Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson's disease (PD). Although several hypotheses suggest a number of different mechanisms ...underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known.
We combined a high-fat diet (HFD) model of diabetes mellitus type 2 (DMT2) with the 6-OHDA lesion model of PD in male mice. We analyzed the association between insulin resistance and the achieved degree of dopaminergic nigrostriatal pathology. We further assessed the impact of the interaction of the two pathologies on motor deficits using a battery of behavioral tests and on microglial activation using immunohistochemistry. Vascular pathology was investigated histologically by analyzing vessel density and branching points, pericyte density, blood-brain barrier leakage, and the interaction between microvessels and microglia in the striatum.
Different degrees of PD lesion were obtained resulting in moderate and severe dopaminergic cell loss. Even though the HFD paradigm did not affect the degree of nigrostriatal lesion in the acute toxin-induced PD model used, we observed a partial aggravation of the motor performance of parkinsonian mice by the diet. Importantly, the combination of a moderate PD pathology and HFD resulted in a significant pericyte depletion, an absence of an angiogenic response, and a significant reduction in microglia/vascular interaction pointing to an aggravation of vascular pathology.
This study provides the first evidence for an interaction of DMT2 and PD at the brain microvasculature involving changes in the interaction of microglia with microvessels. These pathological changes may contribute to the pathological mechanisms underlying the accelerated progression of PD when associated with diabetes.
Aim
The influence of dietary carbohydrates and fats on weight gain is inconclusively understood. We studied the acute impact of these nutrients on the overall metabolic state utilizing the ...insulin:glucagon ratio (IGR).
Methods
Following in vitro glucose and palmitate treatment, insulin and glucagon secretion from islets isolated from C57Bl/6J mice was measured. Our human in vivo study included 21 normoglycaemia (mean age 51.9 ± 16.5 years, BMI 23.9 ± 3.5 kg/m2, and HbA1c 36.9 ± 3.3 mmol/mol) and 20 type 2 diabetes (T2D) diagnosed individuals (duration 12 ± 7 years, mean age 63.6 ± 4.5 years, BMI 29.1 ± 2.4 kg/m2, and HbA1c 52.3 ± 9.5 mmol/mol). Individuals consumed a carbohydrate‐rich or fat‐rich meal (600 kcal) in a cross‐over design. Plasma insulin and glucagon levels were measured at −30, −5, and 0 min, and every 30 min until 240 min after meal ingestion.
Results
The IGR measured from mouse islets was determined solely by glucose levels. The palmitate‐stimulated hormone secretion was largely glucose independent in the analysed mouse islets. The acute meal tolerance test demonstrated that insulin and glucagon secretion is dependent on glycaemic status and meal composition, whereas the IGR was dependent upon meal composition. The relative reduction in IGR elicited by the fat‐rich meal was more pronounced in obese individuals. This effect was blunted in T2D individuals with elevated HbA1c levels.
Conclusion
The metabolic state in normoglycaemic individuals and T2D‐diagnosed individuals is regulated by glucose. We demonstrate that consumption of a low carbohydrate diet, eliciting a catabolic state, may be beneficial for weight loss, particularly in obese individuals.
Abstract
We present the first results from the Mapping Obscuration to Reionization with ALMA (MORA) survey, the largest Atacama Large Millimeter/submillimeter Array (ALMA) blank-field contiguous ...survey to date (184 arcmin
2
) and the only at 2 mm to search for dusty star-forming galaxies (DSFGs). We use the 13 sources detected above 5
σ
to estimate the first ALMA galaxy number counts at this wavelength. These number counts are then combined with the state-of-the-art galaxy number counts at 1.2 and 3 mm and with a backward evolution model to place constraints on the evolution of the IR luminosity function and dust-obscured star formation in the past 13 billion years. Our results suggest a steep redshift evolution on the space density of DSFGs and confirm the flattening of the IR luminosity function at faint luminosities, with a slope of
. We conclude that the dust-obscured component, which peaks at
z
≈ 2–2.5, has dominated the cosmic history of star formation for the past ∼12 billion years, back to
z
∼ 4. At
z
= 5, the dust-obscured star formation is estimated to be ∼35% of the total star formation rate density and decreases to 25%–20% at
z
= 6–7, implying a minor contribution of dust-enshrouded star formation in the first billion years of the universe. With the dust-obscured star formation history constrained up to the end of the epoch of reionization, our results provide a benchmark to test galaxy formation models, to study the galaxy mass assembly history, and to understand the dust and metal enrichment of the universe at early times.
