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Abstract Meningiomas are among the most common primary tumors of the central nervous system. In the past several decades, many researchers have emphasized the importance of radiographic findings and their possible role in predicting the various aspects of the meningioma biology. One of the factors most commonly analyzed with respect to the lesions’ clinical behavior is peritumoral brain edema (PTBE), not only one of the most common signs associated with meningiomas, but also a significant clinical problem. Radiographic predictors of PTBE are usually noted as being the size of the tumor, its location, irregular margins, heterogeneity, and the peritumoral arachnoid plane with its pial vascular recruitment. Here, we review the available literature on the topic of these radiographic predictors of PTBE formation, we analyze the methodology of the research conducted, and we highlight the many controversies still present. Indeed, the evidence about PTBE pathogenesis, predictive factors, and clinical significance still seems to be mostly inconclusive, despite intense research in the area. We believe that by highlighting the many inconsistencies in the methodology used, we can showcase how little is actually known about the pathogenesis of PTBE, which in turn has important clinical implications. Additionally, we provide several MR images of intracranial meningiomas from our own practice which, we believe, showcase the unpredictable nature of PTBE, and demonstrate vividly the topics we discuss.

The aim of the study was to evaluate the antimicrobial activity of the extracted plants basil (Ocimum basilicum L.), sage (Salvia officinalis L.), lavender (Lavandula officinalis L.), immortelle (Helichrysum italicum (Roth) G. Don), savory (Satureja montana L.), and rosemary (Salvia rosmarinus Spenn.) against foodborne and clinical pathogens. Dried plants were used in the production of Dalmatian cow’s milk hard cheese at concentrations of 0.5, 1.0, 1.5, and 2% to evaluate the microbiological safety and sensory properties of novel cheeses. The broadest antimicrobial activity was found in rosemary and sage, inhibiting ten indicator pathogens, and the strongest antimicrobial activity was found in immortelle and sage, which showed the widest zones of inhibition. The most sensitive indicators were Staphylococcus species and Yersinia enterocolitica. The supplemented cheeses met the official microbiological criteria and were mycotoxin negative. The surface mycobiota of control and experimental cheeses consisted mainly of Penicillium sollitum, based on the sequence analysis of the beta-tubulin and calmodulin genes. The antifungal effect of the added plants was clearly demonstrated in cheeses with added basil and sage (p < 0.05).

Abstract Disorders of consciousness (DoC), namely unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), represent severe conditions with significant consequences for patients and their families. Several studies have reported the regaining of consciousness in such patients using deep brain stimulation (DBS) of subcortical structures or brainstem nuclei. Our study aims to present the 10 years’ experience of a single center using DBS as a therapy on a cohort of patients with DoC. Eighty Three consecutive patients were evaluated between 2011 and 2022; entry criteria consisted of neurophysiological and neurological evaluations and neuroimaging examinations. Out of 83, 36 patients were considered candidates for DBS implantation, and 32 patients were implanted: 27 patients had UWS, and five had MCS. The stimulation target was the centromedian-parafascicular complex in the left hemisphere in hypoxic brain lesion or the one better preserved in patients with traumatic brain injury. The level of consciousness was improved in seven patients. Three out of five MCS patients emerged to full awareness, with the ability to interact and communicate. Two of them can live largely independently. Four out of 27 UWS patients showed consciousness improvement with two patients emerging to full awareness, and the other two reaching MCS. In patients with DoC lasting longer than 12 months following traumatic brain injury or 6 months following anoxic-ischemic brain lesion, spontaneous recovery is rare. Thus, DBS of certain thalamic nuclei could be recommended as a treatment option for patients who meet neurological, neurophysiological and neuroimaging criteria, especially in earlier phases, before occurrence of irreversible musculoskeletal changes. Furthermore, we emphasize the importance of cooperation between centers worldwide in studies on the potentials of DBS in treating patients with DoC.

Background: Significant improvement in neonatal care has enabled increasing survival of preterm infants. Metabolic bone disease of prematurity is often overlooked due to other comorbidities of preterm birth. The best approach is screening and prevention of the disease in high-risk infants such as preterm infants. Aim: We followed up the clinical, radiological, and serum biochemical markers of metabolic bone disease in extremely preterm infants (

Protein arginine N-methyltransferase 5 (PRMT5) has been identified as a potential therapeutic target for various cancer types. However, its role in regulating the hepatocellular carcinoma (HCC) transcriptome remains poorly understood. In this study, publicly available databases were employed to investigate PRMT5 expression, its correlation with overall survival, targeted pathways, and genes of interest in HCC. Additionally, we utilized in-house generated NGS data to explore PRMT5 expression in dysplastic nodules compared to hepatocellular carcinoma. Our findings revealed that PRMT5 is significantly overexpressed in HCC compared to normal liver, and elevated expression correlates with poor overall survival. To gain insights into the mechanism driving PRMT5 overexpression in HCC, we analyzed promoter CpG islands and methylation status in HCC compared to normal tissues. Pathway analysis of PRMT5 knockdown in the HCC cells revealed a connection between PRMT5 expression and genes related to the HIF1α pathway. Additionally, by filtering PRMT5-correlated genes within the HIF1α pathway and selecting up/downregulated genes in HCC patients, we identified Ras-related nuclear protein (RAN) as a target associated with overall survival. For the first time, we report that PRMT5 is implicated in the regulation of HIF1A and RAN genes, suggesting the potential prognostic utility of PRMT5 in HCC.

