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Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between  ~ 10 and 100 nm accumulate in many solid tumors by the enhanced permeability and retention effect, but it is controversial whether the effect can be exploited for treatment of brain tumors. PLX038A is a long-acting prodrug of the topoisomerase 1 inhibitor SN-38. It is composed of a 15 nm 4-arm 40 kDa PEG tethered to four SN-38 moieties by linkers that slowly cleave to release the SN-38. The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the life span of mice harboring them. We addressed the important issue of whether the prodrug releases SN-38 systemically and then penetrates the brain to exert anti-tumor effects, or whether it directly penetrates the blood-tumor-brain-barrier and releases the SN-38 cargo within the tumor. We argue that the amount of SN-38 formed systemically is insufficient to inhibit the tumors, and show by PET imaging that a close surrogate of the 40 kDa PEG carrier in PLX038A accumulates and is retained in the GBM. We conclude that the prodrug penetrates the blood-tumor-brain-barrier, accumulates in the tumor microenvironment and releases its SN-38 cargo from within. Based on our results, we pose the provocative question as to whether the 40 kDa nanomolecule PEG carrier might serve as a Trojan horse to carry other drugs past the blood-tumor-brain-barrier and release them into brain tumors.

PRKAG2 is required for the maintenance of cellular energy balance. PRKAG2-AS1, a long non-coding RNA (lncRNA), was found within the promoter region of PRKAG2. Despite the extensive expression of PRKAG2-AS1 in endothelial cells, the precise function and mechanism of this gene in endothelial cells have yet to be elucidated. The localization of PRKAG2-AS1 was predominantly observed in the nucleus, as revealed using nuclear and cytoplasmic fractionation and fluorescence in situ hybridization. The manipulation of PRKAG2-AS1 by knockdown and overexpression within the nucleus significantly altered PRKAG2 expression in a cis-regulatory manner. The expression of PRKAG2-AS1 and its target genes, PRKAG2b and PRKAG2d, was down-regulated in endothelial cells subjected to oxLDL and Hcy-induced injury. This finding suggests that PRKAG2-AS1 may be involved in the mechanism behind endothelial injury. The suppression of PRKAG2-AS1 specifically in the nucleus led to an upregulation of inflammatory molecules such as cytokines, adhesion molecules, and chemokines in endothelial cells. Additionally, this nuclear suppression of PRKAG2-AS1 facilitated the adherence of THP1 cells to endothelial cells. We confirmed the role of nuclear knockdown PRKAG2-AS1 in the induction of apoptosis and inhibition of cell proliferation, migration, and lumen formation through flow cytometry, TUNEL test, CCK8 assay, and cell scratching. Finally, it was determined that PRKAG2-AS1 exerts direct control over the transcription of PRKAG2 by its binding to their promoters. In conclusion, downregulation of PRKAG2-AS1 suppressed the proliferation and migration, promoted inflammation and apoptosis of endothelial cells, and thus contributed to the development of atherosclerosis resulting from endothelial cell injury.

Abstract Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Cardiovascular surgery has a high risk of neurological complications, which can increase the burden of disease. Perioperative real⁃time monitoring of neurological function in cardiovascular surgery can assist clinicians to detect neurological abnormalities as early as possible, intervene and reduce the risk of neurological complications in time. The main monitoring indicators include cerebral oxygen saturation (ScO2), EEG, cerebral blood flow (CBF), etc. In this paper, the common perioperative neuromonitoring techniques and their research advances in cardiovascular surgery are reviewed to provide theoretical basis for reducing neurological complications and improve the prognosis of patients.

