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AbstractNeuroimaging is a powerful tool to investigate potential associations between chronic pain and brain structure. However, the proliferation of studies across diverse chronic pain syndromes and heterogeneous results challenges data integration and interpretation. We conducted a preregistered anatomical likelihood estimate meta-analysis on structural magnetic imaging studies comparing patients with chronic pain and healthy controls. Specifically, we investigated a broad range of measures of brain structure as well as specific alterations in gray matter and cortical thickness. A total of 7849 abstracts of experiments published between January 1, 1990, and April 26, 2021, were identified from 8 databases and evaluated by 2 independent reviewers. Overall, 103 experiments with a total of 5075 participants met the preregistered inclusion criteria. After correction for multiple comparisons using the gold-standard family-wise error correction ( P < 0.05), no significant differences associated with chronic pain were found. However, exploratory analyses using threshold-free cluster enhancement revealed several spatially distributed clusters showing structural alterations in chronic pain. Most of the clusters coincided with regions implicated in nociceptive processing including the amygdala, thalamus, hippocampus, insula, anterior cingulate cortex, and inferior frontal gyrus. Taken together, these results suggest that chronic pain is associated with subtle, spatially distributed alterations of brain structure.

ImportanceFunctional neuroimaging is a valuable tool for understanding how patients with chronic pain respond to painful stimuli. However, past studies have reported heterogenous results, highlighting opportunities for a quantitative meta-analysis to integrate existing data and delineate consistent associations across studies.ObjectiveTo identify differential brain responses to noxious stimuli in patients with chronic pain using functional magnetic resonance imaging (fMRI) while adhering to current best practices for neuroimaging meta-analyses.Data sourcesAll fMRI experiments published from January 1, 1990, to May 28, 2019, were identified in a literature search of PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Library, PsycINFO, and SCOPUS.Study selectionExperiments comparing brain responses to noxious stimuli in fMRI between patients and controls were selected if they reported whole-brain results, included at least 10 patients and 10 healthy control participants, and used adequate statistical thresholding (voxel-height P

Characterizing a reliable, pain-related neural signature is critical for translational applications. Many prior fMRI studies have examined acute nociceptive pain-related brain activation in healthy participants. However, synthesizing these data to identify convergent patterns of activation can be challenging due to the heterogeneity of experimental designs and samples. To address this challenge, we conducted a comprehensive meta-analysis of fMRI studies of stimulus-induced pain in healthy participants. Following pre-registration, two independent reviewers evaluated 4,927 abstracts returned from a search of 8 databases, with 222 fMRI experiments meeting inclusion criteria. We analyzed these experiments using Activation Likelihood Estimation with rigorous type I error control (voxel height p < 0.001, cluster p < 0.05 FWE-corrected) and found a convergent, largely bilateral pattern of pain-related activation in the secondary somatosensory cortex, insula, midcingulate cortex, and thalamus. Notably, these regions were consistently recruited regardless of stimulation technique, location of induction, and participant sex. These findings suggest a highly-conserved core set of pain-related brain areas, encouraging applications as a biomarker for novel therapeutics targeting acute nociceptive pain.

Cinnamon extract has been reported to have positive effects in fruit fly and mouse models for Alzheimer's disease (AD). However, cinnamon contains numerous potential active compounds that have not been individually evaluated. The main objective of this study was to evaluate the impact of cinnamaldehyde, a known putative active compound in cinnamon, on the lifespan and healthspan of Drosophila melanogaster models for Alzheimer's disease, which overexpress Aβ42 and MAPT (Tau). We found that cinnamaldehyde significantly improved the lifespan of both AD and non-AD flies. Cinnamaldehyde also improved the healthspan of AD flies overexpressing the Tau protein by improving climbing ability, evaluated by rapid iterative negative geotaxis (RING), and improving short-term memory, evaluated by a courtship conditioning assay. Cinnamaldehyde had no positive impact on the healthspan of AD flies overexpressing the Aβ42 protein.

Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2, LAG3, TIGIT, and CTLA4. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF. Editor's summary: Patients with myeloid malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), often relapse after standard of care. To improve outcomes, Kumar et al. have investigated the role of natural killer (NK) cells in antitumor immunity against myeloid blasts and have identified global dysfunction of NK cells in these patients. They identified BATF as responsible for this dysfunction, and by knocking out BATF downstream of the TGF-β canonical pathway in NK cells, they were able to enhance NK cell function against AML in vitro and in vivo. This has led to the initiation of a promising clinical trial using these TGFBR2 knockout NK cells against myeloid malignancies. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Assessment of soil health requires complex evaluation of properties and functions responsible for a broad range of ecosystem services. Numerous soil quality indices (SQI) have been suggested for the evaluation of specific groups of soil functions, but comparison of various SQI is impossible because they are based on a combination of specific soil properties. To avoid this problem, we suggest an SQI-area approach based on the comparison of the areas on a radar diagram of a combination of chemical, biological and physical properties. The new approach is independent of the SQI principle and allows rapid and simple comparison of parameter groups and soils. Another approach analyzing the resistance and sensitivity of properties to degradation is suggested for a detailed evaluation of soil health. The resistance and sensitivity of soil properties are determined through comparison with the decrease of soil organic carbon (SOC) as a universal parameter responsible for many functions. The SQI-area and resistance/sensitivity approaches were tested based on the recovery of Phaeozems and Chernozems chronosequences after the abandonment of agricultural soils. Both the SQI-area and the resistance/sensitivity approaches are useful for basic and applied research, and for decision-makers to evaluate land-use practices and measure the degree of soil degradation.

