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Abstract Electrophilic aromatic substitution is one of the most mechanistically studied reactions in organic chemistry. However, precluded by innate substituent effects, the access to certain substitution patterns remains elusive. While selective C–H alkylation of biorelevant molecules is eagerly awaited, especially for the insertion of a methyl group whose magic effect can boost lead molecules potency, one of the most obvious strategies would rely on electrophilic aromatic substitution. Yet, the historical Friedel-Crafts methylation remains to date poorly selective and limited to activated simple aromatics. Here, we report the development of a selective electrophilic methylation enabling the direct access to highly desirable 1,3-disubstituted arenes. This study demonstrates that this reaction is driven by the generation of long-lived arenium intermediates generated by protonation in superacid and can be applied to a large variety of functionalized (hetero)aromatics going from standard building blocks to active pharmaceutical ingredients.

Abstract Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with ß-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine’s effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.

Plasminogen deficiency type 1 (PLGD-1, hypoplasminogenemia) is an ultra-rare, lifelong disease associated with development of fibrinous lesions in multiple organ systems. Depending on lesion location, clinical manifestations of PLGD-1 can result in acute and/or chronic respiratory airway disease which can compromise respiratory function leading to life-threatening events. Early recognition and effective treatment of airway obstruction caused by fibrinous lesions are critical to prevent morbidity due to respiratory compromise. However, physicians may not be familiar with the clinical presentation and management of PLGD-1, causing delays in diagnosis and treatment and potentially contributing to morbidity. Presented here is a case series of one adult and three pediatric patients with severe respiratory complications of PLGD-1 successfully managed by infusions of plasminogen, human-tvmh replacement therapy. Patients’ respiratory symptoms were resolved or greatly improved, and treatment was generally well tolerated. In all patients, baseline plasminogen activity was substantially increased with plasminogen replacement therapy administered initially every one to two days followed by extended interval dosing as symptoms were controlled or resolved. All four described cases support the clinical benefit of replacement therapy with plasminogen, human-tvmh in the resolution of life-threatening respiratory complications associated with PLGD-1. Clinical manifestations in addition to respiratory lesions were also improved or resolved with continued treatment.

BackgroundSocial cognitive impairments are prevalent in schizophrenia spectrum disorder (SSD) and have detrimental effects on functioning. Cognitive remediation (CR) has shown its efficacy in improving social cognitive impairments, although the transfer of these skills to daily life and the personalization of these interventions remain challenging. RC2S (Remédiation Cognitive de la Cognition Sociale dans la Schizophrénie; Cognitive remediation of social cognition in Schizophrenia) is a French CR that combines the learning of strategies and practice using paper-and-pencil exercises and digital relational simulations. This French program was designed as an in-person intervention. ObjectiveThis project aims to culturally adapt the RC2S program, in French-Canadian and North American English and to assess the feasibility, acceptability, safety, and implementation of a remote version in people with SSD. An exploratory objective is to assess the preliminary effect of remote RC2S on goal attainment, social cognition, and psychosocial outcomes. MethodsWe will use a pre-post quasi-experimental design. First, the translation and cultural adaptation in North American English and French-Canadian of RC2S is presented. Then, 20 participants aged ≥18 years with a diagnosis of SSD, presenting with a subjective or an objective impairment in social cognition, will be included to receive RC2S. In addition, 5 therapists will be included as research participants to assess their perspective on RC2S. Participants with SSD will undergo a baseline remote assessment of their social cognition, clinical symptoms, and functioning. They will then start remote RC2S for 24 biweekly individual 1-hour sessions with a therapist. Following the case formulation and goal setting, participants will complete personalized paper-and-pencil exercises to develop strategies and integrative digital relational simulations, during which they will help an avatar navigate through a variety of social contexts and relationships. The last 2 sessions are dedicated to the transfer to daily life. All participants will complete in-session questionnaires assessing therapeutic alliance, motivation, acceptability, feasibility, and implementation. Following RC2S, the participants with SSD will repeat the same assessment as the baseline. Descriptive statistics will be used to summarize the data about acceptability, feasibility, safety, and implementation. To assess the preliminary effect of RC2S, an intention-to-treat approach will be used with linear mixed models for repeated measures with fixed effects of time. ResultsSo far, 45% (9/20) of participants with SSD (mean age 37.9, SD 9.3 years) have completed the project. They received a mean of 20.5 out of 24 (SD 3.5) sessions of RC2S. A total of 5 therapists also completed the project. ConclusionsImproving social cognitive impairments is an important target in SSD to promote functional recovery. Using digital technologies to address these impairments and deliver the intervention is a promising approach to increase the ecological validity of CR and access to the intervention. Trial RegistrationClinicalTrials.gov NCT05017532; https://classic.clinicaltrials.gov/ct2/show/NCT05017532 International Registered Report Identifier (IRRID)DERR1-10.2196/54251