Objective
To evaluate whether colchicine treatment was associated with the inhibition of NLRP3 inflammasome activation in patients with COVID-19.
Methods
We present a post hoc analysis from a ...double-blinded placebo-controlled randomized clinical trial (RCT) on the effect of colchicine for the treatment of COVID-19. Serum levels of NOD-like receptor protein 3 (NLRP3) inflammasome products—active caspase-1 (Casp1p20), IL-1β, and IL-18—were assessed at enrollment and after 48–72 h of treatment in patients receiving standard-of-care (SOC) plus placebo vs. those receiving SOC plus colchicine. The colchicine regimen was 0.5 mg tid for 5 days, followed by 0.5 mg bid for another 5 days.
Results
Thirty-six patients received SOC plus colchicine, and thirty-six received SOC plus placebo. Colchicine reduced the need for supplemental oxygen and the length of hospitalization. On Days 2–3, colchicine lowered the serum levels of Casp1p20 and IL-18, but not IL-1β.
Conclusion
Treatment with colchicine inhibited the activation of the NLRP3 inflammasome, an event triggering the ‘cytokine storm’ in COVID-19.
Trial registration numbers
RBR-8jyhxh
We present spectroscopic redshifts of mJy submillimeter galaxies (SMGs), which have been identified from the ALMA follow-up observations of 870 m detected sources in the Extended Chandra Deep Field ...South (the ALMA-LESS survey). We derive spectroscopic redshifts for 52 SMGs, with a median of z = 2.4 0.1. However, the distribution features a high-redshift tail, with ∼23% of the SMGs at . Spectral diagnostics suggest that the SMGs are young starbursts, and the velocity offsets between the nebular emission and UV ISM absorption lines suggest that many are driving winds, with velocity offsets of up to 2000 km s−1. Using the spectroscopic redshifts and the extensive UV-to-radio photometry in this field, we produce optimized spectral energy distributions (SEDs) using Magphys, and use the SEDs to infer a median stellar mass of = (6 1)× 1010 M for our SMGs with spectroscopic redshift. By combining these stellar masses with the star formation rates (measured from the far-infrared SEDs), we show that SMGs (on average) lie a factor of ∼5 above the so-called "main sequence" at . We provide this library of 52 template fits with robust and uniquely well-sampled SEDs as a resource for future studies of SMGs, and also release the spectroscopic catalog of ∼2000 (mostly infrared-selected) galaxies targeted as part of the spectroscopic campaign.
Resident macrophages are distributed across all tissues and are highly heterogeneous due to adaptation to different tissue-specific environments. The resident macrophages of the sensory ganglia ...(sensory neuron-associated macrophages, sNAMs) are in close contact with the cell body of primary sensory neurons and might play physiological and pathophysiological roles. After peripheral nerve injury, there is an increase in the population of macrophages in the sensory ganglia, which have been implicated in different conditions, including neuropathic pain development. However, it is still under debate whether macrophage accumulation in the sensory ganglia after peripheral nerve injury is due to the local proliferation of resident macrophages or a result of blood monocyte infiltration. Here, we confirmed that the number of macrophages increased in the sensory ganglia after the spared nerve injury (SNI) model in mice. Using different approaches, we found that the increase in the number of macrophages in the sensory ganglia after SNI is a consequence of the proliferation of resident CX3CR1
macrophages, which participate in the development of neuropathic pain, but not due to infiltration of peripheral blood monocytes. These proliferating macrophages are the source of pro-inflammatory cytokines such as TNF and IL-1b. In addition, we found that CX3CR1 signaling is involved in the sNAMs proliferation and neuropathic pain development after peripheral nerve injury. In summary, these results indicated that peripheral nerve injury leads to sNAMs proliferation in the sensory ganglia in a CX3CR1-dependent manner accounting for neuropathic pain development. In conclusion, sNAMs proliferation could be modulated to change pathophysiological conditions such as chronic neuropathic pain.