In this perspective article, we highlight the possible applicability of genetic testing in Parkinson’s disease and dystonia patients treated with deep brain stimulation (DBS). DBS, a neuromodulatory technique employing electrical stimulation, has historically targeted motor symptoms in advanced PD and dystonia, yet its precise mechanisms remain elusive. Genetic insights have emerged as potential determinants of DBS efficacy. Known PD genes such as GBA, SNCA, LRRK2, and PRKN are most studied, even though further studies are required to make firm conclusions. Variable outcomes depending on genotype is present in genetic dystonia, as DYT-TOR1A, NBIA/DYTPANK2, DYT-SCGE and X-linked dystonia-parkinsonism have demonstrated promising outcomes following GPi-DBS, while varying outcomes have been documented in DYT-THAP1. We present two clinical vignettes that illustrate the applicability of genetics in clinical practice, with one PD patient with compound GBA mutations and one GNAL dystonia patient. Integrating genetic testing into clinical practice is pivotal, particularly with advancements in next-generation sequencing. However, there is a clear need for further research, especially in rarer monogenic forms. Our perspective is that applying genetics in PD and dystonia is possible today, and despite challenges, it has the potential to refine patient selection and enhance treatment outcomes.

IntroductionDisorders of consciousness (DOC) has been an object of numbers of research regarding the diagnosis, treatment and prognosis in last few decades. We believe that the DOC could be considered as a disconnection syndrome, although the exact mechanisms are not entirely understood. Moreover, different conceptual frameworks highly influence results interpretation. The aim of this systematic review is to assess the current knowledge regarding neurophysiological mechanisms of DOC and to establish possible influence on future clinical implications and usage.MethodsWe have conducted a systematic review according to PRISMA guidelines through PubMed and Cochrane databases, with studies being selected for inclusion via a set inclusion and exclusion criteria.ResultsEighty-nine studies were included in this systematic review according to the selected criteria. This includes case studies, randomized controlled trials, controlled clinical trials, and observational studies with no control arms. The total number of DOC patients encompassed in the studies cited in this review is 1,533.ConclusionConnectomics and network neuroscience offer quantitative frameworks for analysing dynamic brain connectivity. Functional MRI studies show evidence of abnormal connectivity patterns and whole-brain topological reorganization, primarily affecting sensory-related resting state networks (RSNs), confirmed by EEG studies. As previously described, DOC patients are identified by diminished global information processing, i.e., network integration and increased local information processing, i.e., network segregation. Further studies using effective connectivity measurement tools instead of functional connectivity as well as the standardization of the study process are needed.

IntroductionDystonia is the third most common pediatric movement disorder and is often difficult to treat. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been demonstrated as a safe and effective treatment for genetic dystonia in adolescents and adults. The results of DBS in children are limited to individual cases or case series, although it has been proven to be an effective procedure in carefully selected pediatric cohorts. The aim of our study was to present the treatment outcome for 7- to 9-year-old pediatric patients with disabling monogenic isolated generalized DYT-THAP1 and DYT-KMT2B dystonia after bilateral GPi-DBS.Patients and resultsWe present three boys aged 25% improvement over the first 15 months. However, there was a decline in speech and upper limb function, manifesting with bradylalia, bradykinesia, and dysphonia, which decreased after treatment with trihexyphenidyl.ConclusionAlthough reports of patients with monogenic dystonia, particularly DYT-THAP1, treated with DBS are still scarce, DBS should be considered as an efficient treatment approach in children with pharmacoresistent dystonia, especially with generalized monogenic dystonia and to prevent severe and disabling symptoms that reduce the quality of life, including emotional and social aspects. Patients require an individual approach and parents should be properly informed about expectations and possible outcomes, including relapses and impairments, in addition to DBS responsiveness and related improvements. Furthermore, early genetic diagnosis and the provision of appropriate treatments, including DBS, are mandatory for preventing severe neurologic impairments.

Induction of neoangiogenesis is a hallmark feature during disease progression of hepatocellular carcinoma (HCC). Antiangiogenetic compounds represent a mainstay of therapeutic approaches; however, development of chemoresistance is observed in the majority of patients. Recent findings suggest that tumor‐initiating cells (TICs) may play a key role in acquisition of resistance, but the exact relevance for HCC in this process remains to be defined. Primary and established hepatoma cell lines were exposed to long‐term sorafenib treatment to model acquisition of resistance. Treatment effects on TICs were estimated by sphere‐forming capacity in vitro, tumorigenicity in vivo, and flow cytometry. Adaptive molecular changes were assessed by whole transcriptome analyses. Compensatory mechanisms of resistance were identified and directly evaluated. Sustained antiproliferative effect following sorafenib treatment was observed in three of six HCC cell lines and was followed by rapid regrowth, thereby mimicking responses observed in patients. Resistant cells showed induction in sphere forming in vitro and tumor‐initiating capacity in vivo as well as increased number of side population and epithelial cell adhesion molecule‐positive cells. Conversely, sensitive cell lines showed consistent reduction of TIC properties. Gene sets associated with resistance and poor prognosis, including Hippo/yes‐associated protein (YAP), were identified. Western blot and immunohistochemistry confirmed increased levels of YAP. Combined treatment of sorafenib and specific YAP inhibitor consistently revealed synergistic antioncogenic effects in resistant cell lines. Conclusion: Resistance to antiangiogenic therapy might be driven by transient expansion of TICs and activation of compensatory pro‐oncogenic signaling pathways, including YAP. Specific targeting of TICs might be an effective therapeutic strategy to overcome resistance in HCC.