It was previously reported that crocin, a water-soluble carotenoid isolated from the Crocus sativus L. (saffron), has protective effects on cardiac cells and may neutralize and even prevent the formation of excess number of free radicals; however, functional mechanisms of crocin activity have been poorly understood. In the present research, we aimed to study the functional mechanism of crocin in the heart exposed to oxidative stress. Accordingly, oxidative stress was modeled in vitro on human umbilical vein endothelial cells (HUVECs) and in vivo in mice using cellular stressors. The beneficial effects of crocin were investigated at cellular and molecular levels in HUVECs and mice hearts. Results indicated that oral administration of crocin could have protective effects on HUVECs. In addition, it protects cardiac cells and significantly inhibits inflammation via modulating molecular signaling pathways TLR4/PTEN/AKT/mTOR/NF-κB and microRNA (miR-21). Here we show that crocin not only acts as a direct free radical scavenger but also modifies the gene expression profiles of HUVECs and protects mice hearts with anti-inflammatory action under oxidative stress.

Abstract The implication of reduced proteasomal function in neurodegenerative diseases combined with studies showing the protective effects of increasing proteasome activity in animal models highlight the need to understand the capacity for proteasome activation by small molecules. The C-terminal HbYX motif is present on many proteasome binding proteins and functions to tether activators to the 20S core particle. Previous studies have shown that peptides with a HbYX motif can autonomously activate 20S gate-opening to allow protein degradation. In this study, through an iterative process of peptide synthesis, we design a HbYX-like dipeptide mimetic that represents only the fundamental components of the HbYX motif. The mimetic robustly induces gate-opening in archaeal, yeast, and mammalian proteasomes. We identify multiple proteasome α subunit residues in the archaeal proteasome involved in HbYX-dependent activation. When stimulated by the mimetic, the mammalian 20S can degrade unfolded proteins such as tau. Findings using our peptide mimetic suggest the HbYX-dependent mechanism requires cooperative binding in at least two intersubunit pockets of the α ring. Most significantly, our peptide mimetic reverses proteasome impairment by neurodegenerative disease-associated oligomers. Collectively, these results validate HbYX-like molecules as having robust potential to stimulate proteasome function, which are potentially useful for treating neurodegenerative diseases.

The human Dickkopf (DKK) family includes four main secreted proteins, DKK-1, DKK-2, DKK-3, and DKK-4, as well as the DKK-3 related protein soggy (Sgy-1 or DKKL1). These glycoproteins play crucial roles in various biological processes, and especially modulation of the Wnt signaling pathway. DKK-3 is distinct, with its multifaceted roles in development, stem cell differentiation and tissue homeostasis. Intriguingly, DKK-3 appears to have immunomodulatory functions and a complex role in cancer, acting as either a tumor suppressor or an oncogene, depending on the context. DKK-3 is a promising diagnostic and therapeutic target that can be modulated by epigenetic reactivation, gene therapy and DKK-3-blocking agents. However, further research is needed to optimize DKK-3-based therapies. In this review, we comprehensively describe the known functions of DKK-3 and highlight the importance of context in understanding and exploiting its roles in health and disease.

