Aberrant oligodendroglial-vascular interactions disrupt the blood-brain barrier, triggering CNS inflammation.

Disruption of the blood-brain barrier (BBB) is critical to initiation and perpetuation of disease in multiple sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration. Perivascular OPCs can themselves disrupt the BBB, interfering with astrocyte endfeet and endothelial tight junction integrity, resulting in altered vascular permeability and an associated CNS inflammation. Aberrant Wnt tone in OPCs mediates their dysfunctional vascular detachment and also leads to OPC secretion of Wif1, which interferes with Wnt ligand function on endothelial tight junction integrity. Evidence for this defective oligodendroglial-vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB

Adenosine Actions on Oligodendroglia and Myelination in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is the most commonly diagnosed neurodevelopmental disorder. Independent of neuronal dysfunction, ASD and its associated comorbidities have been linked to hypomyelination and oligodendroglial dysfunction. Additionally, the neuromodulator adenosine has been shown to affect certain ASD comorbidities and symptoms, such as epilepsy, impairment of cognitive function, and anxiety. Adenosine is both directly and indirectly responsible for regulating the development of oligodendroglia and myelination through its interaction with, and modulation of, several neurotransmitters, including glutamate, dopamine, and serotonin. In this review, we will focus on the recent discoveries in adenosine interaction with physiological and pathophysiological activities of oligodendroglia and myelination, as well as ASD-related aspects of adenosine actions on neuroprotection and neuroinflammation. Moreover, we will discuss the potential therapeutic value and clinical approaches of adenosine manipulation against hypomyelination in ASD

Feeding Postures and Substrate Use of François’ Langurs (<i>Trachypithecus francoisi</i>) in the Limestone Forest of Southwest China

The feeding posture of a group of François’ langurs in Fusui County, Guangxi, was studied using instantaneous scan sampling from January to December 2016 to explore how the species adapts to karst limestone forests by collecting data on feeding posture, forest strata height, and substrate use. The results showed that leaves were the main food type of the François’ langurs, with young leaves accounting for 64.97% ± 19.08% of the food composition, mature leaves accounting for 11.88% ± 12.09%, fruits accounting for 12.96% ± 12.89%, flowers accounting for 4.16% ± 4.06%, and other food types, including stems, petioles, and other unknown parts of the tree, accounting for a total of 6.03% ± 9.09%. The François’ langurs had four main postures during feeding, of which sitting and bipedal standing feeding accounted for the largest proportions, at 85.99% ± 5.97% and 12.33% ± 6.08% of the total records, respectively. Quadrupedal standing and suspending were rarely observed and only appeared occasionally during feeding activities at the peak resting period, the two postures together accounting for 1.39% ± 1.59% of the total records. The feeding postures of the langurs had marked seasonal variation, as evidenced by the fact that seated feeding accounted for a significantly higher proportion of the total behavioral records in the rainy season than in the dry season, whereas feeding while standing bipedally was significantly more frequent during the dry season. Correlation analyses showed that feeding posture was correlated with food composition, showing a positive correlation between the proportion of bipedal standing feeding and mature leaf consumption. François’ langurs preferred to forage in the lower and middle forest layers, with the lower forest layer accounting for 55.93% ± 16.50% of the total number of recordings and the middle forest layer accounting for 33.63% ± 18.33%. Langurs were less likely to forage on the ground (rocks), accounting for only 6.79% ± 4.78% of the records. The frequency of langurs feeding in the upper part of the forest layer was the lowest at 3.65% ± 2.73%. Additionally, in the dry season, langurs utilized the lower forest layer more but used the middle forest layer less than in the rainy season. This study demonstrates that the spatial distribution of foods in the limestone forest has an important effect on the feeding posture of François’ langurs and their forest layer utilization

Factors Controlling Shale Reservoirs and Development Potential Evaluation: A Case Study

