Cytotoxic lymphocytes produce granules armed with a set of 5 serine proteases (granzymes (Gzms)), which, together with the pore-forming protein (perforin), serve as a major defense against viral ...infections in humans. This granule-exocytosis pathway subsumes a well-established mechanism in which target cell death is induced upon perforin-mediated entry of Gzms and subsequent activation of various (apoptosis) pathways. In the past decade, however, a growing body of evidence demonstrated that Gzms also inhibit viral replication and potential reactivation in cell death–independent manners. For example, Gzms can induce proteolysis of viral or host cell proteins necessary for the viral entry, release, or intracellular trafficking, as well as augment pro-inflammatory antiviral cytokine response. In this review, we summarize current evidence for the noncytotoxic mechanisms and roles by which killer cells can use Gzms to combat viral infections, and we discuss the potential thereof for the development of novel therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Automatic milking systems (AMS) are increasingly popular throughout the world. Our objective was to analyze 635 North American dairy farms with AMS for (risk) factors associated with increased milk ...production per cow per day and milk production per robot per day. We used multivariable generalized mixed linear regressions, which identified several significant risk factors and interactions of risk factors associated with milk production. Free traffic was associated with increased production per cow and per robot per day compared with forced systems, and the presence of a single robot per pen was associated with decreased production per robot per day compared with pens using 2 robots. Retrofitted farms had significantly less production in the first 4 yr since installation compared with production after 4 yr of installation. In contrast, newly built farms did not see a significant change in production over time since installation. Overall, retrofitted farms did not produce significantly more or less milk than newly constructed farms. Detailed knowledge of factors associated with increased production of AMS will help guide future recommendations to producers looking to transition to an AMS and maximize their production.
The Impact of Alcohol on L1 versus L2 Offrede, Tom F.; Jacobi, Jidde; Rebernik, Teja ...
Language and speech,
09/2021, Letnik:
64, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Alcohol intoxication is known to affect many aspects of human behavior and cognition; one of such affected systems is articulation during speech production. Although much research has revealed that ...alcohol negatively impacts pronunciation in a first language (L1), there is only initial evidence suggesting a potential beneficial effect of inebriation on articulation in a non-native language (L2). The aim of this study was thus to compare the effect of alcohol consumption on pronunciation in an L1 and an L2. Participants who had ingested different amounts of alcohol provided speech samples in their L1 (Dutch) and L2 (English), and native speakers of each language subsequently rated the pronunciation of these samples on their intelligibility (for the L1) and accent nativelikeness (for the L2). These data were analyzed with generalized additive mixed modeling. Participants’ blood alcohol concentration indeed negatively affected pronunciation in L1, but it produced no significant effect on the L2 accent ratings. The expected negative impact of alcohol on L1 articulation can be explained by reduction in fine motor control. We present two hypotheses to account for the absence of any effects of intoxication on L2 pronunciation: (1) there may be a reduction in L1 interference on L2 speech due to decreased motor control or (2) alcohol may produce a differential effect on each of the two linguistic subsystems.
Automatic milking systems (AMS) are implemented in a variety of situations and environments. Consequently, there is a need to characterize individual farming practices and regional challenges to ...streamline management advice and objectives for producers. Benchmarking is often used in the dairy industry to compare farms by computing percentile ranks of the production values of groups of farms. Grouping for conventional benchmarking is commonly limited to the use of a few factors such as farms’ geographic region or breed of cattle. We hypothesized that herds’ production data and management information could be clustered in a meaningful way using cluster analysis and that this clustering approach would yield better peer groups of farms than benchmarking methods based on criteria such as country, region, breed, or breed and region. By applying mixed latent-class model-based cluster analysis to 529 North American AMS dairy farms with respect to 18 significant risk factors, 6 clusters were identified. Each cluster (i.e., peer group) represented unique management styles, challenges, and production patterns. When compared with peer groups based on criteria similar to the conventional benchmarking standards, the 6 clusters better predicted milk produced (kilograms) per robot per day. Each cluster represented a unique management and production pattern that requires specialized advice. For example, cluster 1 farms were those that recently installed AMS robots, whereas cluster 3 farms (the most northern farms) fed high amounts of concentrates through the robot to compensate for low-energy feed in the bunk. In addition to general recommendations for farms within a cluster, individual farms can generate their own specific goals by comparing themselves to farms within their cluster. This is very comparable to benchmarking but adds the specific characteristics of the peer group, resulting in better farm management advice. The improvement that cluster analysis allows for is characterized by the multivariable approach and the fact that comparisons between production units can be accomplished within a cluster and between clusters as a choice.