IntroductionPeople with schizophrenia often present with Theory of mind (ToM) deficits, and the link between these deficits and clinical symptoms remains to be refined, for instance through the use of more recent assessment methods. The objective of this study was to examine the associations between a psychometrically sound ToM task and the clinical symptoms of schizophrenia as measured with the five dimensions of the Positive and Negative Syndrome Scale (PANSS) namely positive, negative, cognitive/disorganization, depression/anxiety and excitability/hostility, while controlling for non-social cognitive abilities.MethodsSeventy participants with recent-onset schizophrenia spectrum disorders (SSD) were assessed for ToM using the Combined stories task (COST) and for clinical symptoms using the PANSS.ResultsThe results revealed significant correlations between ToM and the positive (r = −0.292, p = 0.015) and cognitive/disorganization (r = −0.480, p < 0.001) dimensions when controlling for non-social cognitive abilities. In contrast, the negative symptoms dimension was only significantly correlated with ToM when non-social cognitive abilities were not controlled for (r = −0.278, p = 0.020).DiscussionVery few prior studies used the five-dimensions of the PANSS to examine the link with ToM and this study is the first to rely on the COST, which includes a non-social control condition. This study highlights the importance of taking non-social cognitive abilities into account when considering the relationship between ToM and symptoms.

Purpose: In this paper, the challenging and thorny issue of assessing graduate attributes (GAs) is addressed. An interdisciplinary team at The University of Alberta -- developed a formative model of assessment centered on students and instructor interaction with course content. Design/methodology/approach: The paper starts by laying the theoretical groundwork on which this novel GA assessment tool is based, that is, competency-based education, assessment theory and GA assessment. It follows with a description of the online assessment tool for GAs that was developed in the course of this project. Findings: The online assessment tool for GAs targets three types of stakeholders: (1) students, who self-assess in terms of GAs, (2) instructors, who use the tool to define the extent to which each GA should be inculcated in their course and (3) administrators, who receive aggregate reports based on the data gathered by the system for high-level analysis and decision-making. Collected data by students and professors advance formative assessment of these transversal skills and assist administration in ensuring the GAs are addressed in academic programs. Graduate attributes assessment program (GAAP) is also a space for students to build a personal portfolio that would be beneficial to highlight their skills for potential employers. Research limitations/implications: This research has strong implications for the universities, since it can help institutions, academics and students achieve better results in their practices. This is done by demonstrating strong links between theory and practice. Although this tool has only been used within the university setting by students, instructors and administrators (for self-, course and teaching and program improvement), it could increase its social and practical impact by involving potential employers and increase our understanding of student employability. Moreover, because the tool collects data on a continuous basis, it lends itself to many possible applications in educational data mining, Practical implications: The GAAP can be used and adapted to various educational contexts. The plugin can be added to any Learning Management System (LMS), and students can have access to their data and results throughout their education. Social implications: The GAAP allows institutions to provide a longitudinal formative assessment of students' graduate attributes acquisition. It provides solid and valid evidence of students' progress in a way that would advance society and citizenship. Originality/value: To date, the GAAP is the first online interactive platform that has been developed to longitudinally assess the acquisition of GAs during a complete academic cycle/cohort. It provides a unique space where students and instructors interact with assessment scales and with concrete data for a complete university experience profile.

Background: YouTube® is the preferred source of junior trainees to prepare for surgeries. However, its educational utility is not yet determined. The objectives of this review are to assess the educational quality of YouTube® videos and to evaluate their quality and utility to complement surgical training. Methods: MEDLINE was searched for relevant articles which were screened by two independent reviewers using strict inclusion and exclusion criteria. Results: Of 261 articles retrieved, 29 were included of which 96.6% reported unsatisfactory educational quality. Scarcity in standardized validated methods to assess the educational utility of YouTube® videos was identified. Video metrics (e.g., likes, views) do not necessarily correlate with the educational value of YouTube® videos. Conclusions: The educational quality of surgical YouTube® videos is inadequate, insufficient and heterogenous primarily due to its public nature. Developing a peer review process would improve the quality of uploaded videos. Moreover, academic entities should promote the development of high-quality content on open access platforms.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new drug delivery method for intraabdominal cavity chemotherapy. It combines the benefits of a minimally invasive approach (low morbidity and easy to repeat) with the pharmacokinetic advantages of intraperitoneal administration and tolerance seems excellent. We would like to report one case of a serious adverse event, acute respiratory distress syndrome, which is likely related to oxaliplatin administration; all signs disappeared within a few days.

