Osmolality of Excipients for Parenteral Formulation Measured by Freezing Point Depression and Vapor Pressure - A Comparative Analysis.

PURPOSE: To investigate the difference in methods to determine the osmolality in solutions of stabilizers used for long-acting injectable suspensions. METHODS: The osmolality was measured by freezing point depression and vapor pressure for 11 different polymers and surfactants (PEG 3350, 4000, 6000, 8000, 20,000, PVP K12, K17 and K30, poloxamer 188, 388 and 407, HPMC E5, Na-CMC, polysorbate 20 and 80, vitamin E-TPGS, phospholipid, DOSS and SDS) in different concentrations. RESULTS: Independently of the measuring method, an increase in osmolality with increasing concentration was observed for all polymers and surfactants, as would be expected due to the physicochemical origin of the osmolality. No correlation was found between the molecular weight of the polymers and the measured osmolality. The osmolality values were different for PVPs, PEGs, and Na-CMC using the two different measurement methods. The values obtained by the freezing point depression method tended to be similar or higher than the ones provided by vapor pressure, overall showing a significant difference in the osmolality measured by the two investigated methods. CONCLUSIONS: For lower osmolality values (e.g. surfactants), the choice of the measuring method was not critical, both the freezing point depression and vapor pressure could be used. However, when the formulations contained higher concentrations of excipients and/or thermosensitive excipients, the data suggests that the vapor pressure method would be more suited.

Whole-brain metabolic pattern analysis in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.

BACKGROUND AND PURPOSE: Faciobrachial dystonic seizures (FBDS) and hyponatremia are the distinct clinical features of autoimmune encephalitis (AE) caused by antibodies against leucine-rich glioma-inactivated 1 (LGI1). The present study aims to explore the pathophysiological patterns and neural mechanisms underlying these symptoms. METHODS: We included 30 patients with anti-LGI1 AE and 30 controls from a retrospective observational cohort. Whole-brain metabolic pattern analysis was performed to assess the pathological network of anti-LGI1 AE, as well as the symptom networks associated with FBDS. Logistic regression was applied to explore independent predictors of FBDS. Finally, we used a multiple regression model to investigate the hyponatremia-associated brain network and its effect on serum sodium levels. RESULTS: The pathological network of anti-LGI1 AE involved hypermetabolism in the cerebellum, subcortical structures and Rolandic area, as well as hypometabolism in the medial prefrontal cortex. The symptom network of FBDS included hypometabolism in the cerebellum and Rolandic area (pFDR <0.05). Hypometabolism in the cerebellum was an independent predictor of FBDS (p < 0.001). Hyponatremia-associated network highlighted a negative effect on the caudate nucleus, frontal and temporal white matter. The metabolism of the hypothalamus was negatively associated with (Pearson's R = -0.180, p = 0.342), while not the independent predictor for serum sodium level (path c' = -7.238, 95% confidence interval = -30.947 to 16.472). CONCLUSIONS: Our results provide insights into the whole-brain metabolic patterns of patients with anti-LGI1 AE, including the symptom network associated with FBDS and the hyponatremia-associated brain network. The findings help us to understand the neural mechanisms underlying anti-LGI1 AE and to evaluate the progress of this disease.

MYB Transcription Factors Becoming Mainstream in Plant Roots.

The function of the root system is crucial for plant survival, such as anchoring plants, absorbing nutrients and water from the soil, and adapting to stress. MYB transcription factors constitute one of the largest transcription factor families in plant genomes with structural and functional diversifications. Members of this superfamily in plant development and cell differentiation, specialized metabolism, and biotic and abiotic stress processes are widely recognized, but their roles in plant roots are still not well characterized. Recent advances in functional studies remind us that MYB genes may have potentially key roles in roots. In this review, the current knowledge about the functions of MYB genes in roots was summarized, including promoting cell differentiation, regulating cell division through cell cycle, response to biotic and abiotic stresses (e.g., drought, salt stress, nutrient stress, light, gravity, and fungi), and mediate phytohormone signals. MYB genes from the same subfamily tend to regulate similar biological processes in roots in redundant but precise ways. Given their increasing known functions and wide expression profiles in roots, MYB genes are proposed as key components of the gene regulatory networks associated with distinct biological processes in roots. Further functional studies of MYB genes will provide an important basis for root regulatory mechanisms, enabling a more inclusive green revolution and sustainable agriculture to face the constant changes in climate and environmental conditions.

Lentinan protects against pancreatic ß-cell failure in chronic ethanol consumption-induced diabetic mice via enhancing ß-cell antioxidant capacity.