Abstract Clock synchronization has always been a major challenge when designing wireless networks. This work focuses on tackling the time synchronization problem in 5G networks by adopting a hybrid Bayesian approach for clock offset and skew estimation. Furthermore, we provide an in-depth analysis of the impact of the proposed approach on a synchronization-sensitive service, i.e., localization. Specifically, we expose the substantial benefit of belief propagation (BP) running on factor graphs (FGs) in achieving precise network-wide synchronization. Moreover, we take advantage of Bayesian recursive filtering (BRF) to mitigate the time-stamping error in pairwise synchronization. Finally, we reveal the merit of hybrid synchronization by dividing a large-scale network into local synchronization domains and applying the most suitable synchronization algorithm (BP- or BRF-based) on each domain. The performance of the hybrid approach is then evaluated in terms of the root mean square errors (RMSEs) of the clock offset, clock skew, and the position estimation. According to the simulations, in spite of the simplifications in the hybrid approach, RMSEs of clock offset, clock skew, and position estimation remain below 10 ns, 1 ppm, and 1.5 m, respectively.

Abstract Disorders of consciousness (DOC) are one of the major consequences after anoxic or traumatic brain injury. So far, several studies have described the regaining of consciousness in DOC patients using deep brain stimulation (DBS). However, these studies often lack detailed data on the structural and functional cerebral changes after such treatment. The aim of this study was to conduct a volumetric analysis of specific cortical and subcortical structures to determine the impact of DBS after functional recovery of DOC patients. Five DOC patients underwent unilateral DBS electrode implantation into the centromedian parafascicular complex of the thalamic intralaminar nuclei. Consciousness recovery was confirmed using the Rappaport Disability Rating and the Coma/Near Coma scale. Brain MRI volumetric measurements were done prior to the procedure, then approximately a year after, and finally 7 years after the implementation of the electrode. The volumetric analysis included changes in regional cortical volumes and thickness, as well as in subcortical structures. Limbic cortices (parahippocampal and cingulate gyrus) and paralimbic cortices (insula) regions showed a significant volume increase and presented a trend of regional cortical thickness increase 1 and 7 years after DBS. The volumes of related subcortical structures, namely the caudate, the hippocampus as well as the amygdala, were significantly increased 1 and 7 years after DBS, while the putamen and nucleus accumbens presented with volume increase. Volume increase after DBS could be a result of direct DBS effects, or a result of functional recovery. Our findings are in accordance with the results of very few human studies connecting DBS and brain volume increase. Which mechanisms are behind the observed brain changes and whether structural changes are caused by consciousness recovery or DBS in patients with DOC is still a matter of debate.

The sphenoid bone development occurs in both prenatal and postnatal periods. Sphenoid bone openings are used as surgical landmarks and are of great importance for neurosurgeons in everyday practice. The aim of this study was to identify morphological characteristics, postnatal development and remodeling, as well as clinical aspect of the sphenoid bone openings and to investigate their relationship and difference in size. The macerated sphenoid bones analyzed in this study were scanned by micro-computed tomography. Areas and distance in-between foramen ovale and foramen rotundum were measured. In addition, different shapes of foramen ovale were described. The most common shape of foramen ovale on both sides was oval, followed by the round, almond and elongated shapes. Modest to strong positive correlations between all foramina and age for the whole sample and both subsamples were presented, except for the right foramen rotundum area in the male subsample, which did not show significant correlation with age. Our study revealed changes in postnatal development and anatomy of foramen ovale and foramen rotundum, primarily in the aspects of size and shape, and should contribute to reducing the risk of damage to neurovascular structures during surgical procedures.

There are different options for surgical treatment of brain abscess, mainly standard craniotomy and stereotactic aspiration. It has not yet been established which of these options is associated with a more favorable outcome under similar baseline conditions of patients. Demographic characteristics, microbiology, clinical presentation, and treatment outcome were analyzed for surgically treated adult patients with brain abscess over a 14-year period. A propensity score model was applied to account for baseline conditions that may determine the choice of neurosurgical method. The propensity score was included in the prediction of a favorable outcome, defined as a Glasgow Outcome Scale (GOS) score 4 or 5. We analyzed 91 adult surgically treated patients, of which 53 had standard craniotomy and 38 stereotactic aspiration of brain abscess. Focal neurological deficit was the most common symptom present in 60 (65.9%) patients on admission. Sixty-seven (73.6%) patients had GOS 4 or 5, and seven (7.7%) patients died. The choice of surgery did not influence the outcome (OR 1.181, 95% CI 0.349-3.995), neither did the time elapsed from diagnosis to surgery (OR 0.998, 95% CI 0.981-1.015). Propensity towards standard craniotomy procedure did not influence outcome in brain abscess patients (OR 1.181, 95% CI 0.349-3.995). Worse outcome (GOS below 4) was independently associated with Glasgow Coma Score (GCS) on admission (OR 0.787, CI 0.656-0.944). The choice of neurosurgical procedure did not influence the outcome in patients with brain abscess. Patients with brain abscess who had lower GCS on admission also had worse outcome.

