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Abstract A body entirely covered with long and sharp-pointed spines makes Acanthoniscus spiniger Gosse, 1851, one of the rarest and most ornamented terrestrial isopods in the world. The original description of this species was based on a single specimen collected by the British naturalist Philip Henry Gosse in Jamaica in 1845 and deposited in the British Museum (currently The Natural History Museum, London). A second specimen, presumably of this species, was collected by the American entomologist Henry Guernsey Hubbard in 1877 and deposited in the United States National Museum, Smithsonian Institution, which served as the basis for a further description by Richardson (1909). After Gosse and Hubbard specimens, no additional material appears to have reached any museum collection. Due to the scarce available information on this genus, it has been indistinctly placed in at least four different families through history, without a consensus on its definitive placement to date. Herein, we describe a new species of Acanthoniscus Gosse, 1851, based on a population discovered in the Blue Mountains, Jamaica, above 1,200 m elevation and more than 150 km eastward of A. spiniger’s type locality. We also emend the authorship and diagnoses of the genus Acanthoniscus and its type species. Finally, we discuss the possible relationships of Acanthoniscus at the family level, concluding that, despite some putative autapomorphies, it belongs to Armadillidae, as its present-day status.

The presence of the rotifer Keratella cochlearis (Gosse, 1851) is reported in El Junco Lake, a freshwater crater lake in San Cristóbal Island, Galápagos Islands. This taxon is a known species aggregate containing both eurytopic cosmopolitans as well as local and regional endemics, but also some insufficiently documented cryptic species. This record is the first of a representative of the aggregate for the rotifer fauna of the Galápagos Islands. Considering that the animal is now being recorded from the lake while earlier surveys did not, and the high dispersal capacity of many rotifers, we hypothesize that the organism recorded is one of the more widespread members of the aggregate, which colonized El Junco Lake only recently.

Objective: To investigate the operational outcomes and implementation effects of tiered cardiac telemetry monitoring in a hospital environment using an innovative technology. Patients and Methods: The research focuses on assessing the precision, speed, and reliability of alerts generated by a wireless device in adult patients aged 18 and above, concurrently monitored by a hardwired, continuous cardiac monitor. Using an agile methodology, we tested and validated a nonhardwired, cellular-connected continuous cardiac monitor (InfoBionic MoMe) in 162 patients. A comparison was made between the wireless device and the standard hardwired system, conducted at Mayo Clinic Hospital with Institutional Review Board approval from June 6, 2022, to December 15, 2022. Results: The study revealed a high correlation of events captured compared with the standard care model. Differences in algorithms, alarm parameters, and operational considerations impacting clinical implementation were observed. Connectivity improvements during the study reduced latency from 3-5 minutes to 30 seconds. Delayed alarms were attributed to device damage (4.5% of cases) and poor cellular connections (29% within 31-60 seconds). Conclusion: The implementation of tiered cardiac telemetry in hospital environments, coupled with advancements in remote cardiac monitoring, supports expanded bedside telemetry capabilities and near real-time remote monitoring postdischarge. Although the study successfully validated the wireless device concept, improvements are needed before implementation for inpatient cardiac monitoring. Further research and technological enhancements can build on these findings to enhance health care practices in this domain.

Objective: Immune checkpoint inhibition (ICI) has significantly advanced the field of immuno-oncology, yet not all patients benefit from this therapy. Combining ICI with other therapeutic modalities, including tumor ablation, is currently being explored as a method to enhance ICI efficacy. Mechanical High-Intensity Focused Ultrasound (M-HIFU) represents a promising tumor ablative therapy, inducing cavitation within the tumor, resulting in tumor cell destruction and the release of danger signals and tumor antigens, two key factors contributing to anti-tumor immune responses.Methods/Results: Preclinical studies on the impact of M-HIFU on the anti-tumor immune response are guiding the translational application of this technique in the clinical setting. This review provides a comprehensive overview of the current understanding of the effects of M-HIFU on the immune system. We report on the effect of M-HIFU on soluble immune modulators and immune cells in different preclinical models, and potential contributions to the anti-tumor immune response. We discuss clinical studies applying M-HIFU and studies that have combined ICI with other ablative therapies to draw parallels to clinical implementation of M-HIFU. Further, we will highlight essential questions that should be addressed in future clinical trials exploring the combination of M-HIFU and ICI in the clinical setting.Conclusion: Overall, this review offers guidance for the clinical implementation of combining M-HIFU with ICI and highlights key questions that remain to be addressed in first clinical studies.

We present a synthesis of glacial geomorphology comprising Newfoundland and the surrounding continental shelf. During the last glaciation, this region was encompassed by the Newfoundland Ice Cap that coalesced with the Laurentide Ice Sheet and extended to the continental shelf edge. The subglacial geomorphic signal of terrestrial and marine portions of this ice sheet has been mapped using aerial photography, satellite imagery, SRTM DEMs, multibeam bathymetric data and onshore field mapping over the last 50 years. Here, we build on this, digitizing ∼146,380 features identified in published literature. Using newly available digital elevation data and multibeam bathymetric data, we identify ∼38,550 new features, such as undocumented ice thrust, crevasse and esker ridges and meltwater channels. This updated geomorphological map provides a record of paleo landforms over Newfoundland, enabling future efforts to reconstruct the dynamics, timing and erosion history of ice advance and retreat during the last glacial period..