Abstract Objective To investigate the changes in amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) values before and after acupuncture in young women with non-menstrual migraine without aura (MWoA) through rest blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI). Methods Patients with non-menstrual MWoA (Group 1, n = 50) and healthy controls (Group 2, n = 50) were recruited. fMRI was performed in Group 1 at 2 time points: before acupuncture (time point 1, TP1); and after the end of all acupuncture sessions (time point 2, TP2), and performed in Group 2 as a one-time scan. Patients in Group 1 were assessed with the Migraine Disability Assessment Questionnaire (MIDAS) and the Short-Form McGill Pain Questionnaire (SF-MPQ) at TP1 and TP2 after fMRI was performed. The ALFF and DC values were compared within Group 1 at two time points and between Group 1 and Group2. The correlation between ALFF and DC values with the statistical differences and the clinical scales scores were analyzed. Results Brain activities increased in the left fusiform gyrus and right angular gyrus, left middle occipital gyrus, and bilateral prefrontal cortex and decreased in left inferior parietal lobule in Group 1, which had different ALFF values compared with Group 2 at TP1. The bilateral fusiform gyrus, bilateral inferior temporal gyrus and right middle temporal gyrus increased and right angular gyrus, right superior marginal gyrus, right inferior parietal lobule, right middle occipital gyrus, right superior frontal gyrus, right middle frontal gyrus, right anterior central gyrus, and right supplementary motor area decreased in activity in Group 1 had different DC values compared with Group 2 at TP1. ALFF and DC values of right inferior temporal gyrus, right fusiform gyrus and right middle temporal gyrus were decreased in Group1 at TP1 compared with TP2. ALFF values in the left middle occipital area were positively correlated with the pain degree at TP1 in Group1 (correlation coefficient r, r = 0.827, r = 0.343; P

Investigation of the joining technology of 3D-printed parts into a large physical model has become an important research topic. Rotary friction welding (RFW) is one of the friction welding methods. Understanding the weld interface temperature changes in the weld center zone during RFW is critical because it is related to the weld quality of the welded parts using RFW. Traditionally, the number of revolutions is constant in the RFW. However, rare investigations focus on the fatigue specimen fabricated by RFW with variable rotational speed. This study used RFW with varying rotational speeds to fabricate fatigue specimens. The ANSYS software was used to predict the temperature history of rotary frictionally welded dissimilar polymer rods fabricated by a computer numerical control (CNC) turning machine with variable rotational speed. The RFW experiment of ABS/PC dissimilar polymer rods was conducted to investigate the temperature history and compared with the simulation results. It was found that the temperature history profiles were in good agreement with the experimental and simulation results. Compared with the weld interface heating rate obtained from the experimental results, the simulation results has average discrepancy rate about 4.48 %. Compared with the maximum temperature of the weld interface obtained from the experimental results, the simulation results has average discrepancy rate about 3.16 %. The fatigue life can be increased by approximately 1.4 times. Finally, a database of rotary frictionally welded dissimilar polymer rods fabricated by a CNC turning machine with variable rotational speed was proposed. The average Shore A surface hardness at the weld interface was enhanced by approximately 18 % compared to the base ABS material.

Summary: The intestine is a highly metabolic tissue, but the metabolic programs that influence intestinal crypt proliferation, differentiation, and regeneration are still emerging. Here, we investigate how mitochondrial sirtuin 4 (SIRT4) affects intestinal homeostasis. Intestinal SIRT4 loss promotes cell proliferation in the intestine following ionizing radiation (IR). SIRT4 functions as a tumor suppressor in a mouse model of intestinal cancer, and SIRT4 loss drives dysregulated glutamine and nucleotide metabolism in intestinal adenomas. Intestinal organoids lacking SIRT4 display increased proliferation after IR stress, along with increased glutamine uptake and a shift toward de novo nucleotide biosynthesis over salvage pathways. Inhibition of de novo nucleotide biosynthesis diminishes the growth advantage of SIRT4-deficient organoids after IR stress. This work establishes SIRT4 as a modulator of intestinal metabolism and homeostasis in the setting of DNA-damaging stress.

AimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates tau fragments that may be toxic. Yet the relationship between aCasp-6, different forms of tr-tau and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer's disease (AD) and other tauopathies remains unclear.MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used five-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau and their co-occurrence in healthy controls, AD and primary tauopathies.ResultsCasp-6 activation was strongest in AD and Pick's disease (PiD) but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD and PiD lacked p-tau aggregates, a finding we confirmed using several p-tau antibodies.ConclusionsEarly modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p-tau antibodies. Therapeutic strategies against tr-tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD and PiD supports the development of biofluid biomarkers against tr-tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level.

Objective To investigate the diagnosis and treatment data of neonates with necrotizing enterocolitis (NEC) undergoing surgical treatment in our hospital, and to provide a reference for the selection of optimal surgical timing and approach in clinical practice. Methods A retrospective analysis was performed for the clinical data of 84 neonates with NEC who were admitted to our hospital from January 2015 to December 2020, and all neonates underwent plain abdominal radiography. During the surgery, enterostomy or resection of the necrotic intestinal canal followed by intestinal anastomosis was performed according to the location and extent of necrotic intestinal canal. The neonates were followed up to observe the changes in diet, defecation, and body weight, and their surgical outcome was summarized. Results Among the 84 neonates, 2 underwent intestinal decompression and peritoneal drainage; 72 underwent enterostomy, among whom 67 underwent ileostomy and 5 underwent distal jejunostomy; 7 underwent resection of the necrotic intestinal canal followed by intestinal anastomosis; 3 were withdrawn from treatment. Of all neonates, 77 had good prognosis; 2 had poor prognosis and required regular parenteral nutrition support due to short bowel syndrome; 2 died of necrotic enteritis at 6 months after surgery; 3 were withdrawn from treatment due to extensive bowel necrosis observed during surgery. Conclusion Neonates with NEC tend to have a high mortality rate, and enterostomy is the main treatment method at present. Timely surgical treatment has a good therapeutic effect on children with NEC.

AbstractThe present work examines the analytical solutions of the mathematical fractional Maxwell fluid model near an infinitely vertical plate. The phenomenon has been expressed in terms of partial differential equations, then transformed the governing equations in non-dimensional form. For the sake of better rheology of rate type fluid, developed a fractional model by applying the new definition of Constant Proportional Caputo (CPC) fractional derivative operator that describe the generalized memory effects. For seeking exact solutions in terms of Mittag-Leffler functions for velocity and temperature, Laplace integral transformation technique is applied. For physical significance of various system parameters on fluid velocity and temperature distributions are demonstrated through various graphs by using graphical software. Furthermore, for being validated the acquired solutions, some limiting models such as ordinary Newtonian model had been recovered from fractional model. It is also analyzed that for Newtonian heating and non-uniform velocity conditions, the CPC fractional operator is the finest fractional model to describe the memory effect of velocity and energy distribution. Moreover, the graphical representations of the analytical solutions illustrated the main results of the present work. Also, in the literature, it is observed that to derived analytical results from fractional fluid models developed by the various fractional operators, is difficult and this article contributing to answer the open problem of obtaining analytical solutions the fractionalized fluid models.