Chronic ethanol consumption is a well-established independent risk factor for type 2 diabetes mellitus (T2DM). Recently, increasing studies have confirmed that excessive heavy ethanol exerts direct harmful effect on pancreatic ß-cell mass and function, which may be a mechanism of pancreatic ß-cell failure in T2DM. In this study, we evaluated the effect of Lentinan (LNT), an active ingredient purified from the bodies of Lentinus edodes, on pancreatic ß-cell apoptosis and dysfunction caused by ethanol and the possible mechanisms implicated. Functional studies reveal that LNT attenuates chronic ethanol consumption-induced impaired glucose metabolism in vivo. In addition, LNT ameliorates chronic ethanol consumption-induced ß-cell dysfunction, which is characterized by reduced insulin synthesis, defected insulin secretion and increased cell apoptosis. Furthermore, mechanistic assays suggest that LNT enhances ß-cell antioxidant capacity and ameliorates ethanol-induced oxidative stress by activating Nrf-2 antioxidant pathway. Our results demonstrated that LNT prevents ethanol-induced pancreatic ß-cell dysfunction and apoptosis, and therefore may be a potential pharmacological agent for preventing pancreatic ß-cell failure associated with T2DM and stress-induced diabetes.

MICT ameliorates hypertensive nephropathy by inhibiting TLR4/NF-κB pathway and down-regulating NLRC4 inflammasome.

BACKGROUND: Hypertensive nephropathy (HN) is one of the main causes of end-stage renal disease (ESRD), leading to serious morbidity and mortality in hypertensive patients. However, existing treatment for hypertensive nephropathy are still very limited. It has been demonstrated that aerobic exercise has beneficial effects on the treatment of hypertension. However, the underlying mechanisms of exercise in HN remain unclear. METHODS: The spontaneously hypertensive rats (SHR) were trained for 8 weeks on a treadmill with different exercise prescriptions. We detected the effects of moderate intensity continuous training (MICT) and high intensity interval training (HIIT) on inflammatory response, renal function, and renal fibrosis in SHR. We further investigated the relationship between TLR4 and the NLRC4 inflammasome in vitro HN model. RESULTS: MICT improved renal fibrosis and renal injury, attenuating the inflammatory response by inhibiting TLR4/NF-κB pathway and the activation of NLRC4 inflammasome. However, these changes were not observed in the HIIT group. Additionally, repression of TLR4/NF-κB pathway by TAK-242 inhibited activation of NLRC4 inflammasome and alleviated the fibrosis in Ang II-induced HK-2 cells. CONCLUSION: MICT ameliorated renal damage, inflammatory response, and renal fibrosis via repressing TLR4/NF-κB pathway and the activation of NLRC4 inflammasome. This study might provide new references for exercise prescriptions of hypertension.

Significant correlations between heavy metals and prokaryotes in the Okinawa Trough hydrothermal sediments.

Prokaryotes play crucial roles in hydrothermal vent ecosystems, yet their interactions with heavy metals are not well understood. This study explored the diversity of prokaryotic communities and their correlations with heavy metals and nutrient elements in hydrothermal sediments from Okinawa Trough. A total of 117 bacterial genera in 26 bacterial phyla and 10 archaeal classes in 3 archaeal phyla were identified, including dominant prokaryotic phyla Planctomycetes, Acidobacteria, Verrucomicrobia, and Euryarchaeota. Furthermore, Fe (39.61 mg/g), Mn (2.84 mg/g) and Ba (0.36 mg/g) were found to be the most abundant heavy metals in the Okinawa hydrothermal sediments. Notably, the concentrations of Zn, Ba, Mn, total organic carbon, and total nitrogen significantly increased, whereas the total sulfur concentration distinctively decreased at sampling sites farther from hydrothermal vents. These changes corresponded with reductions in prokaryotic abundance and diversity. Most heavy metals, including Mn, Fe, Co, Cu and As, presented significant positive correlations with a number of prokaryotic genera in the nearby sediment samples. In contrast, both positive and negative correlations with prokaryotes were observed in remote sediment. The keystone taxa include Magnetospirillum, GOUTA19, Lysobacter, Kaistobacter, Treponema, and Clostridium were detected through prokaryote interspecies interactions. The functional predictions revealed significant genes involved in carbon fixation, nitrogen/sulfur cycling, heat shock protein, and metal resistance pathways. Structural equation modeling confirmed that metal and nutrient elements directly influence the composition of prokaryotic communities, which in turn affects the relative abundance of functional genes.

Biodiversity and antifouling activity of microbes associated with gorgonian corals Leptogorgia rigida and Menella kanisa from the South China Sea.

