The adeno-associated virus (AAV) is a small, nonpathogenic parvovirus, which depends on helper factors to replicate. Those helper factors can be provided by coinfecting helper viruses such as ...adenoviruses, herpesviruses, or papillomaviruses. We review the basic biology of AAV and its most-studied helper viruses, adenovirus type 5 (AdV5) and herpes simplex virus type 1 (HSV-1). We further outline the direct and indirect interactions of AAV with those and additional helper viruses.
Therapeutic food interventions have reduced mortality in children with severe acute malnutrition (SAM), but incomplete restoration of healthy growth remains a major problem. The relationships between ...the type of nutritional intervention, the gut microbiota, and therapeutic responses are unclear. In the current study, bacterial species whose proportional representation define a healthy gut microbiota as it assembles during the first two postnatal years were identified by applying a machine-learning-based approach to 16S ribosomal RNA data sets generated from monthly faecal samples obtained from birth onwards in a cohort of children living in an urban slum of Dhaka, Bangladesh, who exhibited consistently healthy growth. These age-discriminatory bacterial species were incorporated into a model that computes a 'relative microbiota maturity index' and 'microbiota-for-age Z-score' that compare postnatal assembly (defined here as maturation) of a child's faecal microbiota relative to healthy children of similar chronologic age. The model was applied to twins and triplets (to test for associations of these indices with genetic and environmental factors, including diarrhoea), children with SAM enrolled in a randomized trial of two food interventions, and children with moderate acute malnutrition. Our results indicate that SAM is associated with significant relative microbiota immaturity that is only partially ameliorated following two widely used nutritional interventions. Immaturity is also evident in less severe forms of malnutrition and correlates with anthropometric measurements. Microbiota maturity indices provide a microbial measure of human postnatal development, a way of classifying malnourished states, and a parameter for judging therapeutic efficacy. More prolonged interventions with existing or new therapeutic foods and/or addition of gut microbes may be needed to achieve enduring repair of gut microbiota immaturity in childhood malnutrition and improve clinical outcomes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study of the effect of a microbiota-directed supplement on the growth of young children with moderate acute malnutrition included tests of association between changes in growth and changes in ...the plasma proteome and fecal microbiota.
Background
The increasing production of nanoplastics and the fragmentation of microplastics into smaller particles suggest a plausible yet unclear hazard in the natural environment, such as soil. We ...investigated the short-term effects (28 days) of polystyrene nanoparticles (PS-NPs) on the activity and biomass of soil microbiota, and the functional diversity of soil enzymes at environmental relevant low levels in an incubation experiment.
Results
Our results showed a significant decrease in microbial biomass in treatments of 100 and 1000 ng PS-NP g
−1
DM throughout the incubation period. Dehydrogenase activity and activities of enzymes involved in
N
-(leucine-aminopeptidase),
P
-(alkaline-phosphatase), and C-(β-glucosidase and cellobiohydrolase) cycles in the soil were significantly reduced at day 28 suggesting a broad and detrimental impact of PS-NPs on soil microbiota and enzymes. Leucine-aminopeptidase and alkaline-phosphatase activities tended to decrease consistently, while β-glucosidase and cellobiohydrolase activities increased at high concentrations (e.g., PS-NP-1000) in the beginning of the incubation period, e.g., at day 1. On the other hand, basal respiration and metabolic quotient increased with increasing PS-NP application rate throughout the incubation period possibly due to increased cell death that caused substrate-induced respiration (cryptic growth).
Conclusions
We herewith demonstrated for the first time the potential antimicrobial activity of PS-NPs in soil, and this may serve as an important resource in environmental risk assessment of PS-NPs in the soil environment.