Introduction: Tumor hypoxia is a feature of many solid malignancies and is known to cause radio resistance. In recent years it has become clear that hypoxic tumor regions also foster an immunosuppressive phenotype and are involved in immunotherapy resistance. It has been proposed that reducing the tumors’ oxygen consumption will result in an increased oxygen concentration in the tissue and improve radio- and immunotherapy efficacy. The aim of this study is to investigate the metabolic rewiring of cancer cells by pharmacological attenuation of oxidative phosphorylation (OXPHOS) and subsequently reduce tumor hypoxia. Material and methods: The metabolic effects of three OXPHOS inhibitors IACS-010759, atovaquone and metformin were explored by measuring oxygen consumption rate, extra cellular acidification rate, and [18F]FDG uptake in 2D and 3D cell culture. Tumor cell growth in 2D cell culture and hypoxia in 3D cell culture were analyzed by live cell imaging. Tumor hypoxia and [18F]FDG uptake in vivo following treatment with IACS-010759 was determined by immunohistochemistry and ex vivo biodistribution respectively. Results: In vitro experiments show that tumor cell metabolism is heterogeneous between different models. Upon OXPHOS inhibition, metabolism shifts from oxygen consumption through OXPHOS towards glycolysis, indicated by increased acidification and glucose uptake. Inhibition of OXPHOS by IACS-010759 treatment reduced diffusion limited tumor hypoxia in both 3D cell culture and in vivo. Although immune cell presence was lower in hypoxic areas compared with normoxic areas, it is not altered following short term OXPHOS inhibition. Discussion: These results show that inhibition of OXPHOS causes a metabolic shift from OXPHOS towards increased glycolysis in 2D and 3D cell culture. Moreover, inhibition of OXPHOS reduces diffusion limited hypoxia in 3D cell culture and murine tumor models. Reduced hypoxia by OXPHOS inhibition might enhance therapy efficacy in future studies. However, caution is warranted as systemic metabolic rewiring can cause adverse effects.

Abstract Background Hypoxia is a common feature of many solid tumors and causes radiotherapy and immunotherapy resistance. Pharmacological inhibition of oxidative phosphorylation (OXPHOS) has emerged as a therapeutic strategy to reduce hypoxia. However, the OXPHOS inhibitors tested in clinical trials caused only moderate responses in hypoxia alleviation or trials were terminated due to dose-limiting toxicities. To improve the therapeutic benefit, FDA approved OXPHOS inhibitors (e.g. atovaquone) were conjugated to triphenylphosphonium (TPP+) to preferentially target cancer cell’s mitochondria. In this study, we evaluated the hypoxia reducing effects of several mitochondria-targeted OXPHOS inhibitors and compared them to non-mitochondria-targeted OXPHOS inhibitors using newly developed spheroid models for diffusion-limited hypoxia. Methods B16OVA murine melanoma cells and MC38 murine colon cancer cells expressing a HIF-Responsive Element (HRE)-induced Green Fluorescent Protein (GFP) with an oxygen-dependent degradation domain (HRE-eGFP-ODD) were generated to assess diffusion-limited hypoxia dynamics in spheroids. Spheroids were treated with IACS-010759, atovaquone, metformin, tamoxifen or with mitochondria-targeted atovaquone (Mito-ATO), PEGylated mitochondria-targeted atovaquone (Mito-PEG-ATO) or mitochondria-targeted tamoxifen (MitoTam). Hypoxia dynamics were followed and quantified over time using the IncuCyte Zoom Live Cell-Imaging system. Results Hypoxic cores developed in B16OVA.HRE and MC38.HRE spheroids within 24 h hours after seeding. Treatment with IACS-010759, metformin, atovaquone, Mito-PEG-ATO and MitoTam showed a dose-dependent reduction of hypoxia in both B16OVA.HRE and MC38.HRE spheroids. Mito-ATO only alleviated hypoxia in MC38.HRE spheroids while tamoxifen was not able to reduce hypoxia in any of the spheroid models. The mitochondria-targeted OXPHOS inhibitors demonstrated stronger anti-hypoxic effects compared to the non-mito-targeted OXPHOS inhibitors. Conclusions We successfully developed a high-throughput spheroid model in which hypoxia dynamics can be quantified over time. Using this model, we showed that the mitochondria-targeted OXPHOS inhibitors Mito-ATO, Mito-PEG-ATO and MitoTam reduce hypoxia in tumor cells in a dose-dependent manner, potentially sensitizing hypoxic tumor cells for radiotherapy.

Tertiary Lymphoid Structures (TLS) are organized aggregates of immune cells such as T cells, B cells, and Dendritic Cells (DCs), as well as fibroblasts, formed postnatally in response to signals from cytokines and chemokines. Central to the function of TLS are DCs, professional antigen-presenting cells (APCs) that coordinate the adaptive immune response, and which can be classified into different subsets, with specific functions, and markers. In this article, we review current data on the contribution of different DC subsets to TLS function in cancer and autoimmunity, two opposite sides of the immune response. Different DC subsets can be found in different tumor types, correlating with cancer prognosis. Moreover, DCs are also present in TLS found in autoimmune and inflammatory conditions, contributing to disease development. Broadly, the presence of DCs in TLS appears to be associated with favorable clinical outcomes in cancer while in autoimmune pathologies these cells are associated with unfavorable prognosis. Therefore, it is important to analyze the complex functions of DCs within TLS in order to enhance our fundamental understanding of immune regulation but also as a possible route to create innovative clinical interventions designed for the specific needs of patients with diverse pathological diseases.

Abstract Objectives PD‐1/PD‐L1 immune checkpoint blockade can be an effective treatment for advanced breast cancer patients. However, patients with oestrogen receptor positive (ER+) tumors often display only low lymphocyte infiltration, while a large part of triple negative (TN) breast tumors does not generate an effective immunotherapy response. Therefore, new treatment strategies have to be developed. Here, we investigate Siglec‐7 and Siglec‐9 as novel ITIM‐bearing inhibitory immune checkpoint receptors similar to PD‐1, but expressed on a broader range of immune cells. Methods We assessed Siglec‐7 and Siglec‐9 (ligand) expression in TN and ER+ breast cancer tumors and their breast cancer cell line‐induced signalling. Results We report that Siglec‐7 and Siglec‐9 are highly expressed in TN tumors, and to a low extent in ER+ tumors. Siglec‐7 was observed on myeloid cells, T cells, and NK cells and Siglec‐9 preferentially on myeloid cells. Expression of sialoglycans, including Siglec‐7 and Siglec‐9 ligands, was observed in both TN and ER+ breast cancer tissue sections. Expression levels of Siglec‐7 and Siglec‐9 ligands were higher on in vitro cultured TN cell lines than ER+ cell lines. Importantly, by applying chimeric Siglec‐7 reporter cells, we showed the induction of Siglec‐7 signalling by multiple TN cell lines, but only by one ER+ cell line. Moreover, Siglec‐7 signalling is directly related to Siglec‐7 ligand expression levels of breast cancer cell lines. Conclusion These data imply that immunotherapy targeting Siglec receptors may be particularly interesting for TN breast cancer patients not responding to current treatment strategies with tumors displaying high immune cell infiltration.