Recently, coral-associated microorganisms have attracted widespread attention, and most of these studies have focused on stony and soft corals. However, our knowledge of the diversity and bioactivity of microorganisms in gorgonian corals is still limited. In this study, the biodiversity of microbes in two gorgonian corals (Leptogorgia rigida and Menella kanisa) from the South China Sea was investigated by combining traditional culture method with molecular biology technique (bacterial 16S or fungal internal transcribed spacer (ITS) rRNA gene sequences). A total of 216 bacterial and 98 fungal isolates were obtained using 4 different isolation media. These isolates were identified and belonged to 31 bacterial and 12 fungal species, suggesting an unexpectedly diverse microbial community harbored in the South China Sea gorgonian corals L. rigida and M. kanisa. Furthermore, 56% of the tested microbial isolates displayed various antifouling activities against four biofouling organisms (including two microfouling bacteria Micrococcus luteus and Shewanella onedensis, and two macrofouling organisms Bugula neritina and Balanus amphitrite). Among the microbial isolates with antifouling activity, Bacillus firmus SCAU-038 and Streptomyces parvulus SCAU-062 displayed moderate or strong antifouling activity against all tested biofouling organisms. This is the first study on the biodiversity and antifouling activity of microorganisms associated with gorgonians L. rigida and M. kanisa from the South China Sea. These results contribute to the further understanding of microorganisms associated with gorgonian corals and provide potential resources for new natural antifouling agents.

An Integrative Nomogram for Identifying Cognitive Impairment Using Seizure Type and Cerebral Small Vessel Disease Neuroimaging Markers in Patients with Late-Onset Epilepsy of Unknown Origin.

INTRODUCTION: Cognitive impairment (CI) is a common comorbidity in patients with late-onset epilepsy of unknown origin (LOEU). However, limited data are available on effective screening methods for CI at an early stage. We aimed to develop and internally validate a nomogram for identifying patients with LOEU at risk of CI and investigate the potential moderating effect of education on the relationship between periventricular white matter hyperintensities (PVHs) and cognitive function. METHODS: We retrospectively reviewed the clinical data of 61 patients aged ≥ 55 years diagnosed with LOEU. The main outcome was CI, reflected as an adjusted Montreal Cognition Assessment score of < 26 points. A nomogram based on a multivariable logistic regression model was constructed. Its discriminative ability, calibration, and clinical applicability were tested using calibration plots, the area under the curve (AUC), and decision curves. Internal model validation was conducted using the bootstrap method. The moderating effect of education on the relationship between PVH and cognitive function was examined using hierarchical linear regression. RESULTS: Forty-four of 61 (72.1%) patients had CI. A nomogram incorporating seizure type, total cerebral small vessel disease burden score, and PVH score was built to identify the risk factors for CI. The AUC of the model was 0.881 (95% confidence interval: 0.771-0.994) and 0.78 (95% confidence interval: 0.75-0.8) after internal validation. Higher educational levels blunted the negative impact of PVH on cognitive function. CONCLUSION: Our nomogram provides a convenient tool for identifying patients with LOEU who are at risk of CI. Moreover, our findings demonstrate the importance of education for these patients.

Biodiversity, Distribution and Functional Differences of Fungi in Four Species of Corals from the South China Sea, Elucidated by High-Throughput Sequencing Technology.

Recent studies have predominantly spotlighted bacterial diversity within coral microbiomes, leaving coral-associated fungi in the shadows of scientific inquiry. This study endeavors to fill this knowledge gap by delving into the biodiversity, distribution and functional differences of fungi associated with soft corals Cladiella krempfi and Sarcophyton tortuosum, gorgonian coral Dichotella gemmacea and stony coral Favia speciosa from the South China Sea. Leveraging high-throughput sequencing of fungal internal transcribed spacer-1 (ITS1) region of the rRNA gene, a total of 431 fungal amplicon sequence variants (ASVs) were identified in this study, which indicated that a large number of fungal communities were harbored in the South China Sea corals. Noteworthy among our findings is that 10 fungal genera are reported for the first time in corals, with Candolleomyces, Exophiala, Fomitopsis, Inaequalispora, Kneiffiella, Paraphaeosphaeria, and Yamadazyma belonging to the Ascomycota, and Cystobasidium, Psathyrella, and Solicoccozyma to the Basidiomycota. Moreover, significant differences (p < 0.05) of fungal communities were observed among the various coral species. In particular, the gorgonian coral D. gemmacea emerged as a veritable haven for fungal diversity, boasting 307 unique ASVs. Contrastingly, soft corals S. tortuosum and C. krempfi exhibited modest fungal diversity, with 36 and 21 unique ASVs, respectively, while the stony coral F. speciosa hosted a comparatively sparse fungal community, with merely 10 unique ASVs in total. These findings not only provide basic data on fungal diversity and function in the South China Sea corals, but also underscore the imperative of nuanced conservation and management strategies for coral reef ecosystems worldwide.