We have previously shown that overexpression of SKI, an endogenous TGF-β
1
repressor, deactivates the pro-fibrotic myofibroblast phenotype in the heart. We now show that SKI also functions ...independently of SMAD/TGF-β signaling, by activating the Hippo tumor-suppressor pathway and inhibiting the Transcriptional co-Activator with PDZ-binding motif (TAZ or WWTR1). The mechanism(s) by which SKI targets TAZ to inhibit cardiac fibroblast activation and fibrogenesis remain undefined. A rat model of post-myocardial infarction was used to examine the expression of TAZ during acute fibrogenesis and chronic heart failure. Results were then corroborated with primary rat cardiac fibroblast cell culture performed both on plastic and on inert elastic substrates, along with the use of siRNA and adenoviral expression vectors for active forms of SKI, YAP, and TAZ. Gene expression was examined by qPCR and luciferase assays, while protein expression was examined by immunoblotting and fluorescence microscopy. Cell phenotype was further assessed by functional assays. Finally, to elucidate SKI’s effects on Hippo signaling, the SKI and TAZ interactomes were captured in human cardiac fibroblasts using BioID2 and mass spectrometry. Potential interactors were investigated in vitro to reveal novel mechanisms of action for SKI. In vitro assays on elastic substrates revealed the ability of TAZ to overcome environmental stimuli and induce the activation of hypersynthetic cardiac myofibroblasts. Further cell-based assays demonstrated that SKI causes specific proteasomal degradation of TAZ, but not YAP, and shifts actin cytoskeleton dynamics to inhibit myofibroblast activation. These findings were supported by identifying the bi-phasic expression of TAZ in vivo during post-MI remodeling and fibrosis. BioID2-based interactomics in human cardiac fibroblasts suggest that SKI interacts with actin-modifying proteins and with LIM Domain-containing protein 1 (LIMD1), a negative regulator of Hippo signaling. Furthermore, we found that LATS2 interacts with TAZ, whereas LATS1 does not, and that LATS2 knockdown prevented TAZ downregulation with SKI overexpression. Our findings indicate that SKI’s capacity to regulate cardiac fibroblast activation is mediated, in part, by Hippo signaling. We postulate that the interaction between SKI and TAZ in cardiac fibroblasts is arbitrated by LIMD1, an important intermediary in focal adhesion-associated signaling pathways. This study contributes to the understanding of the unique physiology of cardiac fibroblasts, and of the relationship between SKI expression and cell phenotype.
Rheumatoid arthritis (RA) is the most common autoimmune articular disorder. It is characterized by chronic inflammation and progressive joint destruction. As research traditionally focused on immune ...cells and cytokines, the role of stromal cells was addressed only to a limited extent. However, cell-cell interactions within the rheumatoid synovium alter the phenotype of synovial fibroblasts (SFs), which are nowadays considered as active and aggressive drivers in the destructive process of RA. SFs actively attach to and invade articular cartilage, thereby expressing increased amounts of adhesion molecules and proinflammatory and matrix-degrading mediators. Furthermore, RASFs stimulate synovial vascularization through the release of proangiogenic factors. As a result, angiogenesis supports the influx of immune cells into affected joints, thereby perpetuating inflammatory processes, and facilitates access of RASFs to the bloodstream, thus boosting dissemination of RA. Despite intensive research, early pathophysiological processes still remain largely unknown. In this respect, a prearthritic phase of RA is discussed. Early and intensive therapy is considered to be very effective and beneficial for long-term outcome. However, although innovative therapy and improved treatment strategies are applied to achieve clinical remission, failure of or only partial response to therapy remains common. Given that none of the currently approved therapies target RASFs, intensive research into new strategies is warranted. In this review, novel findings leading to the altered fibroblast phenotype in RA are discussed in terms of progressive inflammation and destruction. Potential novel therapeutic concepts are also addressed.
The recently discovered three-dimensional or bulk topological insulators are expected to exhibit exotic quantum phenomena. It is believed that a trivial insulator can be twisted into a topological ...state by modulating the spin-orbit interaction or the crystal lattice, driving the system through a topological quantum phase transition. By directly measuring the topological quantum numbers and invariants, we report the observation of a phase transition in a tunable spin-orbit system, BiTl(S₁— δ Se δ )₂, in which the topological state formation is visualized. In the topological state, vortex-like polarization states are observed to exhibit three-dimensional vectorial textures, which collectively feature a chirality transition as the spin momentum—locked electrons on the surface go through the zero carrier density point. Such phase transition and texture inversion can be the physical basis for observing fractional charge (±e/2) and other fractional topological phenomena.
Medical treatment of advanced cutaneous squamous‐cell carcinoma Gellrich, F.F.; Hüning, S.; Beissert, S. ...
Journal of the European Academy of Dermatology and Venereology,
December 2019, 2019-Dec, 2019-12-00, 20191201, Letnik:
33, Številka:
S8
Journal Article
Recenzirano
Odprti dostop
Considering the rising incidence, cutaneous squamous‐cell carcinoma (cSCC) has a high clinical relevance. In patients with localized cSCC, complete surgical resection is indicated. Radiotherapy ...should be performed in patients with non‐resectable tumours or in patients who are not suitable for surgery. Systemic therapy is reserved for cSCC that are neither surgically nor radiotherapeutically curable due to their extensive local spread and/or local or distant metastasis. In the absence of prospective randomized phase 3 trials to evaluate and compare the efficacy and safety of chemotherapeutics, epidermal growth factor receptor (EGFR) inhibitors and anti‐PD‐1 antibodies, no final recommendation for systemic therapy can be given for patients with locally advanced or metastatic cSCC. Anti‐PD‐1 antibodies currently show promising results with response rates of up to 50% in both locally advanced and metastatic cSCC. Anti‐PD‐1 antibodies appear to achieve higher response rates compared with EGFR inhibitors, and the duration of response appears to be superior to both chemotherapy and EGFR inhibitors. Compared with chemotherapy, the side effect profile of anti‐PD‐1 antibodies appears to be favourable. Altogether, PD‐1 inhibitors are expected to become the new standard of care for patients with locally advanced and metastatic cSCC. Currently, placebo‐controlled clinical trials are investigating the adjuvant use of cemiplimab and pembrolizumab in patients undergoing resection and radiotherapy of high‐risk cSCC. Patients not eligible for anti‐PD‐1 treatment, e.g. in organ transplant recipients, or in patients refractory to anti‐PD‐1 may be offered EGFR inhibitors and/or chemotherapies. Chemotherapies appear to be superior to EGFR inhibitors in terms of response rates, whereas EGFR inhibitors have a more favourable toxicity profile. EGFR inhibitors are therefore more suitable for multimorbid and/or frail elderly patients. By combining EGFR inhibitors with local therapy such as surgery or radiotherapy, response rates and duration of response may be improved.