A 20-year-old female with refractory perinatal postischemic catastrophic epilepsy and frequent daily generalized atonic, tonic, tonic-clonic and focal seizures was hospitalized in the progressive phase of illness. The diagnosis was confirmed by semiology, interictal electroencephalogram (EEG), long-term video EEG monitoring, and brain magnetic resonance imaging. Repeated interictal EEG findings showed generalized spike and slow wave complexes with a 2-3 Hz frequency. Interictal EEG showed evidence of electroclinical epileptic status on several occasions. She was treated with various antiepileptic drugs without improvement. After verification of her incompetence for normal autonomous living, which resulted in very low quality of life, this patient with refractory epilepsy underwent implantation of vagus nerve stimulator (VNS). In this case report, we present delayed effect of VNS on interictal epileptiform discharges and pharmacoresistance.

IntroductionParkinson’s disease (PD) patients have a significantly higher risk of developing dementia in later disease stages, leading to severe impairments in quality of life and self-functioning. Questions remain on how deep brain stimulation (DBS) affects cognition, and whether we can individualize therapy and reduce the risk for adverse cognitive effects. Our aim in this systematic review is to assess the current knowledge in the field and determine if the findings could influence clinical practice.MethodsWe have conducted a systematic review according to PRISMA guidelines through MEDLINE and Embase databases, with studies being selected for inclusion via a set inclusion and exclusion criteria.ResultsSixty-seven studies were included in this systematic review according to the selected criteria. This includes 6 meta-analyses, 18 randomized controlled trials, 17 controlled clinical trials, and 26 observational studies with no control arms. The total number of PD patients encompassed in the studies cited in this review is 3677, not including the meta-analyses.ConclusionCognitive function in PD patients can deteriorate, in most cases mildly, but still impactful to the quality of life. The strongest evidence is present for deterioration in verbal fluency, while inconclusive evidence is still present for executive function, memory, attention and processing speed. Global cognition does not appear to be significantly impacted by DBS, especially if cognitive screening is performed prior to the procedure, as lower baseline cognitive function is connected to poor outcomes. Further randomized controlled studies are required to increase the level of evidence, especially in the case of globus pallidus internus DBS, pedunculopontine nucleus DBS, and the ventral intermediate nucleus of thalamus DBS, and more long-term studies are required for all respective targets.

Increased sweetpotato utilization has become an important breeding objective recently, with much emphasis on the development of non-sweet sweetpotatoes for income and food security in Ghana. The objective of this study was to evaluate 26 elite non-sweet and less sweet sweetpotato genotypes with regard to their release as commercial varieties using mother–baby trial. The 26 sweetpotato genotypes were tested multilocational on-farm across five ecozones from 2016 to 2017. These genotypes were selected from accelerated breeding scheme carried out from 2010 to 2013. There were no year-by-ecozone-by-genotype and year-by-ecozone interactions. However, ecozone-by-genotype interaction was significant for storage root dry matter, beta-carotene, iron and zinc content. This implies that the relative performance of the genotypes for storage root yield was stable across locations and years. Genotypic differences were found for all the traits and indicated that selection of superior genotypes across ecozone was possible. Storage root yield ranged from 7 t/ha to 39 t/ha, while dry matter content ranged from 34% to 46%. The storage root cooking quality preference was comparable with farmers’ check. Ten superior genotypes were identified for release as commercial varieties based on their staple-preferred taste, higher storage root yield, higher dry matter content, earliness, resistance to the sweetpotato virus, sweetpotato weevil and Alcidodes.