Abstract The role of PRKAG2 in the maintenance of heart function is well established, but little is known about how PRKAG2 is regulated in cardiomyocytes. In this study, we investigated the role of the lncRNA PRKAG2-AS, which is present at the PRKAG2 promoter, in the regulation of PRKAG2 expression. PRKAG2-AS expression was predominantly nuclear, as determined by RNA nucleoplasmic separation and fluorescence in situ hybridization. Knockdown of PRKAG2-AS in the nucleus, but not the cytoplasm, significantly decreased the expression of PRKAG2b and PRKAG2d. Interestingly, we found that PRKAG2-AS and its target genes, PRKAG2b and PRKAG2d, were reduced in the hearts of patients with ischemic cardiomyopathy, suggesting a potential role for PRKAG2-AS in myocardial ischemia. Indeed, knockdown of PRKAG2-AS in the nucleus resulted in apoptosis of cardiomyocytes. We further elucidated the mechanism by which PRKAG2-AS regulates PRKAG2 transcription by identifying 58 PRKAG2-AS interacting proteins. Among them, PPARG was selected for further investigation based on its correlation and potential interaction with PRKAG2-AS in regulating transcription. Overexpression of PPARG, or its activation with rosiglitazone, led to a significant increase in the expression of PRKAG2b and PRKAG2d in cardiomyocytes, which could be attenuated by PRKAG2-AS knockdown. This finding suggests that PRKAG2-AS mediates, at least partially, the protective effects of rosiglitazone on hypoxia-induced apoptosis. However, given the risk of rosiglitazone in heart failure, we also examined the involvement of PRKAG2-AS in this condition and found that PRKAG2-AS, as well as PRKAG2b and PRKAG2d, was elevated in hearts with dilated cardiomyopathy (DCM) and that overexpression of PRKAG2-AS led to a significant increase in PRKAG2b and PRKAG2d expression, indicating that up-regulation of PRKAG2-AS may contribute to the mechanism of heart failure by promoting transcription of PRKAG2. Consequently, proper expression of PRKAG2-AS is essential for maintaining cardiomyocyte function, and aberrant PRKAG2-AS expression induced by hypoxia or other stimuli may cause cardiac dysfunction.

The assessment of ecotourism suitability is crucial for sustainable regional development and is seen as an effective strategy to achieve both environmental protection and economic growth. One of the key challenges in land research is effectively identifying potential ecotourism resources while balancing regional protection and development. This study mapped the suitability of ecotourism in Zhangjiajie, China, using a combination of various geospatial data sources and four machine-learning techniques. Additionally, an indicator system was developed, covering the ecological environment, geological geomorphology, socioeconomics, and resource availability. The prediction results for suitability classified the area into four categories: highly suitable, moderately suitable, marginally suitable, and unsuitable; based on the ensemble results generated by the four algorithms, these categories accounted for 19.34%, 28.78%, 23.87%, and 28.01% of the total area, respectively. This study’s findings illustrate the spatial distribution of ecotourism suitability in Zhangjiajie, providing valuable insights for identifying potential ecotourism resources as well as informing regional planning and policy-making.

In practical applications, polyurethane (PU) foam must be rigid to meet the demands of various industries and provide comfort and protection in everyday life. PU foam components are extensively used in structural foam, thermal insulation, decorative panels, packaging, imitation wood, and floral foam, as well as in models and prototypes. Conventional technology for producing PU foam parts often leads to defects such as deformation, short shots, entrapped air, warpage, flash, micro-bubbles, weld lines, and voids. Therefore, the development of rigid PU foam parts has become a crucial research focus in the industry. This study proposes an innovative manufacturing process for producing rigid PU foam parts using silicone rubber molds (SRMs). The deformation of the silicone rubber mold can be predicted based on its wall thickness, following a trend equation with a correlation coefficient of 0.9951. The volume of the PU foam part can also be predicted by the weight of the PU foaming agent, as indicated by a trend equation with a correlation coefficient of 0.9824. The optimal weight ratio of the foaming agent to water, yielding the highest surface hardness, was found to be 5:1. The surface hardness of the PU foam part can also be predicted based on the weight of the water used, according to a proposed prediction equation with a correlation coefficient of 0.7517. The average surface hardness of the fabricated PU foam part has a Shore O hardness value of approximately 75. Foam parts made with 1.5 g of water added to 15 g of a foaming agent have the fewest internal pores, resulting in the densest interior. PU foam parts exhibit excellent mechanical properties when 3 g of water is added to the PU foaming agent, as evidenced by their surface hardness and compressive strength. Using rigid PU foam parts as a backing material in the proposed method can reduce rapid tool production costs by about 62%. Finally, an innovative manufacturing process for creating large SRMs using rigid PU foam parts as backing material is demonstrated.