The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. ...However, the recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa), and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1, and EK-1-C4. In contrast, entry of the B.1.351 and P.1 variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from BNT162b2-vaccinated individuals. These results suggest that SARS-CoV-2 may escape neutralizing antibody responses, which has important implications for efforts to contain the pandemic.
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•B.1.1.7, B.1.351, and P.1 do not show augmented host cell entry•Entry inhibitors under clinical evaluation block all variants•B.1.351 and P.1 can escape from therapeutic antibodies•B.1.351 and P.1 evade antibodies induced by infection and vaccination
Comparison of the SARS-CoV-2 variants B.1.1.7, B.1.351, and P.1 shows that inhibitors under clinical evaluation are still effective in blocking entry, though the B.1.351 and P.1 variants evade antibody responses induced upon infection as well as vaccination and evade certain therapeutic antibodies.
Respiratory virus infections, such as influenza, typically induce a robust type I (pro-inflammatory cytokine) immune response, however, the production of type 2 cytokines has been observed. Type 2 ...cytokine production during respiratory virus infection is linked to asthma exacerbation; however, type 2 cytokines may also be tissue protective. Interleukin (IL)-5 is a prototypical type 2 cytokine that is essential for eosinophil maturation and egress out of the bone marrow. However, little is known about the cellular source and underlying cellular and molecular basis for the regulation of IL-5 production during respiratory virus infection. Using a mouse model of influenza virus infection, we found a robust transient release of IL-5 into infected airways along with a significant and progressive accumulation of eosinophils into the lungs, particularly during the recovery phase of infection, i.e. following virus clearance. The cellular source of the IL-5 was group 2 innate lymphoid cells (ILC2) infiltrating the infected lungs. Interestingly, the progressive accumulation of eosinophils following virus clearance is reflected in the rapid expansion of c-kit⁺ IL-5 producing ILC2. We further demonstrate that the enhanced capacity for IL-5 production by ILC2 during recovery is concomitant with the enhanced expression of the IL-33 receptor subunit, ST2, by ILC2. Lastly, we show that NKT cells, as well as alveolar macrophages (AM), are endogenous sources of IL-33 that enhance IL-5 production from ILC2. Collectively, these results reveal that c-kit⁺ ILC2 interaction with IL-33 producing NKT and AM leads to abundant production of IL-5 by ILC2 and accounts for the accumulation of eosinophils observed during the recovery phase of influenza infection.
Family‐oriented services are not as common as one would expect, given the widespread endorsement of family‐centred care, the role of parents in supporting optimal child outcomes, and legislation and ...literature indicating that parent outcomes are important in their own right. There are no published service delivery frameworks describing the scope of services that could be delivered to promote parent and family wellness. A scoping review was conducted to identify types of family‐oriented services for parents of children with physical disabilities and/or intellectual impairments. This information was then synthesized into a conceptual framework of services to inform service selection and design. A scoping review of the recent literature was performed to capture descriptions of services targeting parents/families of children with physical disabilities and/or intellectual impairments, published in a six‐year period (2009 to 2014). Six databases were searched and 557 retrieved articles were screened using inclusion and exclusion criteria. Thirty six relevant articles were identified. Based on descriptions of services in these articles, along with seminal articles describing the nature of desirable services, we propose a needs‐based and capacity‐enhancing framework outlining a continuum of family‐oriented services for parents of children with disabilities. The framework includes six types of services to meet parent/family needs, organized as a continuum from fundamental information/education services, to those supporting parents to deliver services to meet their child's needs, to a variety of services addressing parents' own needs (support groups, psychosocial services and service coordination). The framework provides pediatric rehabilitation service organizations with a way to consider different possible family‐oriented services. Implications include the particular importance of providing information resources, support groups and psychosocial services to meet parents' needs, enhance capacity and promote family wellness. There is also an opportunity to provide composite parent–child services to address the needs of both parents and children.