The prognosis of pancreatic ductal adenocarcinoma (PDAC) is exceedingly poor. Although surgical resection is the only curative treatment option, multimodal treatment is of the utmost importance, as only about 20% of tumors are primarily resectable at the time of diagnosis. The choice of chemotherapeutic treatment regimens involving gemcitabine and FOLFIRINOX is currently solely based on the patient’s performance status, but, ideally, it should be based on the tumors’ individual biology. We established two novel patient-derived primary cell lines from surgical PDAC specimens. LuPanc-1 and LuPanc-2 were derived from a pT3, pN1, G2 and a pT3, pN2, G3 tumor, respectively, and the clinical follow-up was fully annotated. STR-genotyping revealed a unique profile for both cell lines. The population doubling time of LuPanc-2 was substantially longer than that of LuPanc-1 (84 vs. 44 h). Both cell lines exhibited a typical epithelial morphology and expressed moderate levels of CK7 and E-cadherin. LuPanc-1, but not LuPanc-2, co-expressed E-cadherin and vimentin at the single-cell level, suggesting a mixed epithelial-mesenchymal differentiation. LuPanc-1 had a missense mutation (p.R282W) and LuPanc-2 had a frameshift deletion (p.P89X) in TP53. BRCA2 was nonsense-mutated (p.Q780*) and CREBBP was missense-mutated (p.P279R) in LuPanc-1. CDKN2A was missense-mutated (p.H83Y) in LuPanc-2. Notably, only LuPanc-2 harbored a partial or complete deletion of DPC4. LuPanc-1 cells exhibited high basal and transforming growth factor (TGF)-β1-induced migratory activity in real-time cell migration assays, while LuPanc-2 was refractory. Both LuPanc-1 and LuPanc-2 cells responded to treatment with TGF-β1 with the activation of SMAD2; however, only LuPanc-1 cells were able to induce TGF-β1 target genes, which is consistent with the absence of DPC4 in LuPanc-2 cells. Both cell lines were able to form spheres in a semi-solid medium and in cell viability assays, LuPanc-1 cells were more sensitive than LuPanc-2 cells to treatment with gemcitabine and FOLFIRINOX. In summary, both patient-derived cell lines show distinct molecular phenotypes reflecting their individual tumor biology, with a unique clinical annotation of the respective patients. These preclinical ex vivo models can be further explored for potential new treatment strategies and might help in developing personalized (targeted) therapy regimens.

Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, and early (n = 5) and progressed (n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further employed for clonality analyses, indicating multiclonal origin in the majority of investigated HCCs. Alterations in DNA methylation progressively increased from liver cirrhosis (CL) to dysplastic lesions and reached a maximum in early HCCs. Associated early alterations identified by Ingenuity Pathway Analysis (IPA) involved apoptosis, immune regulation, and stemness pathways, while late changes centered on cell survival, proliferation, and invasion. We further validated 23 putative epidrivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated, and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines. Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for potentially novel therapeutic approaches.

Abstract Background Intracranial arachnoid cysts are collections of cerebrospinal fluid within the arachnoid membrane and subarachnoid space of the cisterns and major cerebral fissures that account for about 1% of all intracranial lesions. Expansion of the cyst and compression on surrounding structures may became symptomatic, which reflects its size and anatomic distribution. Case presentation Here, we present a very rare case of patient with supratentorial intraparenchymal arachnoid cyst placed in the left frontal lobe without any communication with the subarachnoid space and ventricle and presented with clinical symptoms. The patient underwent fenestration of the lesion and was clinically improved. Conclusions Although the etiology and the enlargement mechanism of arachnoid cysts remain unclear, both conservative and surgical treatments are optional. According to size, anatomical location, neuroimaging, and clinical symptoms, an arachnoid cyst should be included in the differential diagnosis of primary intracerebral cysts.

Diverse stereotactic neuro-navigation systems are used daily in neurosurgery and novel systems are continuously being developed. Prior to clinical implementation of new surgical tools, methods or instruments, in vitro experiments on phantoms should be conducted. A stereotactic neuro-navigation phantom denotes a rigid or deformable structure resembling the cranium with the intracranial area. The use of phantoms is essential for the testing of complete procedures and their workflows, as well as for the final validation of the application accuracy. The aim of this study is to provide a systematic review of stereotactic neuro-navigation phantom designs, to identify their most relevant features, and to identify methodologies for measuring the target point error, the entry point error, and the angular error (α). The literature on phantom designs used for evaluating the accuracy of stereotactic neuro-navigation systems, i.e., robotic navigation systems, stereotactic frames, frameless navigation systems, and aiming devices, was searched. Eligible articles among the articles written in English in the period 2000–2020 were identified through the electronic databases PubMed, IEEE, Web of Science, and Scopus. The majority of phantom designs presented in those articles provide a suitable methodology for measuring the target point error, while there is a lack of objective measurements of the entry point error and angular error. We identified the need for a universal phantom design, which would be compatible with most common imaging techniques (e.g., computed tomography and magnetic resonance imaging) and suitable for simultaneous measurement of the target point, entry point, and angular errors.

Background: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. Methods: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with 13C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients. Findings: In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. Interpretation: A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. Fund: DFG, BMBF and Sino-German Cooperation Project Keywords: Metabolic state, Kinase inhibitors, Glutamine, Serine, Proliferation, Aerobic glycolysis, HCC

Context: Polyphenols and flavonoids in artichoke leaf tincture (ALT) protect cells against oxidative damage. Objectives: We examined ALT effects on deoxyribonucleic acid (DNA) damage and lipid profiles in rat plasma and gene expression in rat aorta [haemeoxygenase-1 (HO1), haemeoxygenase-2 (HO2), NADPH oxidase 4 (NOX-4), monocyte chemoattractant protein-1 (MCP-1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)]. Materials and methods: Eighteen male Wistar albino rats were divided into three groups (n = 6/group): The control group (CG) was fed with standard pellet chow for 11 weeks; the AD group was fed for a similar period of time with pellet chow supplemented with 2% cholesterol, 3% sunflower oil and 1% sodium cholate. The ADA group was fed with pellet chow (for 1 week), the atherogenic diet (see above) for the following 4 weeks and then with ALT (0.1 mL/kg body weight) and atherogenic diet for 6 weeks. According to HPLC analysis, the isolated main compounds in ALT were chlorogenic acid, caffeic acid, isoquercitrin and rutin. Results: Normalized HO-1 [0.11 (0.04–0.24)] and MCP-1 [0.29 (0.21–0.47)] mRNA levels and DNA scores [12.50 (4.50–36.50)] were significantly lower in the ADA group than in the AD group [0.84 (0.35–2.51)], p = 0.021 for HO-1 [0.85 (0.61–3.45)], p = 0.047 for MCP-1 and [176.5 (66.50–221.25)], p = 0.020 for DNA scores. HO-1 mRNA was lower in the ADA group than in the CG group [0.30 (0.21–0.71), p = 0.049]. Conclusions: Supplementation with ALT limited the effects of the atherogenic diet through reduced MCP-1 expression, thereby preventing oxidative damage.