Helical Dirac fermions-charge carriers that behave as massless relativistic particles with an intrinsic angular momentum (spin) locked to its translational momentum-are proposed to be the key to ...realizing fundamentally new phenomena in condensed matter physics. Prominent examples include the anomalous quantization of magneto-electric coupling, half-fermion states that are their own antiparticle, and charge fractionalization in a Bose-Einstein condensate, all of which are not possible with conventional Dirac fermions of the graphene variety. Helical Dirac fermions have so far remained elusive owing to the lack of necessary spin-sensitive measurements and because such fermions are forbidden to exist in conventional materials harbouring relativistic electrons, such as graphene or bismuth. It has recently been proposed that helical Dirac fermions may exist at the edges of certain types of topologically ordered insulators-materials with a bulk insulating gap of spin-orbit origin and surface states protected against scattering by time-reversal symmetry-and that their peculiar properties may be accessed provided the insulator is tuned into the so-called topological transport regime. However, helical Dirac fermions have not been observed in existing topological insulators. Here we report the realization and characterization of a tunable topological insulator in a bismuth-based class of material by combining spin-imaging and momentum-resolved spectroscopies, bulk charge compensation, Hall transport measurements and surface quantum control. Our results reveal a spin-momentum locked Dirac cone carrying a non-trivial Berry's phase that is nearly 100 per cent spin-polarized, which exhibits a tunable topological fermion density in the vicinity of the Kramers point and can be driven to the long-sought topological spin transport regime. The observed topological nodal state is shown to be protected even up to 300 K. Our demonstration of room-temperature topological order and non-trivial spin-texture in stoichiometric Bi2Se3.Mx (Mx indicates surface doping or gating control) paves the way for future graphene-like studies of topological insulators, and applications of the observed spin-polarized edge channels in spintronic and computing technologies possibly at room temperature.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
The German programme for skin cancer screening was established in 2008 with the aim of reducing skin cancer mortality. However, the effectiveness and risk–benefit ratio of the ...programme remain unclear.
Objectives
To compare the mortality rates of patients with melanoma who participate in a screening programme to those who do not.
Methods
A retrospective cohort study, based on pseudonymized health insurance data of 1 431 327 individuals from Saxony, Germany, was conducted for the period 2010–2016. Patients with prevalent and incident melanoma were defined based on diagnosis, medical procedures and prescriptions. Patients who underwent screening and had a first diagnosis of melanoma within 2 years of screening were assigned to the intervention group. Relative survival and Cox regression were used to assess potential differences in mortality.
Results
We identified 4552 individuals with prevalent and 2475 individuals with incident melanoma. The percentage of screening participants (n = 1801) who had locoregional (4·2% vs. 13·5%) and/or distant metastases (4·3% vs. 8·0%), or who were treated with systemic anticancer therapies (11·6% vs. 21·8%) was lower vs. nonparticipants (n = 674). Screening participants had significantly better survival rates. The unadjusted Cox model gave a hazard ratio (HR) of 0·37 95% confidence interval (CI) 0·30–0·46. After adjusting for named confounders, the effect remained (HR 0·62, 95% CI 0·48–0·80).
Conclusions
Patients who participated in the screening programme had lower mortality than those who had not undergone screening. However, these findings may result from a healthy screen bias and/or overdiagnosis associated with screening, and not from the screening itself.
What is already known about this topic?
There is limited evidence of the effectiveness of the German skin cancer screening programme and its associated risks more than 10 years after its initiation.
The reduction in mortality as a result of early diagnoses that was hoped for has so far not been demonstrated.
What does this study add?
A reduction in mortality is shown, but there is a high potential for bias.
Secondary data alone cannot explain the facts of the matter.
Linked Comment: T. Eigentler. Br J Dermatol 2022; 186:8–9.
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