Urbanization has many benefits, but it also is associated with increased levels of mental illness, including depression. It has been suggested that decreased nature experience may help to explain the ...link between urbanization and mental illness. This suggestion is supported by a growing body of correlational and experimental evidence, which raises a further question: what mechanism(s) link decreased nature experience to the development of mental illness? One such mechanism might be the impact of nature exposure on rumination, a maladaptive pattern of self-referential thought that is associated with heightened risk for depression and other mental illnesses. We show in healthy participants that a brief nature experience, a 90-min walk in a natural setting, decreases both self-reported rumination and neural activity in the subgenual prefrontal cortex (sgPFC), whereas a 90-min walk in an urban setting has no such effects on self-reported rumination or neural activity. In other studies, the sgPFC has been associated with a self-focused behavioral withdrawal linked to rumination in both depressed and healthy individuals. This study reveals a pathway by which nature experience may improve mental well-being and suggests that accessible natural areas within urban contexts may be a critical resource for mental health in our rapidly urbanizing world.
More than 50% of people now live in urban areas. By 2050 this proportion will be 70%. Urbanization is associated with increased levels of mental illness, but itâs not yet clear why. Through a controlled experiment, we investigated whether nature experience would influence rumination (repetitive thought focused on negative aspects of the self), a known risk factor for mental illness. Participants who went on a 90-min walk through a natural environment reported lower levels of rumination and showed reduced neural activity in an area of the brain linked to risk for mental illness compared with those who walked through an urban environment. These results suggest that accessible natural areas may be vital for mental health in our rapidly urbanizing world.
Pancreatic ductal adenocarcinoma (PDAC) is known for its very poor overall prognosis. Accurate early diagnosis and new therapeutic modalities are therefore urgently needed. We used 377 feature ...microRNA (miRNA) arrays to investigate miRNA expression in normal pancreas, chronic pancreatitis, and PDAC tissues as well as PDAC-derived cell lines. A pancreatic miRNome was established comparing the data from normal pancreas with a reference set of 33 human tissues. The expression of miR-216 and -217 and lack of expression of miR-133a were identified as characteristic of pancreas tissue. Unsupervised clustering showed that the three pancreatic tissues types can be classified according to their respective miRNA expression profiles. We identified 26 miRNAs most prominently misregulated in PDAC and a relative quantitative reverse transcriptase-polymerase chain reaction index using only miR-217 and -196a was found to discriminate normal pancreas, chronic pancreatitis and cancerous tissues, establishing a potential utility for miRNAs in diagnostic procedures. Lastly, comparing differentially expressed genes from PDAC with predicted miRNA target genes for the top 26 miRNAs, we identified potential novel links between aberrant miRNA expression and known target genes relevant to PDAC biology. Our data provides novel insights into the miRNA-driven pathophysiological mechanisms involved in PDAC development and offers new candidate targets to be exploited both for diagnostic and therapeutic strategies.
Summary
Background Perturbations in the expression profiles of microRNAs (miRNAs) have been reported for a variety of different cancers. Differentially expressed miRNAs have not been systematically ...evaluated in basal cell carcinoma (BCC) of the skin.
Objectives To initiate a microarray‐based miRNA profiling study to identify specific miRNA candidates that are differentially expressed in BCC.
Methods Patients with BCC (n = 7) were included in this study. Punch biopsies were harvested from the tumour centre (lesional, n = 7) and from adjacent nonlesional skin (intraindividual control, n = 7). Microarray‐based miRNA expression profiles were obtained on an Agilent platform using miRBase 16 screening for 1205 Homo sapiens (hsa)‐miRNA candidates. To validate the microarray data, the expression of seven dysregulated miRNAs was measured by TaqMan quantitative real‐time reverse transcription polymerase chain reaction.