Inflammation, apoptosis and extracellular remodeling play significant roles in cardiovascular disease (CVD) underlying the major causes of mortality in renal patients. In 19 pre-dialysis patients, 21 dialysis patients and 20 control subjects, the concentrations of pentraxin-3, galectin-3, MMP-9 and TIMP-1 were determined by ELISA. CVD risk was calculated according to the Framingham risk score algorithm. Pentraxin-3 was increased in renal patients compared to healthy controls (p

Das deutsche Morphem bzw. Lexem frisch zeigt angesichts seiner verhältnismäßig bescheidenen Distribution in der deutschen Lexik eine überraschende Vielfalt, die auf der morphologischen Ebene (frisch- kommt als Einheit oder deren Teil als Substantiv, Verb, Adjektiv, Adverb und sogar als Interjektion vor) auch wortbildungsmäßig als Produkt von Ableitungen und Zusammensetzungen in unterschiedlichen Ausführungen und Konversionen zum Ausdruck kommt. Der zehnbändige Duden (1999) schreibt dem adjektivischen Lexem frisch fünf Bedeutungen zu. Das semantisch relativ beschränkte frisch in adjektivischen Zusammensetzungen lässt aber im Einklang mit stets veränderlichen außersprachlichen Gegebenheiten unendliche Realisierungen zu (internetfrisch aus Internet frisch renoviert?). Die erste unmittelbare Konstituente in adjektivischen frisch-Zusammensetzungen ist bei weitem das Substantiv. Die Verwendung der frisch-Lexik ist überraschenderweise in der Sprache des Jagdwesens auffallend. Die lexikalisch-semantische Kompatibilität der frisch-Adjektive mit nachfolgenden Substantiven ist ziemlich beschränkt und relativ voraussagbar. Die Mehrdeutigkeit der frisch-Adjektive ist selten, genauso sprach- und funktionalistische Markierung(en). Frisch kann auch Teil von Familiennamen sein und hat zahlreiche Spuren in der Literatur hinterlassen.

Abstract Introduction: Primary intracranial teratoma is a subtype of germ cell tumors, classified into three subtypes. They occur very rarely, with only several reported individual cases in adults. Case Description We present a patient with an intermittent headache in the right frontal region. Magnetic resonance imaging (MRI) revealed a right sided high frontal parasagittal mass that compressed the falx, the right lateral ventricle, as well as the brain parenchyma. Patient underwent surgical treatment. Histopathological analysis described mature teratoma. Four months after the surgical treatment there were no signs of residual intracranial mass or relapse. Discussion Primary intracranial teratoma in adults has a nonspecific clinical presentation. MRI reveals a solitary irregular mass with multilocularity and mixed signals derived from different tissues. The patients age, biochemical markers, and patohistological analysis are necessary to confirm the diagnosis. Conclusion Teratoma treatment strategy still remains controversial. It includes radical resection whenever possible. Since the residual portion of mature teratoma may contain part of immature or malignant tissue, tumor recurrence after surgical removal is possible. Also, new tumor mass could occur at other sites intracranial after the initial one was removed. Thus, although patients usually recover, they should be followed-up for a long period of time.

Ginkgo biloba (EGb761) is a widely used botanical drug. Several reports indicate that EGb761 confers preventive as well as anti-tumorigenic properties in a variety of tumors, including hepatocellular carcinoma (HCC). We here evaluate functional effects and molecular alterations induced by EGb761 in hepatoma cells and non-malignant hepatocytes. Hepatoma cell lines, primary human HCC cells and immortalized human hepatocytes (IH) were exposed to various concentrations (0-1000 μg/ml) of EGb761. Apoptosis and proliferation were evaluated after 72h of EGb761 exposure. Response to oxidative stress, tumorigenic properties and molecular changes were further investigated. While anti-oxidant effects were detected in all cell lines, EGb761 promoted anti-proliferative and pro-apoptotic effects mainly in hepatoma cells. Consistently, EGb761 treatment caused a significant reduction in colony and sphere forming ability in hepatoma cells and no mentionable changes in IH. Transcriptomic changes involved oxidative stress response as well as key oncogenic pathways resembling Nrf2- and mTOR signaling pathway. Taken together, EGb761 induces differential effects in non-transformed and cancer cells. While treatment confers protective effects in non-malignant cells, EGb761 significantly impairs tumorigenic properties in cancer cells by affecting key oncogenic pathways. Results provide the rational for clinical testing of EGb761 in preventive and therapeutic strategies in human liver diseases.