The T cell is an immune cell subset highly effective in eliminating cancer cells. Cancer immunotherapy empowers T cells and occupies a solid position in cancer treatment. The response rate, however, remains relatively low (

Introduction: Dapsone is known to cause drug-induced liver injury (DILI) but can rarely induce the formation of hepatic granulomas. We describe a patient with jaundice who demonstrated granulomas on liver biopsy in response to dapsone. Her symptoms were only evident once steroids, used to also treat her pyoderma gangrenosum, had been tapered. Case Presentation: In this case, a 67-year-old female was hospitalized due to 1 day of jaundice. She had started dapsone and prednisone concurrently 7 weeks ago to treat her pyoderma gangrenosum. Steroids were discontinued 4 days prior to symptoms. Her laboratories were notable for newly elevated alkaline phosphatase (756 U/L), aspartate transaminase (199 U/L), alanine transaminase (273 U/L), and total bilirubin (12.6 mg/dL). Dapsone was held due to suspicion for DILI. A liver biopsy was performed and disclosed non-necrotizing hepatic granulomas. After infectious and autoimmune causes were excluded, dapsone was determined to be the cause of her hepatic granulomas. Her bilirubin and liver enzymes steadily normalized over the next 4 weeks following discontinuation of dapsone. Conclusion: Thus, dapsone-related liver injury may present following a steroid taper if dapsone and steroids had been initially started together. Hepatic granulomas, though rare, can be seen when dapsone causes DILI.

Adair Rounthwaite Minneapolis: University of Minnesota, 2017; 280 pages; 57 b/w photos; 12 color illus.; Paperback: $27.00; Cloth: $108.00 Reviewed by: Johanna Gosse, Visiting Assistant Professor and Scholar-in-Residence, Department of Art and Art History, University of Colorado, Boulder

Abstract Background More than three‐fourths of cervical cancer cases occur in low‐ and middle‐income countries, with sub‐Saharan Africa (SSA) accounting for approximately 25% of global mortality. The significant rise in the prevalence of cervical cancer in SSA amplifies the burden on caregivers, contributing to elevated rates of mental illness, particularly among spouses who provide care. Men who assume the role of caregivers for their partners with cervical cancer encounter unique challenges and substantial adjustments across multiple facets of life, impacting both their own quality of life and that of their partners. Despite this, there is a notable lack of extensive research on the experiences of male partners in caregiving roles, particularly within SSA countries like Tanzania. Therefore, this study aimed to explore the experiences of male partners providing care for women with cervical cancer in Dar es Salaam, Tanzania. Methods An exploratory qualitative study was undertaken to explore the experiences of 13 male partners, selected purposively and guided by the principle of saturation. Data gathering employed in‐depth interviews utilizing a semistructured interview guide, with subsequent analysis conducted via a thematic analysis approach. Results Five themes and 13 subthemes were generated, encompassing psychosocial distress, attitudes towards cervical cancer, unity in the provision of care, economic burden, and altered sexual relationships. Participants reported experiencing emotional distress, shifts in social responsibilities, financial challenges, and unfulfilled sexual needs. Moreover, they expressed the need for social, psychological, financial, and sexual and reproductive support. Conclusion This study underscores the numerous challenges encountered by male partners caring for women with cervical cancer, encompassing emotional distress, financial strain, and shifts in social and sexual dynamics. The identified themes and subthemes highlight the intricate interplay of these difficulties and stress the necessity for holistic support systems addressing the social, psychological, financial, and sexual aspects of male partners' experiences. The findings emphasize the importance of designing and implementing comprehensive support programmes tailored to the diverse needs of male partners, ultimately enhancing their quality of life and overall well‐being. Patient or Public Contribution Before the study, the nursing manager assisted in selecting three male partners randomly. These partners were involved in the design of the participants' information sheet, the evaluation of the interview schedule and rooms, and the dissemination of information about the study's purpose to the target population. Their valuable input contributed to improving the participant information sheet, refining data collection procedures and addressing ethical considerations. However, these individuals were not considered study participants. Throughout the study, in‐charge nurses in the hospital were informed about the study's goals and helped organize appointments with participants and manage the interview schedule.

Background/Objectives: Physical literacy (PL) is essential to the holistic human experience, emphasizing embodied capability and affording opportunities for inclusive engagement. Despite its recent use as a core programming element, PL from the experiential point of view of individuals experiencing disability has yet to be explored. Excluding these perspectives promotes a culture of ableism, one that devalues the embodied capabilities of those experiencing the world differently. The purpose of this study was to highlight the participant perspective related to PL and explore the value individuals experiencing disability attribute to PL and its development. Methods: Using the communities of practice theoretical model of knowledge as a conceptual framework, 13 participants experiencing disability participated in two focus groups. Participants’ experiences were thematized via the use of thematic analysis, and voices were portrayed through composite narratives, highlighting the shared participant experience and value associated with PL. Results: Three themes emerged: (1) imagine the possibilities, (2) dance like nobody's watching, and (3) no wrong way to move. Composite narratives reflect PL as a valued means of exploration and learning, personal growth, and opportunity related to physical activity and social interaction. Participant value was considered to be enhanced via a learning climate affording opportunities for developing autonomy and a sense of belonging. Conclusion: This research provides an authentic understanding of PL within the context of disability, and what might be used to facilitate its development in such an environment. Individuals experiencing disability contributed to this knowledge and must be continually involved to ensure PL development is inclusive to all.

The tumor microenvironment of glioblastoma IDH-wildtype is highly immune suppressive and is characterized by a strong component of myeloid-derived suppressor cells (MDSCs). To interfere with the immune suppressive functions of MDSCs, a comprehensive understanding on how MDSCs acquire their suppressive phenotype is essential. Previously, we and others have shown a distinct Sialic acid-binding immunoglobulin-like lectin (Siglec) receptor expression profile for MDSCs in glioblastoma. Siglec receptors can transmit inhibitory signals comparable to PD-1 and are suggested to act as glyco-immune checkpoints. Here, we investigated how glioma specific Siglec-sialic acid interactions influence myeloid immune suppressive functions. Co-culturing monocytes with glioblastoma cells induced CD163 expression on the monocytes. Upon desialylation of the glioblastoma cells, this induction of CD163 was hampered, and furthermore, the monocytes were now able to secrete higher amounts of IL-6 and TNFα compared to fully sialylated glioblastoma cells. Additionally, Siglec-specific triggering using anti-Siglec-7 or Siglec-9 antibodies displayed a decreased TNFα secretion by the monocytes, validating the role of the Siglec–Sialic axis in the co-culture experiments. Together, our results demonstrate that glioblastoma cells induce a myeloid immune-suppressive phenotype that could be partly rescued by lowering the glioblastoma-associated sialic acid levels. This manuscript supports further research of the Siglec–Sialic acid axis in the context of glioblastoma and its potential to improve clinical outcome.