Severe cognitive impairments and cognitive distortions are core to schizophrenia-spectrum disorders (SSDs) and are associated with deteriorated social functioning. Despite well-established efficacy of group psychosocial therapies targeting cognitive health in SSDs, dissemination of these programs remains limited. Remote delivery offers a promising strategy for increasing the programs' accessibility. Yet, little research has evaluated group therapies for cognitive health delivered in this way. Thus, we aimed to assess, from participants' and therapists' perspectives, the feasibility, acceptability, as well as levels and process of engagement in a videoconference delivery of group psychosocial therapies for SSD patients' cognitive health. Participants, outpatients, attended Action Based Cognitive Remediation or Metacognitive Training, both adapted for videoconference. Then, participants and therapists completed post-therapy questionnaires. Of the 28 participants attending at least one session, 75% completed more than half of sessions and seven dropped out. Technology did not appear to significantly hinder participation in the programs. All completing participants reported a positive experience with therapy, 67% were not bothered by the distance from the therapist, and 77% trusted that the information shared was kept confidential. Therapist-rated levels of attention M = 7.5/9 (SD = 1.04), participation M = 6.91/9 (SD = 1.32), and social interactions M = 5.31/9 (SD = 1.96) were satisfactory. Nonetheless, participants indicated that they would have appreciated more social interactions with group members. These positive results validate the earliest stage in the implementation process for remote group therapies targeting cognitive health in SSDs. Remote delivery promises to improve access to therapies targeting cognitive health and, ultimately, facilitate functional recovery for SSD patients.

We report the case of a 57-year-old woman who presented with local invasion of the anal canal by mucinous adenocarcinoma, the malignant transformation of a long-term preexisting retrorectal tailgut cyst. This progression is infrequent and justifies preemptive surgical treatment of retrorectal cysts.

“The extraordinary instability of such an “ion” accounts for many of the peculiarities of organic reactions” – Franck C. Whitmore (1932). This statement from Whitmore came in a period where carbocations began to be considered as intermediates in reactions. Ninety years later, pointing at the strong knowledge acquired from the contributions of famous organic chemists, carbocations are very well known reaction intermediates. Among them, destabilized carbocations – carbocations substituted with electron-withdrawing groups – are, however, still predestined to be transient species and sometimes considered as exotic ones. Among them, the CF3-substituted carbocations, frequently suggested to be involved in synthetic transformations but rarely considered as affordable intermediates for synthetic purposes, have long been investigated. This review highlights recent and past reports focusing on their study and potential in modern synthetic transformations.

Background: The COVID-19 pandemic has challenged health care systems. We sought to comprehend the impact of the COVID-19 pandemic on surgical residents’ education and mental well-being across Canada. Methods: An online 51-question survey was distributed to surgical residents across all 17 Canadian post- graduate surgical residency programs. The questionnaire contained questions concerning demographic factors, perceived effects of COVID-19 pandemic on surgical training and residents’ mental health (categorically demonstrating whether it improved, stayed the same, or worsened). Health habits were measured as continuous variables and compared before and during the pandemic. Additionally, participants reported the performance of wellness offices’ response to their needs during this crisis. Results: A total of 122 out of 650 (19%) residents from all surgical specialities anonymously completed the survey. The majority (68%) reported a worsening in their surgical training. 94% of participants favored online teaching as a complementary method to in-person teaching. As to health habits, 38% reported a rise in their alcohol consumption and time spent seated. Only a minority (25%) felt happier and 41% reported experiencing more anxiety in comparison to surgical training pre-COVID-19. Merely 14% reported benefitting from wellness programs. Conclusion: The COVID-19 pandemic had a negative effect on the perceived quality of surgical training, education, and resident mental health. There is an urgent need to reconsider the implemented measures in medical education and urge us to develop better agendas to face the current or future waves.