We study the cohesion within and the coalitions between political groups in the Eighth European Parliament (2014-2019) by analyzing two entirely different aspects of the behavior of the Members of the European Parliament (MEPs) in the policy-making processes. On one hand, we analyze their co-voting patterns and, on the other, their retweeting behavior. We make use of two diverse datasets in the analysis. The first one is the roll-call vote dataset, where cohesion is regarded as the tendency to co-vote within a group, and a coalition is formed when the members of several groups exhibit a high degree of co-voting agreement on a subject. The second dataset comes from Twitter; it captures the retweeting (i.e., endorsing) behavior of the MEPs and implies cohesion (retweets within the same group) and coalitions (retweets between groups) from a completely different perspective. We employ two different methodologies to analyze the cohesion and coalitions. The first one is based on Krippendorff's Alpha reliability, used to measure the agreement between raters in data-analysis scenarios, and the second one is based on Exponential Random Graph Models, often used in social-network analysis. We give general insights into the cohesion of political groups in the European Parliament, explore whether coalitions are formed in the same way for different policy areas, and examine to what degree the retweeting behavior of MEPs corresponds to their co-voting patterns. A novel and interesting aspect of our work is the relationship between the co-voting and retweeting patterns.

Aim To investigate the hypothesis that in patients with coronaryatherosclerosis it is possible to measure plasma mRNA levels fromgenes responsible for plaque development and destabilization.Methods Methods for RNA isolation, mRNA transcription and quantitative PCR were evaluated and optimised, in order to achievereliable mRNA quantiication. Results mRNA level was possible to quantify from plasma of patients with coronary atherosclerosis, as well as from healthy volunteers, from genes encoding cathepsin S, cathepsin B, CD40 molecule, monocyte chemotactic protein 1, death-associated protein kinase 1, matrix metallopeptidase 9, vascular cell adhesion molecule 1 and phosphoglycerate kinase 1 (reference gene). Analytical between-run imprecision of average threshold cycle, expressed as coeficient of variation was below 2%. EDTA blood samples should be centrifuged within one hour of venesection. It wasnot possible to quantify plasma mRNA level from genes encodingmacrophage scavenger receptor 1, perilipin, tissue factor, phospholipase A2 group IIA, collagen type I alpha 2 and interleukin 1alpha. Conclusion Further plasma mRNA analysis is reasonable to access its potential usefulness in non-invasive in vivo monitoring ofgene expression proile in vascular beds.

This study was carried out to determine the influence of goat and cow milk fermented by Bifidobacterium longum Bb-46 on the pathogenic Salmonella enteritidis D strain. The basic hypothesis of this study was that fermented goat milk could possibly have a stronger inhibitory effect on the growth of Salmonella enteritidis D than fermented cow milk. The correlation between the inhibitory effect and some fermentation parameters (number of viable cells of Bifidobacterium longum Bb-46 and pH of fermented milk) was also analysed. S enteritidis D strains were isolated directly from the faeces of an infant with diagnosed salmonellosis. The inhibitory effects of goat and cow milk fermented with Bifidobacterium longum Bb-46 were determined on Salmonella-Shigella agar after 0, 5, 10, 15, 20, and 25 h from the start of fermentation. Bifidobacterium longum Bb-46 count and pH values were also measured in samples of goat and cow milk during fermentation. The results obtained have shown a considerably higher inhibitory effect of fermented goat milk on the growth of Salmonella enteritidis D as compared to that of fermented cow milk. At the same time, higher acidity and CFU of Bifidobacterium longum Bb-46 were noted in fermented goat milk in all the phases of the fermentation process. The inhibitory effects of the fermented goat and cow milk on Salmonella enteritidis D growth increased rapidly with the fermentation time. The results indicated high sensitivity of Salmonella enteritidis D to acidity of both fermented milks. Consequently, a significant correlation between the inhibition degree and pH values of fermented goat and cow milk was noted.

Grid computing could be the future computing paradigm for enterprise applications, one of its benefits being that it can be used for executing large scale applications. Utility Management Systems execute very large numbers of workflows with very high resource requirements. This paper proposes architecture for a new scheduling mechanism that dynamically executes a scheduling algorithm using feedback about the current status Grid nodes. Two Artificial Neural Networks were created in order to solve the scheduling problem. A case study is created for the Meter Data Management system with measurements from the Smart Metering system for the city of Novi Sad, Serbia. Performance tests show that significant improvement of overall execution time can be achieved by Hierarchical Artificial Neural Networks.

n diesem Beitrag wird versucht, die Gesetzmässigkeiten der Textsorte Cartoon, wie er in "Zeitmagazin" vorkommt, zu beschreiben und ihre Bedeutung für die Textrezeption zu erklären. Im ersten Teil wird kurz auf die Textsorte Cartoon als Gegenstand des vorliegenden Beitrags eingegangen, im zweiten wird die Rolle des Textproduzenten bei der Textkonstitution und die des Rezipienten beim Textverstehen berührt.

