•TNF-α mRNA and protein are increased by IL-1β in pancreatic β-cells.•Induction of TNF-α requires IκKβ, a component of the NF-κB signaling pathway.•p65, a NF-κB transcriptional subunit, is recruited ...to the TNF-α gene promoter.•Methylation status of histone H3 at the TNF-α gene is altered in response to IL-1β.•RNA polymerase II is recruited to the TNF-α gene promoter in response to IL-1β.
Synthesis and secretion of immunomodulatory proteins, such as cytokines and chemokines, controls the inflammatory response within pancreatic islets. When this inflammation does not resolve, destruction of pancreatic islet β-cells leads to diabetes mellitus. Production of the soluble mediators of inflammation, such as TNF-α and IL-1β, from resident and invading immune cells, as well as directly from islet β-cells, is also associated with suboptimal islet transplantation outcomes. In this study, we found that IL-1β induces rapid increases in TNF-α mRNA in rat and human islets and the 832/13 clonal β-cell line. The surge in transcription of the TNF-α gene required the inhibitor of kappa B kinase beta (IκKβ), the p65 subunit of the NF-κB and a signal-specific recruitment of RNA polymerase II to the gene promoter. Of note was the increased intracellular production of TNF-α protein in a manner consistent with mRNA accumulation in response to IL-1β, but no detectable secretion of TNF-α into the media. Additionally, TNF-α specifically induces expression of CD11b, but not CD11c, on neutrophils, which could contribute to the inflammatory milieu and diabetes progression. We conclude that activation of the NF-κB pathway in pancreatic β-cells leads to rapid intracellular production of the pro-inflammatory TNF-α protein through a combination of specific histone covalent modifications and NF-κB signaling pathways.
Depressive symptoms among people living with HIV (PLWH) are associated with poorer overall health outcomes. We characterized depressive symptoms and improvements in symptomology among PLWH (≥ 19 ...years old) in British Columbia (BC), Canada. We also examined associations between depressive symptomology and antiretroviral therapy (ART) treatment interruptions. Depressive symptoms were measured using the 10-item Center for Epidemiologic Studies Depression Scale (CES-D-10), within a longitudinal cohort study with three surveys administered 18-months apart. We used multivariable logistic regression to model factors associated with improvements in depressive symptoms (CES-D-10 scores from ≥ 10 to < 10). Of the 566 participants eligible for analysis 273 (48.2%) had CES-D scores indicating significant depressive symptoms (score ≥ 10) at enrollment. Improvements in symptoms at first follow-up were associated with greater HIV self-care on the Continuity of Care Scale (adjusted odds ratio: 1.17; 95% CI 1.03–1.32), and not having a previously reported mental health disorder diagnosis (aOR 2.86; 95% CI 1.01–8.13). Those reporting current cocaine use (aOR 0.33; 95% CI 0.12–0.91) and having a high school education, vs. less than, (aOR 0.25; 95% CI 0.08–0.82) had lower odds of improvement in depressive symptomatology. CES-D scores ≥ 10 were not significantly associated with ART treatment interruptions during follow-up (aOR: 1.08; 95% CI:0.65–1.8). Supporting greater self-care and consideration of mental health management strategies in relation to HIV may be useful in promoting the wellbeing of PLWH who experience depressive symptoms.
Synthetic biology has the potential to transform cell‐ and gene‐based therapies for a variety of diseases. Sophisticated tools are now available for both eukaryotic and prokaryotic cells to engineer ...cells to selectively achieve therapeutic effects in response to one or more disease‐related signals, thus sparing healthy tissue from potentially cytotoxic effects. This report summarizes the Keystone eSymposium “Synthetic Biology: At the Crossroads of Genetic Engineering and Human Therapeutics,” which took place on May 3 and 4, 2021. Given that several therapies engineered using synthetic biology have entered clinical trials, there was a clear need for a synthetic biology symposium that emphasizes the therapeutic applications of synthetic biology as opposed to the technical aspects. Presenters discussed the use of synthetic biology to improve T cell, gene, and viral therapies, to engineer probiotics, and to expand upon existing modalities and functions of cell‐based therapies.