The development and application of evolutionary algorithms (EAs) and other metaheuristics for the optimisation of water resources systems has been an active research field for over two decades. ...Research to date has emphasized algorithmic improvements and individual applications in specific areas (e.g. model calibration, water distribution systems, groundwater management, river-basin planning and management, etc.). However, there has been limited synthesis between shared problem traits, common EA challenges, and needed advances across major applications. This paper clarifies the current status and future research directions for better solving key water resources problems using EAs. Advances in understanding fitness landscape properties and their effects on algorithm performance are critical. Future EA-based applications to real-world problems require a fundamental shift of focus towards improving problem formulations, understanding general theoretic frameworks for problem decompositions, major advances in EA computational efficiency, and most importantly aiding real decision-making in complex, uncertain application contexts.
Background and purpose: Chemokines orchestrate neutrophil recruitment to inflammatory foci. In the present study, we evaluated the participation of three chemokines, KC/CXCL1, MIP‐2/CXCL2 and ...LIX/CXCL5, which are ligands for chemokine receptor 2 (CXCR2), in mediating neutrophil recruitment in immune inflammation induced by antigen in immunized mice.
Experimental approach: Neutrophil recruitment was assessed in immunized mice challenged with methylated bovine serum albumin, KC/CXCL1, LIX/CXCL5 or tumour necrosis factor (TNF)‐α. Cytokine and chemokine levels were determined in peritoneal exudates and in supernatants of macrophages and mast cells by elisa. CXCR2 and intercellular adhesion molecule 1 (ICAM‐1) expression was determined using immunohistochemistry and confocal microscopy.
Key results: Antigen challenge induced dose‐ and time‐dependent neutrophil recruitment and production of KC/CXCL1, LIX/CXCL5 and TNF‐α, but not MIP‐2/CXCL2, in peritoneal exudates. Neutrophil recruitment was inhibited by treatment with reparixin (CXCR1/2 antagonist), anti‐KC/CXCL1, anti‐LIX/CXCL5 or anti‐TNF‐α antibodies and in tumour necrosis factor receptor 1‐deficient mice. Intraperitoneal injection of KC/CXCL1 and LIX/CXCL5 induced dose‐ and time‐dependent neutrophil recruitment and TNF‐α production, which were inhibited by reparixin or anti‐TNF‐α treatment. Macrophages and mast cells expressed CXCR2 receptors. Increased macrophage numbers enhanced, while cromolyn sodium (mast cell stabilizer) diminished, LIX/CXCL5‐induced neutrophil recruitment. Macrophages and mast cells from immunized mice produced TNF‐α upon LIX/CXCL5 stimulation. Methylated bovine serum albumin induced expression of ICAM‐1 on mesenteric vascular endothelium, which was inhibited by anti‐TNF‐α or anti‐LIX/CXCL5.
Conclusion and implications: Following antigen challenge, CXCR2 ligands are produced and act on macrophages and mast cells triggering the production of TNF‐α, which synergistically contribute to neutrophil recruitment through induction of the expression of ICAM‐1.
We present detailed studies of a z = 2.12 submillimeter galaxy, ALESS67.1, using sub-arcsecond resolution ALMA, adaptive optics-aided VLT/SINFONI, and Hubble Space Telescope (HST)/CANDELS data to ...investigate the kinematics and spatial distributions of dust emission (870 m continuum), 12CO(J = 3-2), strong optical emission lines, and visible stars. Dynamical modeling of the optical emission lines suggests that ALESS67.1 is not a pure rotating disk but a merger, consistent with the apparent tidal features revealed in the HST imaging. Our sub-arcsecond resolution data set allows us to measure half-light radii for all the tracers, and we find a factor of 4-6 smaller sizes in dust continuum compared to all the other tracers, including 12CO; also, ultraviolet (UV) and H emission are significantly offset from the dust continuum. The spatial mismatch between the UV continuum and the cold dust and gas reservoir supports the explanation that geometrical effects are responsible for the offset of the dusty galaxy on the IRX-β diagram. Using a dynamical method we derive an , consistent with other submillimeter galaxies (SMGs) that also have resolved CO and dust measurements. Assuming a single value we also derive resolved gas and star formation rate surface densities, and find that the core region of the galaxy ( kpc) follows the trend of mergers on the Schmidt-Kennicutt relationship, whereas the outskirts ( kpc) lie on the locus of normal star-forming galaxies, suggesting different star formation efficiencies within one galaxy. Our results caution against using single size or morphology for different tracers of the star formation activity and gas content of galaxies, and therefore argue the need to use spatially resolved, multi-wavelength observations to interpret the properties of SMGs, and perhaps even for galaxies in general.
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