Results We identified 16 significantly upregulated (hsa‐miR‐17, hsa‐miR‐18a, hsa‐miR‐18b, hsa‐miR‐19b, hsa‐miR‐19b‐1*, hsa‐miR‐93, hsa‐miR‐106b, hsa‐miR‐125a‐5p, hsa‐miR‐130a, hsa‐miR‐181c, hsa‐miR‐181c*, hsa‐miR‐181d, hsa‐miR‐182, hsa‐miR‐455‐3p, hsa‐miR‐455‐5p and hsa‐miR‐542‐5p) and 10 significantly downregulated (hsa‐miR‐29c, hsa‐miR‐29c*, hsa‐miR‐139‐5p, hsa‐miR‐140‐3p, hsa‐miR‐145, hsa‐miR‐378, hsa‐miR‐572, hsa‐miR‐638, hsa‐miR‐2861 and hsa‐miR‐3196) miRNAs in BCC compared with nonlesional skin. Data mining revealed connections to many tumour‐promoting pathways, such as the Hedgehog and the mitogen‐activated protein kinase/extracellular signal‐regulated kinase signalling cascades.
Conclusions This study identified several miRNA candidates that may play a role in the molecular pathogenesis of BCC.
Aims/hypothesis
The aim of this work was to compare the glucose-lowering efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors between Asian and non-Asian patients with type 2 diabetes.
Methods
We ...searched MEDLINE, EMBASE, LILACS, CENTRAL, ClinicalTrials.gov and conference proceedings. Studies were eligible if they were randomised controlled trials with a treatment duration of at least 12 weeks, compared a DPP-4 inhibitor with a placebo as either monotherapy or oral combination therapy, had information on ethnicity and HbA
1c
values and were published or described in English. A systematic review and meta-analysis with a meta-regression analysis was conducted.
Results
Among 809 potentially relevant studies, 55 trials were included. A meta-analysis revealed that DPP-4 inhibitors lowered HbA
1c
to a greater extent in studies with ≥50% Asian participants (weighted mean difference WMD −0.92%; 95% CI −1.03, −0.82) than in studies with <50% Asian participants (WMD −0.65%; 95% CI −0.69, −0.60). The between-group difference was −0.26% (95% CI −0.36, −0.17,
p
< 0.001). The baseline BMI significantly correlated with the HbA
1c
-lowering efficacy of DPP-4 inhibitors. The RR of achieving the goal of HbA
1c
<7.0% (53.0 mmol/mol) was higher in studies with ≥50% Asian participants (3.4 95% CI 2.6, 4.7 vs 1.9 95% CI 1.8, 2.0). The fasting plasma glucose-lowering efficacy was higher with monotherapy in the Asian-dominant studies, but the postprandial glucose-lowering efficacy and changes in body weight were comparable between the two groups.
Conclusions/interpretation
DPP-4 inhibitors exhibit a better glucose-lowering efficacy in Asians than in other ethnic groups; this requires further investigation to understand the underlying mechanism, particularly in relation to BMI.
Summary
Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have ...also been found in non‐cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen‐presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs.
Macrophages, found in circulating blood as well as integrated into several tissues and organs throughout the body, represent an important first line of defense against disease and a necessary ...component of healthy tissue homeostasis. Additionally, macrophages that arise from the differentiation of monocytes recruited from the blood to inflamed tissues play a central role in regulating local inflammation. Studies of macrophage activation in the last decade or so have revealed that these cells adopt a staggering range of phenotypes that are finely tuned responses to a variety of different stimuli, and that the resulting subsets of activated macrophages play critical roles in both progression and resolution of disease. This review summarizes the current understanding of the contributions of differentially polarized macrophages to various infectious and inflammatory diseases and the ongoing effort to develop novel therapies that target this key aspect of macrophage biology.
The ability to spatially tailor material biomechanical and biochemical properties at the microscale and to create freeform 3D patterns and gradients within existing photoactive networks (see figure) ...is demonstrated. The ability of patterned substrates to guide cell migration is also shown.
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