Background:. Functional recovery after peripheral nerve injury is often suboptimal despite the intrinsic permissive growth environment of the peripheral nervous system. The objective of this systematic review is to explore the use of electrical stimulation (ES) for peripheral nerve regeneration. Methods:. A systematic literature search was conducted from inception to March 2, 2021 to retrieve articles on ES for peripheral nerve regeneration using the PubMed, Ovid MEDLINE, and Embase databases. Primary outcome measures included objective measures of motor and sensory nerve function. Results:. Four randomized control trials, two case reports, and three case series that addressed the aims were identified. The stimulation parameters varied greatly between studies, without an apparent commonality for a given electrical conduit. Outcomes measured included motor (n = 8) and sensory (n = 7) modalities (cold detection, static two-point discrimination, tactile discrimination, and pressure detection), nerve-specific muscle function and bulk, and electromyography (EMG) motor and sensory terminal latency. Different parameters for measurement were utilized and improvement was observed across the studies compared with controls (n = 4) or pre-intervention measurements (n = 5). One randomized control trial reported no benefit of ES and attributed their findings to their stimulation protocol. Complications were documented in three patients only and included wire remnant removal, skin pigmentation, and bone formation. Conclusions:. ES in peripheral nerve regeneration is beneficial in improving and accelerating recovery. A meta-analysis was not performed due to the heterogeneity, but all studies showed positive findings and minor to no complications. These results provide a primer for further development of delivery methods.

Objective:. Despite the success of composite tissue allograft (CTA) such as face and hand transplant at improving recipients’ quality of life, organ donors’ hesitation needs to be better understood. The aim of the study was to assess Canadian organ donors’ willingness to donate their face and hands, and the efficacy of an educational intervention. Methods:. Canadians registered for organ donation were invited to complete an online survey about CTA. An interactive vignette was introduced part way through to clarify transplant-related concepts, with repeat of questions post-vignette exposure to assess attitudes pliability. Results:. A total of 942 participants completed the survey. Fifty-two percent of donors were willing to donate their face after passing, whereas 80% were willing to donate their hands. Reasons to refuse CTA donation included the risk of upsetting their family, having someone look like them, and wanting their body to remain intact. Donors’ willingness to donate their face (38%, P < 0.001) and hands (79%, P = 0.67) decreased following vignette exposure. Comparative analysis of our interventional vignette with a similar study where donors’ donation readiness increased after an educational intervention revealed that our vignette lacked a strong enough emotional component to positively impact donors’ attitude to CTA, and may have exposed participants to alternatives to transplant they were not previously aware of. Conclusions:. Canadian organ donors surveyed were willing to donate their face and hands following death, a willingness reduced after watching our informative vignette. Further qualitative work is required to better understand the educational needs and areas to address to increase donors’ acceptance of CTA.

Background: Canadian medical school curriculums have undergone major restructuring during the COVID-19 pandemic. This study’s goal was to assess the perceived impact of COVID-19 on medical students’ education and wellbeing. Methods: An online survey was distributed to Canadian medical students. Descriptive analyses and ANOVAs were used to assess changes in mental health, health habits and quality of education during the pandemic. Results: 248 medical students from 13 schools across Canada participated in this study. 74% reported a reduction in the quality of their education since COVID-19. 58% of students found online to be inferior to in-person teaching. 65% of students had more time for wellness and leisure activities, about half of the cohort felt more depressed (48%) and lonelier (52%). Student’s overall health habits worsened after the start of the pandemic (F=37.4, p < 0.001). Alcohol drinking, time spent seated, and screen time also increased since the pandemic (p < 0.001). During the pandemic, students with a prior history of depression or anxiety expressed increased depressive symptoms (66% vs. 42%, p =0.003), increased anxiety (69% vs. 41%, p < 0001), worse sleep quality (34% vs. 18%, p = 0.031), and poorer quality of life (55% vs. 65%, p = 0.024) versus those with no prior history. Conclusion: Canadian medical student’s education and wellbeing has been negatively impacted during the pandemic.

