Rapping about Mechanotransduction Ibar, Consuelo; Irvine, Kenneth D.
Developmental cell,
09/2018, Letnik:
46, Številka:
6
Journal Article
Recenzirano
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Mechanical cues can regulate cell proliferation and differentiation through the Hippo-YAP signaling network. Reporting in Nature, Meng et al. (2018) show that the Ras-related GTPase RAP2 connects ...extracellular matrix stiffness to Hippo pathway regulation, adding to our understanding of how mechanical cues are converted into changes in YAP activity.
Mechanical cues can regulate cell proliferation and differentiation through the Hippo-YAP signaling network. Reporting in Nature, Meng et al. (2018) show that the Ras-related GTPase RAP2 connects extracellular matrix stiffness to Hippo pathway regulation, adding to our understanding of how mechanical cues are converted into changes in YAP activity.
A 45-year-old woman provides her perspective on living with a rare disorder, trimethylaminuria, also known as ‘fish odour syndrome’. She describes the negative quality-of-life impact this diagnosis ...has had on her life, and feeling misunderstood and isolated with this diagnosis.
Disease severity in patients with atopic dermatitis (AD) is directly correlated with colonization by Staphylococcus aureus.1 An increasing body of evidence now also supports a role for S aureus in ...the pathogenesis of AD in genetically susceptible subjects.2 Increased prevalence of S aureus preceding and coinciding with AD onset in an infant cohort suggests that early skin colonization can contribute to the development of clinical AD.3 However, these findings only partially explain the complex role of this organism given that another birth cohort4 did not demonstrate S aureus colonization before development of infantile AD but did show a protective effect of commensal staphylococci against later development of AD. Research is currently underway to investigate the effects of dupilumab, an anti–IL-4 receptor α blocker targeting the TH2 cytokines IL-4 and IL-13 in S aureus–colonized versus noncolonized patients with AD.12 However, active infection causing flares still requires the use of antibiotics, highlighting the role of alternative approaches, including active and passive vaccination strategies (Table I).13-23 Passive immunization strategies using mAbs against specific S aureus toxins are under investigation, although typically as adjuncts to standard antibiotic regimens in high-risk patient groups. Reference Active prophylactic vaccines 1 NDV-3: recombinant Candida albicans Als3p adhesion protein (homologous to S aureus surface proteins) with alum adjuvant NovaDigm Therapeutics, Brookline, Mass 1 2 2 NCT01273922 NCT02996448 NCT03455309 Schmidt et al, 201213 Not published Not published 2 S aureus capsular polysaccharides CP5 and CP8 conjugated to TT, mutated detoxified AT and ClfA ± AS03B adjuvant GlaxoSmithKline, Research Triangle Park, NC 1 NCT01160172 Levy et al, 201514 3 STEBVax: recombinant SEB with alum adjuvant Integrated BioTherapeutics, Gaithersburg, Md 1 NCT00974935 Chen et al, 201615 4 HI, SpA5, mSEB, MntC recombinant proteins and aluminum phosphate adjuvants Olymvax, Chengdu, China 1 1 NCT02820883 NCT02804711 Not published Not published 5 SA3Ag/SA4Ag Pfizer, New York, NY SA3Ag: CP5, CP8, conjugated to CRM197 and recombinant ClfA SA4g: CP5, CP8, conjugated to CRM197, recombinant ClfA and MntC 1 1/2 1/2 1 1/2a 2b NCT01018641 NCT01364571 NCT01643941 NCT02364596 NCT02492958 NCT02388165 Nissen et al, 201516 Marshall et al, 201617 Frenck RW Jr, et al, 201718 Creech et al, 201719 Begier et al, 201720 Not published Not published 6 Recombinant α-toxoid (rAT) and subunit of Panton-Valentine leukocidin (rLukS-PV).
Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a ...cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, becausewild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.
High-yield H-form trititanate nanotubes have been synthesized, and their structures have been characterized by using X-ray diffraction and high-resolution transmission electron microscopy. According ...to combined TGA/XRD studies, the nanotubes are not stable at high temperature. Thermal analysis suggests that the stoichiometry of the material is H2Ti3O7·0.8H2Oabs. Conductivity measurements indicate that mainly protonic transport occurs at temperatures below 150 °C and that with increasing temperature and progressive breakdown of nanotubes and formation of crystalline TiO2 phases protonic conductivity is lost, leaving only residual defect electronic conduction. The proton conductivity is ca. 5.5 × 10-6 S cm-1 at 300 K. The structural protons and trapped water were confirmed by solid-state NMR.