Background Cognitive deficits are associated with poor quality of life and increased risk of development of dementia in patients with Parkinson’s disease (PD) psychosis. The trajectory of cognitive decline in PD psychosis remains however unclear.Objective We examined this using data from the Parkinson’s Progression Markers Initiative study.Methods We analysed data from patients with drug-naïve PD (n=676) and healthy controls (HC, n=187) over 5 years, and examined all cognitive measures assessed at each time point. We classified patients with PD into those who developed psychosis over the course of the study (PDP) and those without psychosis throughout (PDnP) using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale part I hallucinations/psychosis item. We used linear mixed-effect models with restricted maximum likelihood. Age, sex, ethnicity, education and neuropsychiatric and PD-specific symptoms were entered as covariates of interest.Findings There were no baseline cognitive differences between PD patient groups. There were differences in cognitive performance between PD and HC across the majority of the assessments.Patients with PDP exhibited greater cognitive decline over 5 years compared with PDnP across most domains even after controlling for sociodemographics, depression, sleepiness, rapid eye movement sleep behaviour disorder and motor symptom severity (immediate recall, b=−0.288, p=0.003; delayed recall, b=−0.146, p=0.003; global cognition, Montreal Cognitive Assessment, b=−0.206, p

Proverbs 30:3–5 depends on Job 38–39, hence, the use of the divine name Eloah in Prov 30:5. We note the same in Ps 18:31 but with the substitution of the name of YHWH for Eloah, as part of the messianic Yahwist reaffirmation of the writing of the whole Psalter. In this perspective, Ps 18:32 identifies Eloah with YHWH. In the parallel of 2 Sam 22 to Ps 18, the name Eloah is not repeated, the emphasis being on the relationship between David and the Psalter. Deuteronomy 32 agrees with the overall redaction of the Psalter, which jointly reaffirms the Davidic Messiah and the Torah of Moses, in the general introduction (Ps 1, the Torah and Ps 2, the Messiah), in the first Book, Pss 3––41 (Ps 18, the Messiah and Ps 19, the Torah) and the fifth Book, Pss 107–150 (Ps 119, the Torah and Pss 120–132, the Messiah). Thus as inclusion, Deut 32:2–4 is based on Ps 18:31–32 with the reference to YHWH the ROCK, an allusion to the Temple and its cult, including the performance of the Psalter. The vocabulary of this passage from Ps 18 appears again in the following verses of Deut 32, including the name Eloah in Dt 32:15, 17, its only occurrences in Deuteronomy.

The weathering alkalinity flux from mid-latitudes to the ocean will be strongly altered by climate warming by 2100. Under different emissions scenarios either a strengthening or a weakening of the flux and thus of the oceanic CO2 buffer is predicted.

Abstract Background Fitspiration is a social media phenomenon purported to inspire viewers to lead healthier lifestyles but can result in negative psychological outcomes such as body dissatisfaction. This study aimed to develop a tool to audit Instagram fitspiration accounts and screen for content that could have potentially negative psychological effects. Methods This study developed and implemented an audit tool to (1) identify credible fitspiration accounts (i.e., accounts that do not portray potentially harmful or unhealthy content) and (2) describe the content of identified accounts. The most recent 15 posts of 100 leading Instagram fitspiration accounts were audited. Accounts were deemed non-credible and were excluded if they contained fewer than four fitness-related posts or portrayed nudity or inappropriate clothing, sexualisation or objectification, extreme body types, “thinspiration”, or negative messages. Results Many accounts contained fewer than four fitness-related posts (n = 41), sexualisation or objectification (n = 26), nudity or inappropriate clothing (n = 22), and/or extreme body types (n = 15). Three accounts failed on all four criteria, while 13, 10 and 33 failed on three, two, or one criterion, respectively. Therefore, only 41% of accounts were considered credible. Inter-rater reliability (percentage agreement and Brennan and Prediger’s coefficient κq) was high (Stage 1: 92% agreement [95% CI 87, 97], κq 0.84 [95% CI 0.73, 0.95]; Stage 2: 93% agreement [95% CI 83, 100], κq 0.85 [95% CI 0.67, 1.00]). Account holders of credible fitspiration accounts were predominantly female (59%), aged 25–34 (54%), Caucasian (62%), and from the United States (79%). Half held a qualification related to physical activity or physical health (e.g., personal trainer, physiotherapy; 54%). Most included accounts included an exercise video (93%) and example workout (76%). Conclusion While many popular Instagram fitspiration accounts offered credible content such as example workouts, many accounts contained sexualisation, objectification or promotion of unhealthy or unrealistic body shapes. The audit tool could be used by Instagram users to ensure the accounts they follow do not portray potentially harmful or unhealthy content. Future research could use the audit tool to identify credible fitspiration accounts and examine whether exposure to these accounts positively influences physical activity.

Deglaciation of the northwestern Laurentide Ice Sheet in the central Mackenzie Valley opened the northern portion of the deglacial Ice-Free Corridor between the Laurentide and Cordilleran ice sheets and a drainage route to the Arctic Ocean. In addition, ice sheet saddle collapse in this section of the Laurentide Ice Sheet has been implicated as a mechanism for delivering substantial freshwater influx into the Arctic Ocean on centennial timescales. However, there is little empirical data to constrain the deglaciation chronology in the central Mackenzie Valley where the northern slopes of the ice saddle were located. Here, we present 30 new 10Be cosmogenic nuclide exposure dates across six sites, including two elevation transects, which constrain the timing and rate of thinning and retreat of the Laurentide Ice Sheet in the area. Our new 10Be dates indicate that the initial deglaciation of the eastern summits of the central Mackenzie Mountains began at ∼15.8 ka (17.1–14.6 ka), ∼1000 years earlier than in previous reconstructions. The main phase of ice saddle collapse occurred between ∼14.9 and 13.6 ka, consistent with numerical modelling simulations, placing this event within the Bølling–Allerød interval (14.6–12.9 ka). Our new dates require a revision of ice margin retreat dynamics, with ice retreating more easterly rather than southward along the Mackenzie Valley. In addition, we quantify a total sea level rise contribution from the Cordilleran–Laurentide ice saddle region of ∼11.2 m between 16 and 13 ka.