Aerobic exercise inhibits renal EMT by promoting irisin expression in SHR.

To determine the effect of aerobic exercise in different intensities on renal injury and epithelial-mesenchymal transformation (EMT) in the kidney of spontaneously hypertensive rats (SHR) and explore possible mechanisms, we subjected SHR to different levels of 14-week aerobic treadmill training. We tested the effects of aerobic exercise on irisin level, renal function, and EMT modulators in the kidney. We also treated angiotensin II-induced HK-2 cells with irisin and tested the changes in EMT levels. The data showed low and moderate aerobic exercise improved renal function and inhibited EMT through promoting irisin expression in SHR. However, high-intensity exercise training had no effect on renal injury and EMT in SHR but did significantly activate STAT3 phosphorylation in the kidney. These results clarify the mechanisms of exercise in improving hypertension-related renal injury and suggest that irisin might be a therapeutic target for patients with kidney injury.

A Privacy-Preserving Medical Data Sharing Scheme Based on Blockchain.

With the increasing penetration of the Internet of things (IoT) into people's lives, the limitations of traditional medical systems are emerging. First, the typical way of handling sensitive information can easily lead to privacy disclosure. Second, the medical system is relatively isolated. It is difficult for one medical system to share data with another, and the scope of users' activities is limited within the system boundary. To solve these two problems, we propose a new privacy-preserving medical data-sharing scheme by introducing the authorization mechanism and attribute-based encryption (ABE) based on blockchain, which breaks system boundaries and realizes data sharing among several medical institutions. ABE is used to realize scalable access control. In addition, doctors can share their knowledge to diagnose users by introducing many-to-many matching, which means that patients' health data can be represented by multiple keywords and doctors' expertise can be represented by multiple interests. We provide the correctness and security analysis of our scheme and implement a prototype tool on Ethereum. The experimental results show that our scheme solves the contradiction between the privacy preservation of medical data and the necessity of data sharing.

Multimodal imaging-based diagnostic approach for MRI-negative posterior cortex epilepsy.

Background: Posterior cortex epilepsy (PCE) primarily comprises seizures originating from the occipital, parietal, and/or posterior edge of the temporal lobe. Electroclinical dissociation and subtle imaging representation render the diagnosis of PCE challenging. Improved methods for accurately identifying patients with PCE are necessary. Objectives: To develop a novel voxel-based image postprocessing method for better visual identification of the neuroimaging abnormalities associated with PCE. Design: Multicenter, retrospective study. Methods: Clinical and imaging features of 165 patients with PCE were retrospectively reviewed and collected from five epilepsy centers. A total of 37 patients (32.4% female, 20.2 ± 8.9 years old) with magnetic resonance imaging (MRI)-negative PCE were finally included for analysis. Image postprocessing features were calculated over a neighborhood for each voxel in the multimodality data. The postprocessed maps comprised structural deformation, hyperintense signal, and hypometabolism. Five raters from three different centers were blinded to the clinical diagnosis and determined the neuroimaging abnormalities in the postprocessed maps. Results: The average accuracy of correct identification was 55.7% (range from 43.2 to 62.2%) and correct lateralization was 74.1% (range from 64.9 to 81.1%). The Cronbach's alpha was 0.766 for the correct identification and 0.683 for the correct lateralization with similar results of the interclass correlation coefficient, thus indicating reliable agreement between the raters. Conclusion: The image postprocessing method developed in this study can potentially improve the visual detection of MRI-negative PCE. The technique could lead to an increase in the number of patients with PCE who could benefit from the surgery.

Radiotherapy Enhancement for Human Pancreatic Carcinoma Using a Peptide-Gold Nanoparticle Hybrid.

Pancreatic ductal adenocarcinoma (PDAC) is radioresistant. Due to their strong X-ray absorption capacity, gold nanoparticles (AuNPs) have been used as radiosensitizers for cancer therapeutics. Herein, we describe a novel conjugate complex consisting of a peptide for targeting plectin-1 (PTP) specifically expressed on the PDAC cell membrane and AuNPs, termed AuNP-PTP, to be used for PDAC radiotherapy in vitro and in vivo. Previous studies revealed that compared with unmodified AuNPs, AuNP-PTP along with relevant low-energy X-ray irradiation of 6 MV at a dose of 2 Gy (RF) increased the targeting efficiency and induced apoptosis in treated PANC-1 cells and tumours. Importantly, extensive histopathological examination did not reveal evidence of acute or chronic injury in mice due to AuNPs or AuNP-PTP for up to six weeks despite the presence of X-ray exposure. The delicate AuNP-PTP hybrid provides a novel strategy to enhance radiotherapy efficiency in PDAC treatment.