Tumor associated macrophages (TAMs) are important components of the tumor microenvironment (TME). They are characterized by a remarkable functional plasticity, thereby mostly promoting cancer ...progression. Changes in immune cell metabolism are paramount for this functional adaptation. Here, we review the functional consequences of the metabolic programming of TAMs and the influence of local and systemic targeted therapies on the metabolic characteristics of the TME that shape the functional phenotype of the TAMs. Understanding these metabolic changes within the context of the cross-talk between the different components of the TME including the TAMs and the tumor cells is an essential step that can pave the way towards identifications of ways to improve responses to different treatments, to overcome resistance to treatments, tumor progression and reduce treatment-specific toxicity.
In the era of value-based healthcare, one strives for the most optimal outcomes and experiences from the perspective of the patient. So, patient experiences have become a key quality indicator for ...healthcare. While these are supposed to drive quality improvement (QI), their use and effectiveness for this purpose has been questioned. The aim of this systematic review was to provide insight into QI interventions used in a hospital setting and their effects on improving patient experiences, and possible barriers and promoters for QI work.
Prisma guidelines were used to design this review. International academic literature was searched in Embase, Medline OvidSP, Web of Science, Cochrane Central, PubMed Publisher, Scopus, PsycInfo, and Google Scholar. In total, 3,289 studies were retrieved and independently screened by the first two authors for eligibility and methodological quality. Data was extracted on the study purpose, setting, design, targeted patient experience domains, QI strategies, results of QI, barriers, and promotors for QI.
Twenty-one pre-post intervention studies were included for review. The methodological quality of the included studies was assessed using a Critical Appraisal Skills Program (CASP) Tool. QI strategies used were staff education, patient education, audit and feedback, clinician reminders, organizational change, and policy change. Twenty studies reported improvement in patient experience, 14 studies of the 21 included studies reported statistical significance. Most studies (n=17) reported data-related barriers (eg, questionnaire quality), professional, and/or organizational barriers (eg, skepticism among staff), and 14 studies mentioned specific promoters (eg, engaging staff and patients) for QI.
Several patient experience domains are targeted for QI using diverse strategies and methodological approaches. Most studies reported at least one improvement and also barriers and promoters that may influence QI work. Future research should address these barriers and promoters in order to enhance methodological quality and improve patient experiences.
Circulating tumour cell (CTC)–derived organoids have the potential to provide a powerful tool for personalised cancer therapy but are restrained by low CTC numbers provided by blood samples. Here, we ...used diagnostic leukapheresis (DLA) to enrich CTCs from patients with metastatic prostate cancer (mPCa) and explored whether organoids provide a platform for ex vivo treatment modelling.
We prospectively screened 102 patients with mPCa and performed DLA in 40 patients with ≥5 CTCs/7.5 mL blood. We enriched CTCs from DLA using white blood cell (WBC) depletion alone or combined with EpCAM selection. The enriched CTC samples were cultured in 3D to obtain organoids and used for downstream analyses.
The DLA procedure resulted in a median yield of 5312 CTCs as compared with 22 CTCs in 7.5 mL of blood. Using WBC depletion, we recovered 46% of the CTCs, which reduced to 12% with subsequent EpCAM selection. From the isolated and enriched CTC samples, organoid expansion succeeded in 35%. Successful organoid cultures contained significantly higher CTC numbers at initiation. Moreover, we performed treatment modelling in one organoid cell line and identified substantial tumour heterogeneity in CTCs using single cell DNA sequencing.
DLA is an efficient method to enrich CTCs, although the modest success rate of culturing CTCs precludes large scale clinical application. Our data do suggest that DLA and subsequent processing provides a rich source of viable tumour cells. Therefore, DLA offers a promising alternative to biopsy procedures to obtain sufficient number of tumour cells to study sequential samples in patients with mPCa.
NL6019.
•Leukapheresis offers 240-fold more circulating tumour cells (CTCs) than blood samples.•Using optimised methods, 46% of the CTCs were recovered.•Organoid expansion succeeded in 35% of the patient samples.•Substantial intra-patient heterogeneity was suggested by single cell DNA sequencing.•CTC derived organoid line reflected patient's treatment response.
Children with severe hearing loss are known to have more behavioral problems and may perform worse at school than children without. Few large-scale studies of slight to mild hearing loss are ...available.
To examine the relevance of slight to mild hearing loss by studying its association with behavioral problems and school performance.