In this study, we reported that novel single-chain fusion proteins linking thromboxane A2 (TXA2) receptor (TP) to a selected G-protein α-subunit q (SC-TP-Gαq) or to α-subunit s (SC-TP-Gαs) could be stably expressed in megakaryocytes (MKs). We tested the MK-released platelet-linked particles (PLPs) to be used as a vehicle to deliver the overexpressed SC-TP-Gαq or the SC-TP-Gαs to regulate human platelet function. To understand how the single-chain TP-Gα fusion proteins could regulate opposite platelet activities by an identical ligand TXA2, we tested their dual functions—binding to ligands and directly linking to different signaling pathways within a single polypeptide chain—using a 3D structural model. The immature MKs were cultured and transfected with cDNAs constructed from structural models of the individual SC-TP-Gαq and SC-TP-Gαs, respectively. After transient expression was identified, the immature MKs stably expressing SC-TP-Gαq or SC-TP-Gαs (stable cell lines) were selected. The stable cell lines were induced into mature MKs which released PLPs. Western blot analysis confirmed that the released PLPs were carrying the recombinant SC-TP-Gαq or SC-TP-Gαs. Flow cytometry analysis showed that the PLPs carrying SC-TP-Gαq were able to perform the activity by promoting platelet aggregation. In contrast, PLPs carrying SC-TP-Gαs reversed Gq to Gs signaling to inhibit platelet aggregation. This is the first time demonstrating that SC-TP-Gαq and SC-TP-Gαs were successfully overexpressed in MK cells and released as PLPs with proper folding and programmed biological activities. This bio-engineering led to the formation of two sets of biologically active PLP forms mediating calcium and cAMP signaling, respectively. As a result, these PLPs are able to bind to identical endogenous TXA2 with opposite activities, inhibiting and promoting platelet aggregation as reprogrammed for therapeutic process. Results also demonstrated that the nucleus-free PLPs could be used to deliver recombinant membrane-bound GPCRs to regulate cellular activity in general. [ABSTRACT FROM AUTHOR]

Taking the Member 1 oil reservoir of Dongying Formation in Nanpu Sag as an example, this article puts forward an integrated study method for oil reservoir description and evaluation. First, with the correlation of seismic, log, and geological data, the isochronous stratigraphic framework of the oil reservoir is built up, sequence boundaries are interpreted, the sequence constrained prestack seismic inversion is processed, and a geological conceptual model of reservoir is established. Second, with the results of prestack seismic inversion and the Petrel software, the structure model of the isochronous stratigraphic framework and the quantitative geological database are built up. Third, through contrasting and selecting the most reasonable method of stochastic modeling, the reservoir facies modeling and the petrophysical modeling with the constraint of facies models are processed, the oil geological reserves are computed and evaluated, and some oil reservoirs are described finely. The study shows that the Member 1 oil reservoir is a layered, structure-controlled, edge water drive reservoir. It has thick sands, good properties, and complicated oil–water systems. The geological reserves estimated by the nine designed implementation models are the realization of Monte Carlo methods and conform to a certain probability distribution. The models are favorable for the reasonable evaluation of reserves. Key words: Nanpu No. 1 structure, Dongying Member 1 oil reservoir, integrated oil-reservoir description and evaluation, stochastic modeling under determinable constraints

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants and children worldwide. We wished to determine whether intratracheal administration of [beta]-agonists improved alveolar fluid clearance (AFC) across the distal respiratory epithelium of RSV-infected mice. Following intranasal infection with RSV strain A2, AFC was measured in anesthetized, ventilated BALB/c mice by instillation of 5% BSA into the dependent lung. We found that direct activation of protein kinase A by forskolin or 8-bromo-cAMP increased AFC at day 2 after infection with RSV. In contrast, short- and long-acting [beta]-agonists had no effect at either day 2 or day 4. Insensitivity to [beta]-agonists was not a result of elevated plasma catecholamines or lung epithelial cell [beta]-adrenergic receptor degradation. Instead, RSV-infected mice had significantly higher levels of phosphorylated PKC[zeta] in the membrane fractions of their lung epithelial cells. In addition, insensitivity to [beta]-agonists was mediated in a paracrine fashion by KC (the murine homolog of CXCL8) and reversed by inhibition of either PKC[zeta] or G protein-coupled receptor kinase 2 (GRK2). These results indicate that insufficient response to [beta]-agonists in RSV may be caused, at least in part, by impaired [beta]-adrenergic receptor signaling, as a consequence of GRK2-mediated uncoupling of [beta]-adrenergic receptors from adenylyl cyclase. paramyxovirus; protein kinase C; G protein-coupled receptor kinase 2; CXCL8