Physical literacy (PL) has been readily accepted and integrated globally, including organizations affording services to individuals experiencing disability. Despite its uptake, recent research has illustrated that understandings of PL reflect the normative standards of those who do not experience disability, leading to practices that diminish the unique and embodied capability of others while simultaneously validating ableism. While a shift towards recognizing and valuing the heterogeneity associated with PL has recently occurred, the ableist narrative persists. As a result, the operationalization of PL directly contradicts its conceptualization, fostering a physical activity climate that continues to marginalize individuals experiencing disability. With this in mind, this paper critically unpacks PL, challenging the existing ableist narrative and offering suggestions to heighten the level of inclusivity that underscores PL. Pathways, where physical activity professionals contribute to reproducing ableism, will be discussed.

Introduction A major issue confronting clinicians treating hypertension in pregnancy is the limited number of pharmacological options. Endovascular catheter-based renal denervation (RDN) is a new method to lower blood pressure (BP) in patients with hypertension by reducing the activity of the renal sympathetic nervous system. Drugs that affect this system are safe in pregnant women. So there is reasonable evidence that RDN performed before pregnancy should not have deleterious effects for the fetus. Because the efficacy of RDN may be greater in younger patients and in women, we may expect a larger proportion of BP normalisation in young hypertensive women, but this remains to be proven. Our primary objective is to quantify the proportion of BP normalisation with RDN in this population.Methods and analysis WHY-RDN is a multicentre randomised sham-controlled trial conducted in six French hypertension centres that will include 80 women with essential hypertension treated or untreated, who are planning a pregnancy in the next 2 years and will be randomly assigned to RDN or classic renal arteriography and sham RDN in a ratio of 1:1. The primary outcome is the normalisation of 24-hour BP (

Background Adjuvants are key for effective vaccination against cancer and chronic infectious diseases. Saponin-based adjuvants (SBAs) are unique among adjuvants in their ability to induce robust cell-mediated immune responses in addition to antibody responses. Recent preclinical studies revealed that SBAs induced cross-presentation and lipid bodies in otherwise poorly cross-presenting CD11b+ murine dendritic cells (DCs).Method Here, we investigated the response of human DC subsets to SBAs with RNA sequencing and pathway analyses, lipid body induction visualized by laser scanning microscopy, antigen translocation to the cytosol, and antigen cross-presentation to CD8+ T cells.Results RNA sequencing of SBA-treated conventional type 1 DC (cDC1) and type 2 DC (cDC2) subsets uncovered that SBAs upregulated lipid-related pathways in CD11c+ CD1c+ cDC2s, especially in the CD5− CD163+ CD14+ cDC2 subset. Moreover, SBAs induced lipid bodies and enhanced endosomal antigen translocation into the cytosol in this particular cDC2 subset. Finally, SBAs enhanced cross-presentation only in cDC2s, which requires the CD163+ CD14+ cDC2 subset.Conclusions These data thus identify the CD163+ CD14+ cDC2 subset as the main SBA-responsive DC subset in humans and imply new strategies to optimize the application of saponin-based adjuvants in a potent cancer vaccine.

Myeloid cells contribute to the tumor microenvironment of thyroid cancers, but their functional relevance is lesser known. Here authors show that myeloid cells infiltrating non-medullary thyroid carcinomas upregulate their antigen presentation-related genes, release less cytokines and over-produce reactive oxygen species, with transcriptional changes already present in extra-tumoral myeloid cells.

Abstract Tectonics imparts a first-order control on the overall morphology of alluvial fan systems in extensional settings by influencing sediment flux and accommodation space, while other factors such as climate, catchment lithology, and fault footwall characteristics are secondary. Previous alluvial fan modeling studies have focused on the link between the three-dimensional development of alluvial fans and rock uplift, however, despite the potential influence of tectonics on the overall three-dimensional morphology of alluvial fans, the controlling mechanisms, as well as their relative importance, remain largely unquantified in a natural setting with a targeted source-to-sink approach. Here, we examine 45 alluvial fans and their catchments along the southern mountain front of the Aydın Range, delimited by segmented normal faults in the western Anatolia Extensional Province, to quantify the role of rock uplift. We quantify river incision rates and catchment-wide erosion rates together with a series of topographic analyses across the southern flank of the Aydın Range as a proxy for rock uplift. Our results indicate that the spatial distribution of thicker and steeper alluvial fans fit well with higher rock uplift rates along the strike of the mountain front. In contrast, a lower uplift rate is responsible for prograding alluvial fans with decreasing thickness and gradients. Also, our data shows that alluvial fan thickness compared to other alluvial fan metrics strongly associated with the pattern of the rock uplift. This study demonstrates a field-based, quantitative linkage between three-dimensional alluvial fan morphology and rock uplift which has significant implications for improving alluvial fan models and understanding how alluvial fans respond to tectonics in extensional regions.

Abstract Pathogenic variants in the NDUFV1 gene, which codes for complex I of the mitochondrial respiratory chain, have been associated with a variety of clinical phenotypes, including a progressive cavitating leukoencephalopathy. The neuropathology of NDUFV1-associated leukoencephalopathy is not well-described. We present a report of a 24-year-old female with two pathogenic variants in the NDUFV1 gene, together with antemortem skeletal muscle biopsy and postmortem neuropathologic examination. Autopsy neuropathology showed a cavitating leukoencephalopathy with extensive white matter involvement, regions of active demyelination, and sparing of the subcortical U-fibers. Muscle biopsy showed subtle but distinct histologic abnormalities by light microscopy, and ultrastructural analysis demonstrated mitochondrial abnormalities including abnormal subsarcolemmal mitochondrial accumulation, electron-dense inclusions, and enlarged mitochondria with abnormal cristae. Our report is the first comprehensive description of the neuropathology in a patient with compound heterozygous variants in the NDUFV1 gene and progressive cavitating leukoencephalopathy. This case is evidence of pathogenicity of one NDUFV1 variant (c.565 T > C, p.S189P), which has not been previously described as pathogenic. These findings, in combination with the ultrastructural abnormalities in the mitochondria by electron microscopy, support the mitochondrial nature of the pathology. Together, this case highlights the link between mitochondrial abnormalities and demyelinating processes in the central nervous system (CNS).