Synthetic biology‐based therapies typically consist of engineered bacteria; viruses; or implantable, circulating, or tissue‐resident cells that are armed with the ability to secrete effector molecules, perform complex enzymatic transformations, or activate cellular activities based on signals from the environment. Synthetic biology therapeutics thereby offer the potential for increased specificity, as well as tunability, that can improve their therapeutic effectiveness and safety profile relative to molecule‐based therapies. On Demand content: https://keysym.us/21EK41NYAS
In most heat-assisted magnetic recording (HAMR) systems, the laser is ON and kept constant during the entire sector. In this architecture, the transitions are defined whenever the magnetic writer ...changes polarity. In a pulsed HAMR system, the laser pulses once per bit. In this architecture, the transition is defined by the rising edge of the first laser pulse after a magnetic writer current transition. In this paper, we compare the bit error rate (BER) and areal density capability (ADC) of both continuous wave (CW) HAMR and pulsed HAMR. For our testing conditions, we find that there is no penalty for using a pulsed HAMR system over a CW HAMR system in terms of BER and ADC capability.
The ability to quantify synaptic density in vivo in human adults and adolescents is of vital importance to understanding neuropsychiatric disorders. Here, we performed whole-body scans to determine ...organ radiation dosimetry of
11
C-UCB-J in humans.
Methods
Dynamic whole-body PET scans were performed in four healthy adults after injection of
11
C-UCB-J. Regions of interest (ROIs) were drawn manually for the brain, heart, stomach, kidneys, liver, pancreas, spleen, gallbladder, lungs, urinary bladder, and intestines. ROIs were applied to dynamic images to generate time-activity curves (TACs). Decay correction was removed from TACs, and the area under the curve (AUC) for each ROI was calculated. AUCs were then normalized by injected activity and organ volumes to produce radioligand residence times for each organ. These times were then used as input into the OLINDA/EXM 1.0 software to determine the total radiation dose in each organ and the effective dose for these OLINDA models: 55-kg female, 70-kg male, and 15-year-old adolescent.
Results
Visual evaluation detected high uptake in the liver, brain, gallbladder, gastrointestinal tract, and urinary bladder. The dose-limiting organ was the urinary bladder for adult males (0.0224 mSv/MBq) and liver for adult females (0.0248 mSv/MBq) with single-study dose limits of 2239 MBq and 2017 MBq
11
C-UCB-J, respectively. For adolescents, the large intestine was the dose-limiting organ (0.0266 mSv/MBq) with a single-study dose limit of 188 MBq.
Conclusions
11
C-UCB-J dosimetry in adults is consistent with those for many carbon-11-labeled ligands. Overall,
11
C-UCB-J can be used safely in adolescents, as in adults, to measure synaptic density in various neuropsychiatric and other relevant disorders.
General obesity, as reflected by BMI, is an established risk factor for esophageal adenocarcinoma (EAC), a suspected risk factor for gastric cardia adenocarcinoma (GCC) and appears unrelated to ...gastric non‐cardia adenocarcinoma (GNCC). How abdominal obesity, as commonly measured by waist circumference (WC), relates to these cancers remains largely unexplored. Using measured anthropometric data from 391,456 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) study and 11 years of follow‐up, we comprehensively assessed the association of anthropometric measures with risk of EAC, GCC and GNCC using multivariable proportional hazards regression. One hundred twenty‐four incident EAC, 193 GCC and 224 GNCC were accrued. After mutual adjustment, BMI was unrelated to EAC, while WC showed a strong positive association (highest vs. lowest quintile HR = 1.19; 95% CI, 0.63–2.22 and HR = 3.76; 1.72–8.22, respectively). Hip circumference (HC) was inversely related to EAC after controlling for WC, while WC remained positively associated (HR = 0.35; 0.18–0.68, and HR=4.10; 1.94‐8.63, respectively). BMI was not associated with GCC or GNCC. WC was related to higher risks of GCC after adjustment for BMI and more strongly after adjustment for HC (highest vs. lowest quintile HR = 1.91; 1.09–3.37, and HR = 2.23; 1.28–3.90, respectively). Our study demonstrates that abdominal, rather than general, obesity is an indisputable risk factor for EAC and also provides evidence for a protective effect of gluteofemoral (subcutaneous) adipose tissue in EAC. Our study further shows that general obesity is not a risk factor for GCC and GNCC, while the role of abdominal obesity in GCC needs further investigation.
