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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.

While copying skills are used daily at school and involve spelling abilities, studies examining copying performance in children with dyslexia are very scarce. The present study aims to determine whether children with dyslexia present a specific deficit in their copying processes or if their difficulties in copying are a consequence of their spelling deficit. Nineteen children with dyslexia were compared to two groups of typically developing children: 19 chronological age matched children and 19 spelling age matched children. All children were asked to perform a copying task of 40 words, varying in orthographic complexity. This task was scored on spelling accuracy, handwriting quality and speed, and gaze lifts. Our main results showed that children with dyslexia do have difficulties in copying. They made more spelling errors than their age-matched peers, despite the model provided by the task. Gaze lift analyses revealed that children with dyslexia used different copying strategies compared to their classmates. Globally, children with dyslexia seem to behave like younger children, suggesting that their difficulties arise from their spelling deficit. These findings may have practical implications. Given that children with dyslexia face copying difficulties, one possible way to help them could be to enable them to improve their copying strategies, and not just their spelling skills.

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.

A growing body of research reveals that some scholars face online harassment and that such harassment leads to a wide variety of adverse impacts. Drawing on data collected from an online survey of 182 scholars, we report on the factors and triggers involved in scholars' experiences of online harassment; the environments where said experiences take place, and; the consequences it has for personal and professional relationships. We find that online harassment is heavily entwined with the work, identity, and in some cases, the requirements of being a scholar. The online harassment scholars experience is often compounded by other factors, such as gender and physical appearance. We build on prior research in this area to further argue that universities ought to widen their scope of what constitutes workplace harassment and workplace safety to include online spaces.

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.

For educators, the content of the curriculum really is like oxygen: it is the necessary precondition for improving schools, closing the achievement gap, engaging parents, and preparing teachers. However, when educators take the content of the curriculum for granted, they lose opportunities to coordinate and collaborate. Good curriculum instruction should be carefully planned to introduce topics early, and then teachers can intentionally revisit, deepen, and extend learning on these topics in later grades. This article presents the "Core Knowledge Language Arts" (CKLA) program that begins with preschool through third grade reading models to assist teachers incorporate a curriculum that helps students get the mastery for fluent reading, writing, and language comprehension. The program contains seven units, each with a teacher guide. Students and teachers engage in activities that build and deepen background knowledge using teaching practices that are appropriate for young children and early educators. The CKLA domains are carefully organized to build on each other within and across grades, giving students opportunities to refine and expand their knowledge and vocabulary over time. Included with this article are two sidebars: (1) Content on the Cutting-Room Floor: A Brief History of the Elementary Curriculum (Ruth Wattenberg); and (2) Preschoolers to Presidents: CKLA Builds Knowledge Step by Step.

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