Measles virus is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths. Although it was long believed to replicate in the ...respiratory epithelium before disseminating, it was recently shown to infect initially macrophages and dendritic cells of the airways using signalling lymphocytic activation molecule family member 1 (SLAMF1; also called CD150) as a receptor. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs where measles virus replicates vigorously. How and where the virus crosses back into the airways has remained unknown. On the basis of functional analyses of surface proteins preferentially expressed on virus-permissive human epithelial cell lines, here we identify nectin-4 (ref. 8; also called poliovirus-receptor-like-4 (PVRL4)) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains measles virus entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is downregulated in infected epithelial cells, including those of macaque tracheae. Although other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that measles virus targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer, which has implications for ongoing measles-virus-based clinical trials of oncolysis.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit ...SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.
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•Adenovirus transduction of human ACE2 enables SARS-CoV-2 infection of BALB/c mice•High levels of viral RNA and infectious SARS-CoV-2 accumulate in lungs•Mice transduced with human ACE2 develop viral pneumonia after SARS-CoV-2 infection•Neutralizing mAbs protect from SARS-CoV-2-induced lung infection and inflammation
Laboratory mice transduced with adenoviruses encoding human ACE2 are permissive for SARS-CoV-2 and develop pneumonia. Passive transfer of a neutralizing monoclonal antibody reduces lung infection, inflammation, and disease.
High-intensity interval training (HIT), in a variety of forms, is today one of the most effective means of improving cardiorespiratory and metabolic function and, in turn, the physical performance of ...athletes. HIT involves repeated short-to-long bouts of rather high-intensity exercise interspersed with recovery periods. For team and racquet sport players, the inclusion of sprints and all-out efforts into HIT programmes has also been shown to be an effective practice. It is believed that an optimal stimulus to elicit both maximal cardiovascular and peripheral adaptations is one where athletes spend at least several minutes per session in their 'red zone,' which generally means reaching at least 90% of their maximal oxygen uptake (VO2max). While use of HIT is not the only approach to improve physiological parameters and performance, there has been a growth in interest by the sport science community for characterizing training protocols that allow athletes to maintain long periods of time above 90% of VO2max (T@VO2max). In addition to T@VO2max, other physiological variables should also be considered to fully characterize the training stimulus when programming HIT, including cardiovascular work, anaerobic glycolytic energy contribution and acute neuromuscular load and musculoskeletal strain. Prescription for HIT consists of the manipulation of up to nine variables, which include the work interval intensity and duration, relief interval intensity and duration, exercise modality, number of repetitions, number of series, as well as the between-series recovery duration and intensity. The manipulation of any of these variables can affect the acute physiological responses to HIT. This article is Part I of a subsequent II-part review and will discuss the different aspects of HIT programming, from work/relief interval manipulation to the selection of exercise mode, using different examples of training cycles from different sports, with continued reference to T@VO2max and cardiovascular responses. Additional programming and periodization considerations will also be discussed with respect to other variables such as anaerobic glycolytic system contribution (as inferred from blood lactate accumulation), neuromuscular load and musculoskeletal strain (Part II).
Palladium-catalyzed aerobic oxidation reactions have been the focus of industrial application and extensive research efforts for nearly 60 years. A significant transition occurred in this field ...approximately 20 years ago, with the introduction of catalysts supported by ancillary ligands. The ligands play crucial roles in the reactions, including promotion of direct oxidation of palladium(0) by O2, bypassing the typical requirement for Cu salts or related redox cocatalysts to facilitate oxidation of the reduced Pd catalyst; facilitation of key bond-breaking and bond-forming steps during substrate oxidation; and modulation of chemo-, regio-, or stereoselectivity of a reaction. The use of ligands has contributed to significant expansion of the scope of accessible aerobic oxidation reactions. Increased understanding of the role of ancillary ligands should promote the development of new synthetic transformations, enable improved control over the reaction selectivity, and improve catalyst activity and stability. This review surveys the different ligands that have been used to support palladium-catalyzed aerobic oxidation reactions and, where possible, describes mechanistic insights into the role played by the ancillary ligand.
•rTMS is an effective treatment for depression that is mostly well tolerated and safe.•There are multiple forms of rTMS with established efficacy but no form appears superior to the others.•rTMS is ...effective in patients with various levels of treatment resistance.•Clinical rTMS practice is evolving in terms of treatment paradigms, targeting and scheduling.
Repetitive transcranial magnetic stimulation (rTMS) is an increasingly used treatment for patients with depression. The use of rTMS in depression is supported by over 20 years of clinical trials. There has been a significant increase in knowledge around the use of rTMS in recent years.
The aim of this paper was to review the use of rTMS in depression to provide an update for rTMS practitioners and clinicians interested in the clinical use of this treatment.
A targeted review of the literature around the use of rTMS treatment of depression with a specific focus on studies published in the last 3 years.
High-frequency rTMS applied to the left dorsolateral prefrontal cortex is an effective treatment for acute episodes of major depressive disorder. There are several additional methods of rTMS delivery that are supported by clinical trials and meta-analyses but no substantive evidence that any one approach is any more effective than any other. rTMS is effective in unipolar depression and most likely bipolar depression. rTMS courses may be repeated in the management of depressive relapse but there is less evidence for the use of rTMS in the maintenance phase.