What's new?
While mainly general obesity, as measured by body mass index, has been investigated in relation to gastric and esophageal cancer, the effect of a large waist on these cancer sites is unknown. In this article, the authors report results of extensive analysis of measured anthropometry, including measures of general (BMI) and abdominal obesity (waist circumference), collected by the European Prospective Investigation into Cancer and Nutrition (EPIC). They show that general obesity is not a risk factor for esophageal and gastric cancer, while waist circumference strongly increases risk of esophageal cancer and may potentially be related to gastric cardia cancer.
ABSTRACT
The Square Kilometre Array (SKA) is the largest radio interferometer under construction in the world. The high accuracy, wide-field, and large size imaging significantly challenge the ...construction of the Science Data Processor (SDP) of SKA. We propose a hybrid imaging method based on improved W-Stacking and snapshots. The w-range is reduced by fitting the snapshot uv plane, thus effectively enhancing the performance of the improved W-Stacking algorithm. We present a detailed implementation of WS-Snapshot. With full-scale SKA1-LOW simulations, we present the imaging performance and imaging quality results for different parameter cases. The results show that the WS-Snapshot method enables more efficient distributed processing and significantly reduces the computational time overhead within an acceptable accuracy range, which would be crucial for subsequent SKA science studies.
Aquatic fishes face osmotic stress continuously, and the gill is the first tissue that senses and responds to the external osmotic challenges. However, the understandings of how the gill microbiota ...could respond to osmotic stress and their potential host-bacterium relationships are limited. The objectives of the current study are to identify the hypotonic responsive genes in the gill cells and profile the gill microbiota communities after fresh water transfer experiment via transcriptome sequencing and 16S rRNA gene sequencing. Transcriptome sequencing identified 1,034 differentially expressed genes (DEGs), such as aquaporin and sodium potassium chloride cotransporter, after the fresh water transfer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis further highlighted the steroid biosynthesis and glycosaminoglycan biosynthesis pathways in the gill. Moreover, the 16S rRNA gene sequencing identified
as the dominant bacterium in the seawater, which changed to Pseudomonas and
after the fresh water transfer. The alpha diversity analysis suggested that the gill bacterial diversity was lower in the fresh water transferred group. The KEGG and MetaCyc analysis further predicted the alteration of the glycosaminoglycan and chitin metabolisms in the gill bacteria. Collectively, the common glycosaminoglycan and chitin pathways in both the gill cells and gill microbiota suggest the host-bacterium interaction in gill facilitates the fresh water acclimation.
This is the first study using the transcriptome and 16S rRNA gene sequencing to report the hypotonic responsive genes in gill cells and the compositions of gill microbiota in marine medaka. The overlapped glycosaminoglycan- and chitin-related pathways suggest host-bacterium interaction in fish gill during osmotic stress.
In the boreal spring of 2014, the oceanic and atmospheric conditions were favorable for an El Niño's development. It was predicted that in 2014, a super El Niño or at least a regular El Niño with ...normal magnitude, would initiate. However, the growth rate of the sea surface temperature anomaly (SSTA) in the equatorial eastern Pacific suddenly declined in the boreal summer. The physical processes responsible for the termination of the 2014 El Niño were addressed in this study. We hypothesized that a meridional dipole of SSTA, characterized by a pronounced warm SSTA over the eastern North Pacific (ENP) and cold SSTA over the eastern South Pacific (ESP), played a crucial role in blocking the 2014 El Niño’s development. The observational analysis revealed that the meridional dipole of SSTA and the relevant anomalous cross-equatorial flow in the tropical eastern Pacific, induced anomalous westward (
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