This cross-sectional study was performed within an ongoing prospective birth cohort study in Rotterdam, the Netherlands. Participants were part of a population-based sample of children. Between ages 9 and 11 years, 5355 children underwent audiometric and behavioral evaluations. Children were excluded if they had missing data for either audiometry or both outcomes. Data were collected from April 2012 through October 2015. Data were analyzed from March to June 2018.
Audiometric evaluation included pure-tone audiometry tests and speech-in-noise testing.
Child behavior was rated by the primary caregiver using the Child Behavior Checklist at ages 9 to 11 years (n = 4471). School performance was measured with a standardized test at age 12 years (n = 2399).
The final sample included 4779 participants who were a mean (SD) age of 9.8 (0.3) years. The sample had nearly equal distribution between boys (n = 2200; 49.2%) and girls (n = 2271; 50.8%). Associations of hearing thresholds with behavioral problems differed between boys and girls. Among boys, higher pure-tone hearing thresholds at low frequencies were associated with higher total problem, social problem, and attention problem scores (total problems for the better-hearing ear: β = 0.01; 95% CI, 0-0.02). Higher speech reception thresholds were associated with higher attention problem scores among girls (β = 0.04; 95% CI, 0-0.08). Higher speech reception thresholds were associated with poorer school performance scores for both boys and girls (β = -0.06; 95% CI, -0.10 to -0.02).
Higher hearing thresholds during pure-tone audiometric and speech-in-noise testing were associated with higher behavioral problem scores and poorer school performance. This supports the relevance of slight to mild hearing loss with these outcomes in school-aged children.
Background:
A recently published validated classification system divides all orofacial cleft (OFC) subphenotypes into groups based on underlying developmental mechanisms, that is, fusion and ...differentiation, and their timing, that is, early and late periods, in embryogenesis of the primary and secondary palates.
Aims:
The aim of our study was to define gender differences in prevalence for all subphenotypes in newborns with OFC in the Netherlands.
Methods:
This was a retrospective cross-sectional study on children with OFC born from 2006 to 2016. Clefts were classified in early (E-), late (L-), and early/late (EL-) embryonic periods, in primary (P-), secondary (S-), and primary/secondary (PS-) palates, and further divided into fusion (F-), differentiation (D-), and fusion/differentiation (FD-) defects, respectively.
Results:
A total of 2089 OFC children were analyzed (1311 males and 778 females). Orofacial cleft subphenotypes in females occurred significantly more frequent in the L-period compared to males (66% vs 55%, P = .000), whereas clefts in males occurred significantly more in the EL-periods (40% vs 27%, P = .000). Females had significantly more S-palatal clefts (42% vs 23%, P = .000), while males had significantly more PS-palatal clefts (44% vs 30%, P = .000). Furthermore, the clefts in females were significantly more frequent the result of an F-defect (60% vs 52%, P = .000).
Conclusions:
Orofacial cleft in females mainly occur in the L-period are mostly S-palatal clefts, and are usually the result of an F-defect. Orofacial cleft in males more commonly occur in the EL-periods, are therefore more often combined PS-palatal clefts, and are more frequent D- and FD-defects.
Purpose
Blood–brain barrier (BBB) disruption is commonly measured with DCE‐MRI using continuous dynamic scanning. For precise measurement of subtle BBB leakage, a long acquisition time (>20 minutes) ...is required. As extravasation of the contrast agent is slow, discrete sampling at strategic time points might be beneficial, and gains scan time for additional sequences. Here, we aimed to explore the feasibility of a sparsely sampled MRI protocol at 7 T.
Methods
The scan protocol consisted of a precontrast quantitative T1 measurement, using an MP2RAGE sequence, and after contrast agent injection, a fast‐sampling dynamic gradient‐echo perfusion scan and two postcontrast quantitative T1 measurements were applied. Simulations were conducted to determine the optimal postcontrast sampling time points for measuring subtle BBB leakage. The graphical Patlak approach was used to quantify the leakage rate (Ki) and blood plasma volume (vp) of normal‐appearing white and gray matter.
Results
The simulations showed that two postcontrast T1 maps are sufficient to detect subtle leakage, and most sensitive when the last T1 map is acquired late, approximately 30 minutes, after contrast agent administration. The in vivo measurements found Ki and vp values in agreement with other studies, and significantly higher values in gray matter compared with white matter (both p = .04).
Conclusion
The sparsely sampled protocol was demonstrated to be sensitive to quantify subtle BBB leakage, despite using only three T1 maps. Due to the time‐efficiency of this method, it will become more feasible to incorporate BBB leakage measurements in clinical research MRI protocols.
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