Recent advances in MRI technology have enabled richer multi-shell sequences to be implemented in diffusion MRI, allowing the investigation of both the microscopic and macroscopic organization of the brain white matter and its complex network of neural fibers. The emergence of advanced diffusion models has enabled a more detailed analysis of brain microstructure by estimating the signal received from a voxel as the combination of responses from multiple fiber populations. However, disentangling the individual microstructural properties of different macroscopic white matter tracts where those pathways intersect remains a challenge. Several approaches have been developed to assign microstructural properties to macroscopic streamlines, but often present shortcomings. ROI-based heuristics rely on averages that are not tract-specific. Global methods solve a computationally-intensive global optimization but prevent the use of microstructural properties not included in the model and often require restrictive hypotheses. Other methods use atlases that might not be adequate in population studies where the shape of white matter tracts varies significantly between patients. We introduce UNRAVEL, a framework combining the microscopic and macroscopic scales to unravel multi-fixel microstructure by utilizing tractography. The framework includes commonly-used heuristics as well as a new algorithm, estimating the microstructure of a specific white matter tract with angular weighting. Our framework grants considerable freedom as the inputs required, a set of streamlines defining a tract and a multi-fixel diffusion model estimated in each voxel, can be defined by the user. We validate our approach on synthetic data and in vivo data, including a repeated scan of a subject and a population study of children with dyslexia. In each case, we compare the estimation of microstructural properties obtained with angular weighting to other commonly-used approaches. Our framework provides estimations of the microstructure at the streamline level, volumetric maps for visualization and mean microstructural values for the whole tract. The angular weighting algorithm shows increased accuracy, robustness to uncertainties in its inputs and maintains similar or better reproducibility compared to commonly-used analysis approaches. UNRAVEL will provide researchers with a flexible and open-source tool enabling them to study the microstructure of specific white matter pathways with their diffusion model of choice.

The COVID-19 pandemic has mandated a re-imagination of how healthcare is administered and delivered, with a view towards focusing on person-centred care and advancing population health while increasing capacity, access and equity in the healthcare system. These goals can be achieved through healthcare integration. In 2019, the University Health Network (UHN), a consortium of four quaternary care hospitals in Ontario, Canada, established the first stage of a pilot program to increase healthcare integration at the institutional level and vertically with other primary, secondary and tertiary institutions in the Ontario healthcare system. Implementation of the program was accelerated during the COVID-19 pandemic and demonstrated how healthcare integration improves person-centred care and population health; therefore serving as the foundation for a health system response for the COVID-19 pandemic recovery and beyond.

Le Moïse des livres prophétiques renvoie, au rôle de Moïse dans les Ps 105-106 ; 99 et 77.[1] En relation étroite avec ces mentions de Moïse, le comportement de Balaam est donné en exemple, contemporain du Moïse des plaines de Moab selon Nb 22-24, en opposition aux comportements des Israélites en Nb 25,1-5.[2] Balaam a obéi à Yahvé refusant de maudire [verbes ארר et קבב (Nb 22,11.17 ; 23,8.11.13.25.27 ; 24,10 pour toute la Bible) ; נקב (Nb 23,8.25); voir הקבה en Nb 25,8 !)] Israël. Ce dernier n’ayant pas suivi l’exemple d’obéissance de Balaam doit finalement affronter la malédiction [Voir le verbe ארר en Nb 22-24 et 5,18-27 et substantifs אלה en Nb 5,21-27 et שבועה en 5,21 (cf.: אלה et שבועה en Dn 9,11)]. https://doi.org/10.17159/2312-3621/2022/v35n3a6 [1] Moïse est mentionné dans le Psautier en : Ps 77,21 ; et dans le quatrième livre du Psautier, Ps 90-106, en Ps 90,1 ; 99,6 ; 103,7 ; 105,26 ; 106,16.23.32. On note les relations antagonistes avec 1 Ch 16. Dans le titre du Ps 77 sont cités ידותון mentionné en 1 Ch 16,41.42.42, et אסף mentionné en 1 Ch 16,5.5.7.37. Le texte de Ps 105,1-15 est cité en 1 Ch 16,8-22 et Ps 106,1.47-48 en 1 Ch 16,34-36 (passages sans Moïse !, réinterprétation davidique). Voir également le Ps 96 en 1 Ch 16,23-33, avec « Yahvé règne » en 96,10 (1 Ch 16,31), et Ps 99,1. Lee Roy Martin, « The Chiastic Structure of Psalm 106 », OTE 31 (2018) : 506-521, souligne que les Ps 105 et 106 se réfèrent à la même histoire, côté « victories », pour le Ps 105, côté « disobedience », pour le Ps 106 (Voir Nb 25). Dans la catégorie « Psaume historique » il relie aux Ps 105-106, le Ps 78, or on peut noter la mention de Moïse au terme du Ps 77, le Pasteur Moïse se substituant au Pasteur David, justement au terme du Ps 78. L’insertion du rôle de Moïse dans les Ps 105-106 correspond également à la disparition de la dynastie davidique selon le Ps 89. La mention de Moïse en Ps 99,6, concerne le thème de l’ « intercession » (comme en Ps 106,23, suite au veau de l’Horeb en 106,19, cf. Ex 33), en substitution de l’intercession royale, dans la même ligne, on peut comparer les titres des Ps 86 (David) et 90 (Moïse). [2] Moïse en Nb 25,4.5.6.10.16. L’infidélité avec le Baal de Péor en 25,3, provoque la fureur de Yahvé. Moïse intervient en 25,4 pour apaiser la fureur de Yahvé. Jan-Albert Roetman and Caspar Visser’t Hooft, « Le Psaume 106 et le Pentateuque », ETR 85 (2010) : 233-243. Pages 239-241, les auteurs rapprochent les événements mentionnés dans le Ps 106 des récits du Pentateuque. Les liens avec le livre des Nombres sont prépondérants. Page 241, ils rapprochent Nb 25,1-4 et Ps 106,28-31. Le verbe קבב est propre à Nb 22-24. The mentions of Moshe in the prophetic books look to the part of Moshe in Ps 105-106; 99 and 77. In relation to these prophetic references we note the mention of the good example of Balaam, contemporary of Moses in the country of Moab in Num 22-24. Balaam obeyed to Yahweh and did not curse [verb ארר and קבב (Num 22,11.17 ; 23,8.11.13.25.27 ; 24,10 only in the Bible) ; נקב (Num 23,8.25); see הקבה in Num 25,8 !] Israel. But Israel did not obey in the line of Balaam, and must be cursed [See the verb ארר in Num 22-24 and Num 5,18-27 and אלה in Num. 5,21-27 and שבועה in Num 5,21 (cf.: אלה et שבועה in Dn 9,11)].