Objective: Studies exploring the relationship between neonatal abstinence syndrome (NAS) and congenital anomalies (CA) in the United States are limited given the small sample size or data prior to the opioid epidemic. We aimed to determine if there is an association between NAS and CA in a nationally representative cohort of newborn hospitalization in the United States., Study Design: This was a cross-sectional analysis of NAS-related hospitalizations within the 2016 Kids Inpatient Database. International Classification of Diseases (ICD-10-CM) diagnostic codes were used to identify NAS hospitalizations and those with and without CA. The primary outcome was the odds of CAs in NAS hospitalizations. Multivariate survey logistic regression was used to analyze the relationship between NAS and CA., Results: Among 3.7 million newborn hospitalizations, 25,394 had NAS (6.7 per 1,000). The prevalence of any CA was higher in those with NAS when compared with non-NAS hospitalizations (10.3 vs. 4.9%; odds ratio = 2.27; 95% confidence interval [CI]: 2.13-2.43). Adjusted analysis showed similar results (adjusted odds ratio: = 1.83, CI: 1.71-1.95). NAS hospitalizations with CA had a higher mortality rate (0.6 vs 0.04%, p  < 0.0001) and higher resource use., Conclusion: This nationwide study shows that NAS may be associated with increased odds of CAs, suggesting that NAS may be a risk factor for increased morbidity in the newborn period., Key Points: · 1 in 10 newborns with NAS had at least one congenital anomaly.. · NAS hospitalization with congenital anomalies had higher resource use and mortality.. · Pediatricians caring for newborns with NAS should have a high index of suspicion for birth defects.., Competing Interests: None declared., (Thieme. All rights reserved.)

Expanding β cell mass is a critical goal in the fight against diabetes. CDK4, an extensively characterized cell cycle activator, is required to establish and maintain β cell number. β cell failure in the IRS2-deletion mouse type 2 diabetes model is, in part, due to loss of CDK4 regulator cyclin D2. We set out to determine whether replacement of endogenous CDK4 with the inhibitor-resistant mutant CDK4-R24C rescued the loss of β cell mass in IRS2-deficient mice. Surprisingly, not only β cell mass but also β cell dedifferentiation was effectively rescued, despite no improvement in whole body insulin sensitivity. Ex vivo studies in primary islet cells revealed a mechanism in which CDK4 intervened downstream in the insulin signaling pathway to prevent FOXO1-mediated transcriptional repression of critical β cell transcription factor Pdx1. FOXO1 inhibition was not related to E2F1 activity, to FOXO1 phosphorylation, or even to FOXO1 subcellular localization, but rather was related to deacetylation and reduced FOXO1 abundance. Taken together, these results demonstrate a differentiation-promoting activity of the classical cell cycle activator CDK4 and support the concept that β cell mass can be expanded without compromising function.

The purpose of this paper is to explore how social influence (SI), which is disaggregated into subjective norms (SN), social image (SIM), and social identity (SID), predicts perceived usefulness (PU), perceived pleasure (PP), and continuance intention (CI) toward sports and fitness applications. The underlying context is the socialization and gamification of exercise during the Covid-19 pandemic. Based on the theory of SI and the technology acceptance model, a theoretical framework was built where PU and PP mediate the influence of SI on CI, and proposed hypotheses were tested. The responses of 296 Keep users (a popular sports and fitness application in China) to a questionnaire survey were analyzed. SN and SIM were found to have significant positive effects on SID; SID has significant positive effects on PU and PP; both PU and PP have significant positive effects on the CI of users; SID and PU positively and significantly mediate the relationship between SN/SIM and CI; PU positively and significantly mediates the SID-CI relationship. However, the role of PP in mediating the influence of SI on CI is non-significant. This paper deepens the current understanding of the mechanisms that influence the relationship between SI and CI under the context of socialization and gamification services., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Du, Wang and Oteng-Darko.)

Aging is associated with loss of proliferation of the insulin-secreting β-cell, a possible contributing factor to the increased prevalence of type 2 diabetes in the elderly. Our group previously discovered that moderate endoplasmic reticulum (ER) stress occurring during glucose exposure increases the adaptive β-cell proliferation response. Specifically, the ATF6α arm of the tripartite Unfolded Protein Response (UPR) promotes β-cell replication in glucose excess conditions. We hypothesized that β-cells from older mice have reduced proliferation due to aberrant UPR signaling or an impaired proliferative response to ER stress or ATF6α activation. To investigate, young and old mouse islet cells were exposed to high glucose with low-dose thapsigargin or activation of overexpressed ATF6α, and β-cell proliferation was quantified by BrdU incorporation. UPR pathway activation was compared by qPCR of target genes and semi-quantitative Xbp1 splicing assay. Intriguingly, although old β-cells had reduced proliferation in high glucose compared to young β-cells, UPR activation and induction of proliferation in response to low-dose thapsigargin or ATF6α activation in high glucose were largely similar between young and old. These results suggest that loss of UPR-led adaptive proliferation does not explain the reduced cell cycle entry in old β-cells, and raise the exciting possibility that future therapies that engage adaptive UPR could increase β-cell number through proliferation even in older individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Snyder, Darko, Sharma and Alonso.)