A recent paper [Thibaudeau, Slud, and Gottschalck (2017). Modeling log-linear conditional probabilities for estimation in surveys. The Annals of Applied Statistics, 11, 680–697] proposed a ‘hybrid’ method of survey estimation combining coarsely cross-classified design-based survey-weighted totals in a population with loglinear or generalised-linear model-based conditional probabilities for cells in a finer cross-classification. The models were compared in weighted and unweighted forms on data from the US Survey of Income and Program Participation (SIPP), a large national longitudinal survey. The hybrid method was elaborated in a book-chapter [Thibaudeau, Slud, & Cheng (2019). Small-area estimation of cross-classified gross flows using longitudinal survey data. In P. Lynn (Ed.), Methodology of longitudinal surveys II. Wiley] about estimating gross flows in (two-period) longitudinal surveys, by considering fixed versus mixed effect versions of the conditional-probability models and allowing for 3 or more outcomes in the later-period categories used to define gross flows within generalised logistic regression models. The methodology provided for point and interval small-area estimation, specifically area-level two-period labour-status gross-flow estimation, illustrated on a US Current Population Survey (CPS) dataset of survey respondents in two successive months in 16 states. In the current paper, that data analysis is expanded in two ways: (i) by analysing the CPS dataset in greater detail, incorporating multiple random effects (slopes as well as intercepts), using predictive as well as likelihood metrics for model quality, and (ii) by showing how Bayesian computation (MCMC) provides insights concerning fixed- versus mixed-effect model predictions. The findings from fixed-effect analyses with state effects, from corresponding models with state random effects, and fom Bayes analysis of posteriors for the fixed state-effects with other model coefficients fixed, all confirm each other and support a model with normal random state effects, independent across states.

Abstract In the reconstruction of the mangled lower extremity, muscle flaps are well known for their reliable use in soft tissue coverage, however very few reports document their functional reconstruction potential as neurotized muscle flaps. This case illustrates that free neurotized latissimus dorsi flaps are a good option for long-term functional reconstruction in the mangled lower extremity. Our report is the first case in the literature to date describing a subacute reconstruction with a functional latissimus dorsi in lower extremity trauma.

Purpose: No study in the literature compares different external distractors for PIPJ injury. We compared a device described by Suzuki et al and another by Hynes & Giddins in non-injured cadaveric fingers. Main outcome measures were articular space and PIPJ flexion resistance. Methods: Thirty-two Thiel embalmed fingers were used. The elastics based model was performed with 3 and 5 elastics per side (3E and 5E); the 2-pin model used no elastics (2P). Articular distraction of each device was measured using x-ray imaging. The force required to flex the PIP joint to 45˚ and 90˚ in each group was measured with a dynamometer. Main findings: The articular distraction was statistically significant for all groups. The difference in articular distraction was significant in the AP view between groups 3E and 2P, and 5E and 2P. Flexion forces were only significant between group 5E and 2P at 90˚ flexion, but resistance was notably higher in group 2P than in groups 3E and 5E. Group 2P was more difficult to engage and often disengaged in flexion compared to groups 3E and 5E. Conclusion: All devices achieved significant articular distraction (>99% in AP) but optimal distraction has not been clinically determined and may depend on each unique fracture, hence a variable distraction device may be optimal. The 3E and 5E models can be adjusted for distraction by adding the sufficient elastics to reduce individual fractures. The increased resistance to PIP flexion found in the 2P model may limit post-op mobilization, but clinical correlation is needed.

Study Design Retrospective cohort study (level of evidence: 4). Purpose To describe the potential comorbid, operative, and radiographic risk factors for the development of clinically-relevant pseudarthrosis following minimally-invasive transforaminal lumbar interbody fusion (MIS-TLIF). Overview of Literature MIS-TLIF has shown long-term clinical outcomes with decreased perioperative morbidity and earlier return to work, similar to those of open TLIF. However, unsuccessful fusion still remains a concern. The impacts of various patient, operative, and radiographic risk factors have not been evaluated for their potential association with pseudarthrosis related to MIS-TLIF. Methods Between 2012 and 2015, 204 consecutive patients underwent one or two-level MIS-TLIF at St. Joseph's University Medical Center, Paterson, NJ, USA; they had a minimum of 1 year of follow-up. The patients were divided into two cohorts: those who developed clinically-relevant pseudarthrosis and those who did not. Clinically-relevant pseudarthrosis was determined by both evidence on computed tomography and presence of continued clinical symptoms at 1-year follow-up. Results Revision surgery was the only identified non-radiographic factor associated with pseudarthrosis. Disc angle had the highest (R2=0.8), followed by anterior disc height (R2=0.79). Although posterior disc height and the ratio of anterior to posterior disc height showed a marked relationship with the outcome, the R2-values were

Disruption of the ubiquitin proteasome system (UPS) is often associated with neurodegenerative diseases. Here the authors demonstrate the existence of a general mechanism of proteasomal impairment triggered by a specific protein oligomer structure, irrespective of its protein constituent.