IntroductionIn situ tumor ablation releases a unique repertoire of antigens from a heterogeneous population of tumor cells. High-intensity focused ultrasound (HIFU) is a completely noninvasive ablation therapy that can be used to ablate tumors either by heating (thermal (T)-HIFU) or by mechanical disruption (mechanical (M)-HIFU). How different HIFU ablation techniques compare with respect to their antigen release profile, their activation of responder T cells, and their ability to synergize with immune stimuli remains to be elucidated.Methods and resultsHere, we compare the immunomodulatory effects of T-HIFU and M-HIFU ablation with or without the TLR9 agonist CpG in the ovalbumin-expressing lymphoma model EG7. M-HIFU ablation alone, but much less so T-HIFU, significantly increased dendritic cell (DC) activation in draining lymph nodes (LNs). Administration of CpG following T- or M-HIFU ablation increased DC activation in draining LNs to a similar extend. Interestingly, ex vivo co-cultures of draining LN suspensions from HIFU plus CpG treated mice with CD8+ OT-I T cells demonstrate that LN cells from M-HIFU treated mice most potently induced OT-I proliferation. To delineate the mechanism for the enhanced anti-tumor immune response induced by M-HIFU, we characterized the RNA, DNA and protein content of tumor debris generated by both HIFU methods. M-HIFU induced a uniquely altered RNA, DNA and protein profile, all showing clear signs of fragmentation, whereas T-HIFU did not. Moreover, western blot analysis showed decreased levels of the immunosuppressive cytokines IL-10 and TGF-β in M-HIFU generated tumor debris compared to untreated tumor tissue or T-HIFU.ConclusionCollectively, these results imply that M-HIFU induces a unique context of the ablated tumor material, enhancing DC-mediated T cell responses when combined with CpG.

Abstract Replicative vectors derived from live-attenuated measles virus (MV) carrying additional non-measles vaccine antigens have long demonstrated safety and immunogenicity in humans despite pre-existing immunity to measles. Here, we report the vaccination of cynomolgus macaques with MV replicative vectors expressing simian-human immunodeficiency virus Gag, Env, and Nef antigens (MV-SHIV Wt) either wild type or mutated in the immunosuppressive (IS) domains of Nef and Env antigens (MV-SHIV Mt). We found that the inactivation of Nef and Env IS domains by targeted mutations led to the induction of significantly enhanced post-prime cellular immune responses. After repeated challenges with low doses of SHIV-SF162p3, vaccinees were protected against high viremia, resulting in a 2-Log reduction in peak viremia, accelerated viral clearance, and a decrease -even complete protection for nearly half of the monkeys- in reservoir cell infection. This study demonstrates the potential of a replicative viral vector derived from the safe and widely used measles vaccine in the development of a future human vaccine against HIV-1.

Abstract Sixteen borate glass compositions comprising K2O and SrO were screened, using a design of mixtures approach, to model compositional effects on dissolution, CT imageability, and MRI relaxivity (R2). Based on the characteristics of each network, together with dose determination and toxicological risk, the composition identified as BKSA16 was selected as a preferred composition for pre-clinical evaluations related to geniculate artery embolization (GAE). Accordingly, BKSA16 particles were subjected to a flame spheroidization process and recharacterized, including the evaluation of residual mass at 72 h in physiologically representative media along with clinical determinations of suspension time (ease of use). For both the irregular particles and microspheres residual mass was present at 72 h in physiologically representative media. Additionally, both the microspheres and irregular particles achieved suspension times deemed to be acceptable for clinical use. The collective data confirms that BKSA16 microspheres have a range of beneficial features (specifically both degradable and imageable) suited to GAE.

This article examines how imagined audiences and impression management strategies shape COVID-19 health information sharing practices on social media and considers the implications of this for combatting the spread of misinformation online. In an interview study with 27 Canadian adults, participants were shown two infographics about masks and vaccines produced by the World Health Organization (WHO) and asked whether or not they would share these on social media. We find that interviewees’ willingness to share the WHO infographics is negotiated against their mental perception of the online audience, which is conceptualized in three distinct ways. First, interviewees who would not share the infographics frequently describe a self-similar audience of peers that are “in the know” about COVID-19; second, those who might share the infographics conjure a specific and contextual audience who “needs” the information; and finally, those who said they would share the infographics most frequently conjure an abstract audience of “the public” or “my community” to explain that decision. Implications of these sharing behaviors for combatting the spread of misinformation are discussed.

Von Hippel Lindau(VHL)syndrome presents with cerebellar and spinal hemangioblastomas, renal cell cancer, neuroendocrine pancreatic tumor, and pheochromocytoma and it is caused by germline mutations in the VHL gene. Pathogenic germline variants in the succinate dehydrogenase A (SDHA) gene are associated with paraganglioma and pheochromocytoma. Here we report co-occurrence of germline pathogenic variants in both VHL and SDHA genes in a patient who presented with pancreatic neuroendocrine tumor. As these genes converge on the pseudo-hypoxia signaling pathway, further studies are warranted to determine the significance of co-occurrence of these variants in relation to tumor penetrance, disease severity, treatment response and clinical outcomes in this selected group of patients.