The shale of the Lower Silurian Longmaxi Formation is an important gas-producing layer for shale gas development in southern China. This set of shale reservoir characteristics and shale gas development potential provide an important foundation for shale gas development. This study takes wellblock XN111 in the Sichuan Basin, China, as an example and uses X-ray diffraction (XRD), scanning electron microscopy (SEM), isothermal adsorption, and other techniques to analyze the shale reservoir characteristics of the Lower Silurian Longmaxi Formation. The results show that the Lower Silurian Longmaxi Formation was deposited in a deep-water shelf environment. During this period, carbonaceous shale and siliceous shale characterized by a high brittle mineral content (quartz>40 wt.%, carbonate mineral>10 wt.%) and a low clay mineral content (<30 wt.%, mainly illite) were widely deposited throughout the region. The total organic carbon (TOC) content reaches up to 6.07 wt.%, with an average of 2.66 wt.%. The vitrinite reflectance is 1.6–2.28%, with an average of 2.05%. The methane adsorption capacity is 0.84–4.69 m3/t, with an average of 2.92 m3/t. Pores and fractures are developed in the shale reservoirs. The main reservoir space is composed of connected mesopores with an average porosity of 4.78%. The characteristics and development potential of the shale reservoirs in the Lower Silurian Longmaxi Formation are controlled by the following factors: (1) the widespread deep-water shelf deposition in wellblock XN111 was a favorable environment for the development of high-quality shale reservoirs with a cumulative thickness of up to 50 m; (2) the high TOC content enabled the shale reservoir to have a high free gas content and a high adsorptive gas storage capacity; and (3) the shale’s high maturity or over maturity is conducive to the development of pores and fractures in the organic matter, which effectively improves the storage capacity of the shale reservoirs. The reservoir characteristic index was constructed using the high-quality shale’s thickness, gas content, TOC, fracture density, and clay content. Using production data from shale gas wells in adjacent blocks, a mathematical relationship was established between the Estimated Ultimate Recovery (EUR) of a single well and the Reservoir Characteristics Index (Rci). The EUR of a single well in wellblock XN111 was estimated

Day-Ahead Forecasting of Hourly Photovoltaic Power Based on Robust Multilayer Perception

Photovoltaic (PV) modules convert renewable and sustainable solar energy into electricity. However, the uncertainty of PV power production brings challenges for the grid operation. To facilitate the management and scheduling of PV power plants, forecasting is an essential technique. In this paper, a robust multilayer perception (MLP) neural network was developed for day-ahead forecasting of hourly PV power. A generic MLP is usually trained by minimizing the mean squared loss. The mean squared error is sensitive to a few particularly large errors that can lead to a poor estimator. To tackle the problem, the pseudo-Huber loss function, which combines the best properties of squared loss and absolute loss, was adopted in this paper. The effectiveness and efficiency of the proposed method was verified by benchmarking against a generic MLP network with real PV data. Numerical experiments illustrated that the proposed method performed better than the generic MLP network in terms of root mean squared error (RMSE) and mean absolute error (MAE)

Aberrant oligodendroglial-vascular interactions disrupt the blood-brain barrier, triggering CNS inflammation.

Disruption of the blood-brain barrier (BBB) is critical to initiation and perpetuation of disease in multiple sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration. Perivascular OPCs can themselves disrupt the BBB, interfering with astrocyte endfeet and endothelial tight junction integrity, resulting in altered vascular permeability and an associated CNS inflammation. Aberrant Wnt tone in OPCs mediates their dysfunctional vascular detachment and also leads to OPC secretion of Wif1, which interferes with Wnt ligand function on endothelial tight junction integrity. Evidence for this defective oligodendroglial-vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB

Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human ALK mutant neuroblastoma cell lines and xenograft models

The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end, we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective treatment for TP53 wild-type neuroblastoma with ALK aberrations

Antitarget selectivity and tolerability of novel pyrrolo[2,3-d]pyrimidine RET inhibitors

The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively

Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma

RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-a]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (1), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse in vivo studies, compound 1 demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of 1, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold