physicochemical approaches (i.e., electron microscopy, elemental mapping, Raman microspectroscopy, and synchrotron-based X-ray fluorescence). The enamel morphology, formation time, organization, and microstructure appeared to be within the natural variability. However, we identified accentuated strontium variations within the HELIX enamel, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. These markings were also present in dentin. These data suggest that the enamel wear associated with HELIX may not be related to a disruption of enamel microstructure but rather to xerostomia. However, the occurrence of events of strontium variations within dental tissues might indicate repeated episodes of worsening of the renal dysfunction that may require further investigations., Published by New York Acad. of Sciences, New York, NY

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Ancient shoreline–shelf depositional systems are influenced by an unusually wide array of geological, biological and hydrodynamic processes, with sediment transport and deposition primarily determined by the interaction of river, wave (including storm) and tidal processes, and changes in relative sea level. Understanding the impact of these processes on shoreline–shelf morphodynamics and stratigraphic preservation remains challenging. Numerical modelling integrated with traditional facies analysis provides an increasingly viable approach, with the potential to quantify, and thereby improve understanding of, the impact of these complex coastal sedimentary processes. An integrated approach is presented here that focuses on palaeotidal modelling to investigate the controls on ancient tides and their influence on sedimentary deposition and preservation – one of the three cornerstones of the ternary process classification scheme of shoreline-shelf systems. Numerical tidal modelling methodology is reviewed and illustrated in three palaeotidal model case studies of different scales and focus. The results are synthesised in the context of shoreline–shelf processes, including a critique and modification of the process-based classification scheme. The emphasis on tidal processes reflects their global importance throughout Earth’s history. Ancient palaeotidal models are able to highlight and quantify the following four controls on tidal processes: (1) the physiography (shape and depth) of oceans (1000s km scale) determines the degree of tidal resonance; (2) the physiography of ocean connections to partly enclosed water bodies (100–1000s km scale) determines the regional-scale flux of tidal energy (inflow versus outflow); (3) the physiography of continental shelves influences shelf tidal resonance potential; and (4) tides in relatively local-scale embayments (typically 1–10s km scale) are influenced by the balance of tidal amplification due to funnelling, shoaling and resonance effects versus frictional damping. In deep time, palaeogeographic and palaeobathymetric uncertainty can be accounted for in palaeotidal models by performing sensitivity analyses to different scenarios, across this range of spatial scales. These tidal process controls are incorporated into an updated predictive decision tree for determining shoreline–shelf process regime in terms of the relative interaction of wave, fluvial and tidal processes. The predictive decision tree considers the effects of basin physiography, shelf width and shoreline morphology on wave, fluvial and tidal processes separately. Uncertainty and ambiguity in applying the widely used three-tier process classification scheme are reduced by using the decision tree in conjunction with a proposed two-tier classification of process regime that is limited to primary and secondary processes. This two-tier classification scheme is illustrated in the three case studies, showing how integration of numerical modelling with facies analysis of the preserved stratigraphic record improves confidence in prediction of tide-influenced shoreline-shelf process regimes. Wider application of this approach will further improve process-based classifications and predictions of modern and ancient shoreline–shelf systems.

During the early Pleistocene, Java was inhabited by a high variety of hominid and hominin taxa with hitherto unclear seasonal dietary demands. We undertook the first geochemical analyses of Pongo sp., Homo erectus and mammalian Pleistocene teeth from Sangiran. We reconstructed past dietary strategies at daily resolution and inferred sub-seasonal ecological patterns. Histologically-controlled spatially-resolved elemental analyses by LA-ICPMS, confirmed the preservation of authentic biogenic signals despite very weak diagenetic overprint. The Sr/Ca record of mammals is in line with expected trophic positions, contextualizing fossil hominid diet. Herbivorous Pongo sp. displays marked seasonal cycles with ~3-month-long strongly elevated Sr/Ca peaks, reflecting highly nutritional plant food during monsoon seasons. Lower Sr/Ca signals suggest different food availability during the dry season. In contrast, omnivorous Homo erectus shows low and less accentuated intra-annual Sr/Ca variability. We infer that Homo erectus maintained its nutritional demands independent of seasonal fluctuations by exploiting the regional diversity of high-quality food resources.

Canonical nuclear factor κB (NF-κB) signaling mediated by homo- and heterodimers of the NF-κB subunits p65 (RELA) and p50 (NFKB1) is associated with age-related pathologies and with disease progression in posttraumatic models of osteoarthritis (OA). Here, we established that NF-κB signaling in articular chondrocytes increased with age, concomitant with the onset of spontaneous OA in wild-type mice. Chondrocyte-specific expression of a constitutively active form of inhibitor of κB kinase β (IKKβ) in young adult mice accelerated the onset of the OA-like phenotype observed in aging wild-type mice, including degenerative changes in the articular cartilage, synovium, and menisci. Both in vitro and in vivo, chondrocytes expressing activated IKKβ had a proinflammatory secretory phenotype characterized by markers typically associated with the senescence-associated secretory phenotype (SASP). Expression of these factors was differentially regulated by p65, which contains a transactivation domain, and p50, which does not. Whereas the loss of p65 blocked the induction of genes encoding SASP factors in chondrogenic cells treated with interleukin-1β (IL-1β) in vitro, the loss of p50 enhanced the IL-1β–induced expression of some SASP factors. The loss of p50 further exacerbated cartilage degeneration in mice with chondrocyte-specific IKKβ activation. Overall, our data reveal that IKKβ-mediated activation of p65 can promote OA onset and that p50 may limit cartilage degeneration in settings of joint inflammation including advanced age.