After hydrofluorination of ynesulphonamides in superacid or in the presence of hydrofluoric acid/base reagents, a series of α-fluoroenamides has been synthesised and tested for the inhibition of carbonic anhydrase (CA, EC 4.2.1.1) isoforms. This study reveals a new, highly selective family of cancer-related transmembrane human (h) CA IX/XII inhibitors. These original fluorinated ureido isosters do not inhibit the widespread cytosolic isoforms hCA I and II and selectively inhibit the transmembrane cancer-related hCA IX and XII, offering interesting new leads for future studies.

Metal complexes based on transition metals have rich photochemical and photophysical properties that are derived from a variety of excited state electronic configurations triggered by visible and near-infrared light. These properties can be exploited to produce powerful energy and electron transfer processes that can lead to oxygen-(in)dependent photobiological activity. These principles are the basis of photodynamic therapy (PDT), which is a clinically approved treatment that offers a promising, effective, and noninvasive complementary treatment or even an alternative to treat several types of cancers. PDT is based on a reaction involving a photosensitizer (PS), light, and oxygen, which ultimately generates cytotoxic reactive oxygen species (ROS). However, skin photosensitivity, due to the accumulation of PSs in skin cells, has hampered, among other elements, its clinical development and application. Therefore, these is an increasing interest in the use of (metal-based) PSs that are more specific to tumor cells. This may increase efficacy and corollary decrease side-effects. To this end, metal-containing nanoparticles with photosensitizing properties have recently been developed. In addition, several studies have reported that the use of immunogenic/immunomodulatory metal-based nanoparticles increases the antitumor efficacy of immune-checkpoint inhibitor-based immunotherapy mediated by anti-PD-(L)1 or CTLA-4 antibodies. In this review, we discuss the main metal complexes used as PDT PSs. Lastly, we review the preclinical studies associated with metal-based PDT PSs and immunotherapies. This therapeutic association could stimulate PDT.

Abstract Background Bull fertility is the degree of sperm’s ability to fertilize and activate the egg and support embryo development, and this is critical for herd reproductive performance. We used the bull as a unique model organism for the study of male fertility because cattle genetics and physiology is similar to those of other mammals including humans. Moreover, reliable fertility data along with well-established in vitro systems are available for bovine. The objective of this original study was to ascertain evolutionary diversification and expression dynamics of Testis Specific Histone 2B (TH2B) in sperm from Holstein bulls with different fertility scores. Methods The intensity of TH2B was determined by using flow cytometry in sperm from 13 high and 13 low fertility bulls. Expression levels of TH2B were measured using immunofluorescence and Western blotting in sperm from five high and five low fertility bulls. Sequence identity, evolutionary distance and interactome of TH2B were evaluated by dotmatcher, STRING and Cytoscape. Data were analyzed using linear mixed effects model and regression plots were drawn. Results The intensity of TH2B as measured by flow cytometry was significantly affected by an interaction between fertility group and fertility score (P = 0.0182). The intensity of TH2B in sperm from the high fertility group decreased (P = 0.0055) as fertility increased. TH2B was constantly detectable in sperm and expression levels of TH2B decreased in relation to fertility in sperm from the high fertility group (P = 0.018). TH2B biological functions include male gamete generation, chromosome organization, DNA packaging, DNA conformation change, chromatin organization, nucleosome organization, chromatin disassembly, spermatid nucleus elongation, spermatid nucleus differentiation, sperm motility, chromatin organization, chromatin condensation, chromatin silencing, nucleus organization, and chromatin remodeling (P