The science around the use of rTMS is rapidly evolving and there is a considerable need for practitioners to remain abreast of the current state of this literature and its implications for clinical practice. rTMS is an effective antidepressant treatment but its optimal use should be continually informed by knowledge of the state of the art.
The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled ...activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.
Summary An unprecedented number of humanitarian emergencies of large magnitude and duration is causing the largest number of people in a generation to be forcibly displaced. Yet the existing ...humanitarian system was created for a different time and is no longer fit for purpose. On the basis of lessons learned from recent crises, particularly the Syrian conflict and the Ebola epidemic, I recommend four sets of actions that would make the humanitarian system relevant for future public health responses: (1) operationalise the concept of centrality of protection; (2) integrate affected persons into national health systems by addressing the humanitarian–development nexus; (3) remake, do not simply revise, leadership and coordination; and (4) make interventions efficient, effective, and sustainable. For these recommendations to be implemented, governments, UN agencies, multilateral organisations, and international non-governmental organisations will need to put aside differences and relinquish authority, influence, and funding.
Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for patients with depression who have not achieved optimal outcomes with one or more trials of antidepressant ...medication. It is an effective antidepressant treatment but there remains considerable scope for improving clinical outcomes. One method to potentially enhance the efficacy of rTMS is through the improvement of methods of stimulation localization.
The purpose of this paper is to review the literature pertaining to rTMS localization methods and approaches relevant to the treatment of major depressive disorder (MDD) and provide specific opinions on the state of the art in regards to targeting of rTMS treatment in depression.
A targeted review of the literature on rTMS targeting in depression.
There is emerging evidence that optimal rTMS treatment outcomes are likely to be achieved with stimulation at a relatively anterior stimulation site in the left dorsolateral prefrontal cortex (DLPFC). However, some lines of research suggest that there may be two effective stimulation sites: one quite posterior, and one more anterior, in the DLPFC. The ‘Beam F3’ method provides reasonable localization to the anterior stimulation site and the posterior stimulation site corresponds to that typically used in studies using the ‘5 cm method’. Neuro-navigational methods are generally most likely to consistently ensure placement of the TMS coil such that it results in stimulation of a selected cortical site. fMRI – connectivity based approaches to targeting specific circuits in the DLPFC are intellectually attractive but it may not be possible to demonstrate differential effectiveness of these over the methods most commonly been used in clinical practice.
There is an emerging literature helping to improve our understanding of the optimal methods for targeting rTMS treatment for depression. However, we lack substantive prospective clinical trials demonstrating improved clinical outcomes with these techniques.
•rTMS is an effective treatment for MDD and response rates should be able to be improved by enhanced methods for targeting.•Clinical responses seem to be better when treatment is provided at sites more anterior and lateral in the DLPFC.•There is emerging evidence that antidepressant responses may be achieved by stimulation of two separate sites.•The Beam F3 approach is a good method for targeting of stimulation at the more anterior stimulation site within the DLPFC.•Connectivity analysis of resting state fMRI data has potential to be used in the personalisation of stimulation targeting.
Dipeptidyl peptidase 4 (DPP4, CD26), a type II transmembrane ectopeptidase, is the receptor for the Middle Eastern respiratory syndrome coronavirus (MERS-CoV). MERS emerged in 2012 and has a high ...mortality associated with severe lung disease. A lack of autopsy studies from MERS fatalities has hindered understanding of MERS-CoV pathogenesis. We investigated the spatial and cellular localization of DPP4 to evaluate an association MERS clinical disease. DPP4 was rarely detected in the surface epithelium from nasal cavity to conducting airways with a slightly increased incidence in distal airways. DPP4 was also found in a subset of mononuclear leukocytes and in serous cells of submucosal glands. In the parenchyma, DPP4 was found principally in type I and II cells and alveolar macrophages and was also detected in vascular endothelium (eg, lymphatics) and pleural mesothelia. Patients with chronic lung disease, such as chronic obstructive pulmonary disease and cystic fibrosis, exhibited increased DPP4 immunostaining in alveolar epithelia (type I and II cells) and alveolar macrophages with similar trends in reactive mesothelia. This finding suggests that preexisting pulmonary disease could increase MERS-CoV receptor abundance and predispose individuals to MERS morbidity and mortality, which is consistent with current clinical observations. We speculate that the preferential spatial localization of DPP4 in alveolar regions may explain why MERS is characterized by lower respiratory tract disease.
Transcranial magnetic stimulation (TMS) is an effective treatment for depression but is limited in that the optimal therapeutic target remains unknown. Early TMS trials lacked a focal target and thus ...positioned the TMS coil over the prefrontal cortex using scalp measurements. Over time, it became clear that this method leads to variation in the stimulation site and that this could contribute to heterogeneity in antidepressant response. Newer methods allow for precise positioning of the TMS coil over a specific brain location, but leveraging these precise methods requires a more precise therapeutic target. We review how neuroimaging is being used to identify a more focal therapeutic target for depression. We highlight recent studies showing that more effective TMS targets in the frontal cortex are functionally connected to deep limbic regions such as the subgenual cingulate cortex. We review how connectivity might be used to identify an optimal TMS target for use in all patients and potentially even a personalized target for each individual patient. We address the clinical implications of this emerging field and highlight critical questions for future research.
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