Anthropocene East Anglia Irvine, Richard DG
The Sociological review (Keele),
03/2017, Letnik:
65, Številka:
1_suppl
Journal Article
Recenzirano
Odprti dostop
As we find ourselves in a geological epoch of our own making, it becomes
necessary to reconsider the temporal scale of ethnographic enquiry; the effect
of human behaviour is shown as a mark in deep ...time. Focusing on the East Anglian
fenland, UK, this article considers the importance of thinking about long-term
environmental change for the understanding of human life. First, the article
explores the way in which human geological agency has transformed the landscape.
It then goes on to argue that while the scale of such changes can only be
understood against the backdrop of geological time, social life in the region
nevertheless demonstrates ‘temporal lock-in’, which is defined in the article as
an increasing fixation with the landscape of a single point in history. The
consequence of such temporal lock-in is that long-term environmental variability
becomes, literally, unthinkable; yet surface-level certainties of the present
are called into question when the timescale of deep history is brought into
view.
Regeneration is a process by which organisms replace damaged or amputated organs to restore normal body parts. Regeneration of many tissues or organs requires proliferation of stem cells or stem ...cell-like blastema cells. This regenerative growth is often initiated by cell death pathways induced by damage. The executors of regenerative growth are a group of growth-promoting signaling pathways, including JAK/STAT, EGFR, Hippo/YAP, and Wnt/β-catenin. These pathways are also essential to developmental growth, but in regeneration, they are activated in distinct ways and often at higher strengths, under the regulation by certain stress-responsive signaling pathways, including JNK signaling. Growth suppressors are important in termination of regeneration to prevent unlimited growth and also contribute to the loss of regenerative capacity in nonregenerative organs. Here, we review cellular and molecular growth regulation mechanisms induced by organ damage in several models with different regenerative capacities.
Background Atopic dermatitis (AD) is associated with an increased risk for viral infections including those caused by herpes simplex virus and varicella zoster virus. Objectives This study examined ...treatment-emergent (TE) herpes simplex infection including eczema herpeticum (EH), and herpes zoster (HZ), in adult patients with AD receiving >= 1 dose of baricitinib (BARI), an oral selective inhibitor of Janus kinase 1/2. Methods We evaluated data from six double-blinded, randomized, placebo-controlled (PC) trials and two long-term extension studies, within three analysis sets: PC, 2-4-mg BARI extended and All-BARI-AD. Frequency, incidence rate (IR)/100 person-years (PYs) and clinical characteristics of TE-herpes simplex, EH and HZ were reported. Results In the All-BARI-AD dataset (n = 2531;2247 PYs), herpes simplex was reported in 8.9% of patients (n = 224;IR = 10.3). Most herpes simplex events were rated as mild or moderate (93.3%), rarely led to permanent discontinuation (2.2%) and presented mostly as oral/perioral herpes simplex (51.3%). TE-EH occurred at a low frequency (All-BARI-AD 1.7% n = 43;IR = 2.0) and were reported in 0.5%, 0.2% and 1.4% of patients receiving placebo, 2-mg or 4-mg BARI respectively. In the All-BARI-AD dataset, most events were investigator-rated as mild/moderate (79.1%), affected <= 2% of the body surface area (74.2%) and occurred as single events (88.4%). Serious TE-EH (n = 11) occurred exclusively in patients with poor disease control (vIGA-AD (TM) score >= 3) at infection onset. TE-HZ was reported in 2.1% of BARI patients (n = 53;IR = 2.3), without a dose relationship during the PC period (IR = 2.7 and IR = 0.0) or the extended dataset (IR = 3.7 and IR = 1.7) for 2- or 4-mg BARI respectively. Conclusions TE-herpes simplex was common, while occurrence of EH was uncommon. Most events of EH were localized with involvement of a small BSA and were linked to poor disease control. Events of HZ were rare in the PC dataset and without a dose dependent increase in frequency.
Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine ...if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated ("HIV sectors"). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses.
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