Dès leurs premières années d’existence, la photographie et le cinéma ont eu partie liée avec les révolutions, en témoignent les clichés de la Commune de Paris ou les actualités filmées sur la Révolution Russe. Tout en révolutionnant nos modes de représentation et notre perception du réel, ces deux médias ont excellé à représenter les révolutions humaines, à en capter les fulgurances pour s’en faire le témoin, voire leur étendard, autant qu’à les adapter aux goûts et aux idées du jour, par l’entremise de la fiction. C’est sur ces différents rapports qui se jouent entre l’événement révolutionnaire et les images filmiques et photographiques que se penche ce numéro de Fotocinema. Qu'entendons-nous par " événement révolutionnaire " ? Quoi de commun entre les révolutions russe, mexicaine ou cubaine, et " Mai 68 ", le 15-M et la " Semaine Tragique " ? Entre ceux qui ont abouti à des changements majeurs dans l'organisation politique, sociale et économique des sociétés, et ceux qui ont échoué, voire qui ont été écrasés dans le sang ? Sans doute conviendrait-il de distinguer le soulèvement, la révolte, l'insurrection et la révolution proprement dite, mais c'est une distinction qui se mesure aux résultats. Tout soulèvement porte en lui le germe d'une révolution, et nul ne sait jamais quel élément en sera le déclencheur ni quelles conjonctions la favoriseront. C'est pourquoi nous avons choisi de ne pas exclure les " révolutions vaincues " (Traverso, 2017), ni les mouvements pacifiques porteurs de nouveaux projets de société radicaux. Toutes les révoltes ne relèvent pas d’un projet révolutionnaire mais certains soulèvements ont cette ambition qu’ils conservent, même s’ils échouent ; et de nombreuses révoltes isolées ont entraîné dans leur sillage de véritables évolutions émancipatrices.

Desde los primeros años de su existencia, la fotografía y el cine han estado relacionados con las revoluciones, como podemos comprobar en los clichés de la Comuna de París o en las actualidades fílmicas de la Revolución Rusa. Al mismo tiempo que revolucionaban los modos de representación y nuestra percepción de la realidad, ambos medios supieron como ningún otro representar las revoluciones humanas, captar sus fulguraciones para convertirse en su testigo, cuando no en su estandarte, así como, mediante la ficción, adaptarlas a los gustos y a las ideas del día. En este número de FOTOCINEMA nos interesamos por las distintas relaciones que se producen entre el acontecimiento revolucionario y las imágenes fílmicas y fotográficas. ¿Qué entendemos por "acontecimiento revolucionario"? ¿Qué tienen en común las revoluciones rusa, mexicana o cubana y "el Mayo del 68", el 15-M o la "Semana Trágica"?, ¿no cabría diferenciar las que produjeron cambios radicales en la organización política, social y económica de las sociedades, de las que fracasaron, algunas aplastadas de manera sangrienta? Convendría seguramente distinguir entre la insurrección, el levantamiento, la rebelión y la revolución propiamente dicha, pero son distinciones que se establecen a partir de los resultados. Cualquier insurrección alberga el germen de una revolución y nadie sabe nunca cuál será el factor desencadenante ni las conjunciones que la favorecerán. Por eso no hemos excluido las "revoluciones vencidas" (Traverso, 2017), ni los movimientos pacíficos portadores de nuevos proyectos radicales de sociedad. Por supuesto, todas las insurrecciones no proceden de un proyecto revolucionario, pero algunos levantamientos poseen esa ambición y la conservan por más que fracasen. De la misma manera, numerosas revueltas aisladas han dado lugar a evoluciones emancipadoras.

Retention of iron in tissue macrophages via upregulation of hepcidin (HAMP) and downregulation of the iron exporter ferroportin (FPN) is thought to participate in the establishment of anemia of inflammation after infection. However, an upregulation of FPN has been proposed to limit macrophages iron access to intracellular pathogens. Therefore, we studied the iron homeostasis and in particular the regulation of FPN after infection with Salmonella enterica serovar Typhimurium in mice presenting tissue macrophages with high iron (AcB61), basal iron (A/J and wild-type mice), or low iron (Hamp knock out, Hamp−/−) levels. The presence of iron in AcB61 macrophages due to extravascular hemolysis and strong erythrophagocytosis activity favored the proliferation of Salmonella in the spleen and liver with a concomitant decrease of FPN protein expression. Despite systemic iron overload, no or slight increase in Salmonella burden was observed in Hamp−/− mice compared to controls. Importantly, FPN expression at both mRNA and protein levels was strongly decreased during Salmonella infection in Hamp−/− mice. The repression of Fpn mRNA was also observed in Salmonella-infected cultured macrophages. In addition, the downregulation of FPN was associated with decreased iron stores in both the liver and spleen in infected mice. Our findings show that during Salmonella infection, FPN is repressed through an iron and hepcidin-independent mechanism. Such regulation likely provides the cellular iron indispensable for the growth of Salmonella inside the macrophages.