Caves are extreme, often oligotrophic, environments that house diverse groups of microorganisms. Many of these microbes can perform microbiologically induced carbonate precipitation (MICP) to form crystalline secondary cave deposits known as speleothems. The urease family is a group of enzymes involved in MICP that catalyze the breakdown of urea, which is a source of energy, into ammonia and carbonate. Carbonate anions are effluxed to the extracellular surface of the bacterium where it then binds to environmental calcium to form calcium carbonate which then continues to grow in crystal form. Here, we studied bacterial communities from speleothems collected from the Iron Curtain Cave (ICC) in Chilliwack, B.C., Canada, to characterize these organisms and determine whether urease-positive (U+) bacteria were present in the cave and their potential impact on speleothem formation. The ICC is a carbonate cave located on the northside of Chipmunk Ridge, presenting a unique environment with high iron content sediment and limestone structures throughout. With six pools of water throughout the cave, the environment is highly humid, with temperatures ranging between 4 and 12°C depending on the time of year. Ninety-nine bacterial strains were isolated from popcorn (PCS) and soda straw (SSS) speleothems. These isolates were screened for urease enzymatic activity, with 11 candidates found to be urease-positive. After incubation, species-specific crystal morphologies were observed. Popcorn speleothem provided more bacterial diversity overall when compared to soda straw speleothem when examined under a culture-based method. Nearly twice as many U+ isolates were isolated from popcorn speleothems compared to soda straw speleothems. The U+ candidates were identified to the genus level by 16S rRNA analysis, and two isolates underwent whole-genome sequencing. Two novel species were identified as Sphingobacterium sp. PCS056 and Pseudarthrobacter sp. SSS035. Both isolates demonstrated the most crystal production as well as the most morphologically dissimilar crystal shapes in broth culture and were found to produce crystals as previously observed in both agar and broth media. The results from this study are consistent with the involvement of urease-positive bacteria isolated from the ICC in the formation of cave speleothems. 16S rRNA sequencing revealed a diverse set of microbes inhabiting the speleothems that have urease activity. Whole-genome sequencing of the two chosen isolates confirmed the presence of urease pathways, while revealing differences in urease pathway structure and number. This research contributes to understanding microbial-associated cave formation and degradation, with applications to cave conservation, microbiota composition, and their role in shaping the cave environment.

Rapamycin is an immunosuppressant macrolide that exhibits anti-proliferative properties through inhibiting the mTOR kinase. In fact, the drug first associates with the FKBP12 enzyme before interacting with the FRB domain of its target. Despite the availability of structural and thermodynamic information on the interaction of FKBP12 with rapamycin, the energetic and mechanistic understanding of this process is still incomplete. We recently reported a multiple-walker umbrella sampling simulation approach to characterizing the protein–protein interaction energetics along curvilinear paths. In the present paper, we extend our investigations to a protein-small molecule duo, the FKBP12•rapamycin complex. We estimate the binding free energies of rapamycin with wild-type FKBP12 and two mutants in which a hydrogen bond has been removed, D37V and Y82F. Furthermore, the underlying mechanistic details are analyzed. The calculated standard free energies of binding agree well with the experimental data, and the roles of the hydrogen bonds are shown to be quite different for each of these two mutated residues. On one hand, removing the carboxylate group of D37 strongly destabilizes the association; on the other hand, the hydroxyl group of Y82 is nearly unnecessary for the stability of the complex because some nonconventional, cryptic, indirect interaction mechanisms seem to be at work.

Abstract Background Depression and anxiety are common psychiatric complications affecting patients with diabetes mellitus. However, data on the prevalence of depression, anxiety, and associated factors among Malaysian diabetic patients is scarce. The Anxiety, Depression, and Personality Traits in Diabetes Mellitus (ADAPT-DM) study aimed to determine the prevalence of depression and anxiety, and their associated factors in the Malaysian diabetic population. Methods This cross-sectional study recruited 300 diabetic patients via convenience sampling from the Endocrine outpatient clinic of Universiti Kebangsaan Malaysia Medical Centre, a tertiary referral healthcare facility in Kuala Lumpur. Socio-demographic characteristics and clinical history were obtained from each participant. The Generalised Anxiety Disorder-7 (GAD-7) was administered to assess anxiety symptoms, the Beck Depression Inventory (BDI) to assess depressive symptoms, the Big Five Inventory (BFI) to evaluate personality traits, and the World Health Organization Quality of Life-BREF (WHOQOL-BREF) to measure quality of life (QOL). Stepwise multiple logistic regression analyses were performed to determine the association between various factors, and depression and anxiety. Results The prevalence of depression was 20% (n = 60) while anxiety was 9% (n = 27). Co-morbid depression (adjusted odds ratio [OR] = 9.89, 95% confidence interval [CI] = 2.63–37.14, p = 0.001) and neuroticism (adjusted OR = 11.66, 95% CI = 2.69–50.47, p = 0.001) increased the odds of developing anxiety, while conscientiousness (adjusted OR = 0.45, 95% CI = 0.23–0.80, p = 0.004) and greater psychological-related QOL (adjusted OR = 0.47, 95% CI = 0.29–0.75, p = 0.002) were protective. Co-morbid anxiety (adjusted OR = 19.83, 95% CI = 5.63–69.92, p

Recent advances in multilingual language modeling have brought the idea of a truly universal parser closer to reality. However, such models are still not immune to the “curse of multilinguality”: Cross-language interference and restrained model capacity remain major obstacles. To address this, we propose a novel language adaptation approach by introducing contextual language adapters to a multilingual parser. Contextual language adapters make it possible to learn adapters via language embeddings while sharing model parameters across languages based on contextual parameter generation. Moreover, our method allows for an easy but effective integration of existing linguistic typology features into the parsing model. Because not all typological features are available for every language, we further combine typological feature prediction with parsing in a multi-task model that achieves very competitive parsing performance without the need for an external prediction system for missing features. The resulting parser, UDapter, can be used for dependency parsing as well as sequence labeling tasks such as POS tagging, morphological tagging, and NER. In dependency parsing, it outperforms strong monolingual and multilingual baselines on the majority of both high-resource and low-resource (zero-shot) languages, showing the success of the proposed adaptation approach. In sequence labeling tasks, our parser surpasses the baseline on high resource languages, and performs very competitively in a zero-shot setting. Our in-depth analyses show that adapter generation via typological features of languages is key to this success.1