Abstract
The common phenomenon of lightning still harbors many secrets such as what are the conditions for lightning initiation and what is driving the discharge to propagate over several tens of ...kilometers through the atmosphere forming conducting ionized channels called leaders. Since lightning is an electric discharge phenomenon, there are positively and negatively charged leaders. In this work we report on measurements made with the LOFAR radio telescope, an instrument primarily build for radio-astronomy observations. It is observed that a negative leader rather suddenly changes, for a few milliseconds, into a mode where it radiates 100 times more VHF power than typical negative leaders after which it spawns a large number of more typical negative leaders. This mode occurs during the initial stage, soon after initiation, of all lightning flashes we have mapped (about 25). For some flashes this mode occurs also well after initiation and we show one case where it is triggered twice, some 100 ms apart. We postulate that this is indicative of a small (order of 5 km
$$^2$$
2
) high charge pocket. Lightning thus appears to be initiated exclusively in the vicinity of such a small but dense charge pocket.
Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy ...using mesenchymal stem cells (MSCs)-derived proteomes and OS-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with cisplatin. CM was enriched with proteins such as calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of
transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein, a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.
We use the Low Frequency Array (LOFAR) to probe the dynamics of the stepping process of negatively charged plasma channels (negative leaders) in a lightning discharge. We observe that at each step of ...a leader, multiple pulses of vhf (30-80 MHz) radiation are emitted in short-duration bursts (<10 μs). This is evidence for streamer formation during corona flashes that occur with each leader step, which has not been observed before in natural lightning and it could help explain x-ray emission from lightning leaders, as x rays from laboratory leaders tend to be associated with corona flashes. Surprisingly, we find that the stepping length is very similar to what was observed near the ground, however with a stepping time that is considerably larger, which as yet is not understood. These results will help to improve lightning propagation models, and eventually lightning protection models.
In cancer, the mouse double minute 2 (MDM2) is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival ...versus cell death is complex and dependent on levels of MDM2 isoforms, p53 status, and cellular context. Extensive investigations have demonstrated that MDM2 protein-protein interactions with p53 and other p53 family members (p63 and p73) block their ability to function as transcription factors that regulate cell growth and survival. Upon genotoxic insults, a dynamic and intricately regulated DNA damage response circuitry is activated leading to release of p53 from MDM2 and activation of cell cycle arrest. What ensues following DNA damage, depends on the extent of DNA damage and if the cell has sufficient DNA repair capacity. The well-known auto-regulatory loop between p53-MDM2 provides an additional layer of control as the cell either repairs DNA damage and survives (i.e., MDM2 re-engages with p53), or undergoes cell death (i.e., MDM2 does not re-engage p53). Furthermore, the decision to live or die is also influenced by chromatin-localized MDM2 which directly interacts with the Mre11-Rad50-Nbs1 complex and inhibits DNA damage-sensing giving rise to the potential for increased genome instability and cellular transformation.
While most pediatric sarcomas respond to front-line therapy, some bone sarcomas do not show radiographic response like soft-tissue sarcomas (rhabdomyosarccomas) but do show 90% necrosis. Though, new ...therapies are urgently needed to improve survival and quality of life in pediatric patients with sarcomas. Complex chromosomal aberrations such as amplifications and deletions of DNA sequences are frequently observed in pediatric sarcomas. Evaluation of copy number variations (CNVs) associated with pediatric sarcoma patients at the time of diagnosis or following therapy offers an opportunity to assess dysregulated molecular targets and signaling pathways that may drive sarcoma development, progression, or relapse. The objective of this study was to utilize publicly available data sets to identify potential predictive biomarkers of chemotherapeutic response in pediatric Osteosarcoma (OS), Rhabdomyosarcoma (RMS) and Ewing's Sarcoma Family of Tumors (ESFTs) based on CNVs following chemotherapy (OS n = 117, RMS n = 64, ESFTs n = 25 tumor biopsies).
There were 206 CNV profiles derived from pediatric sarcoma biopsies collected from the public databases TARGET and NCBI-Gene Expression Omnibus (GEO). Through our comparative genomic analyses of OS, RMS, and ESFTs and 22,255 healthy individuals called from the Database of Genomic Variants (DGV), we identified CNVs (amplifications and deletions) pattern of genomic instability in these pediatric sarcomas. By integrating CNVs of Cancer Cell Line Encyclopedia (CCLE) identified in the pool of genes with drug-response data from sarcoma cell lines (n = 27) from Cancer Therapeutics Response Portal (CTRP) Version 2, potential predictive biomarkers of therapeutic response were identified.
Genes associated with survival and/recurrence of these sarcomas with statistical significance were found on long arm of chromosome 8 and smaller aberrations were also identified at chromosomes 1q, 12q and x in OS, RMS, and ESFTs. A pool of 63 genes that harbored amplifications and/or deletions were frequently associated with recurrence across OS, RMS, and ESFTs. Correlation analysis of CNVs from CCLE with drug-response data of CTRP in 27 sarcoma cell lines, 33 CNVs out of 63 genes correlated with either sensitivity or resistance to 17 chemotherapies from which actionable CNV signatures such as IGF1R, MYC, MAPK1, ATF1, and MDM2 were identified. These CNV signatures could potentially be used to delineate patient populations that will respond versus those that will not respond to a particular chemotherapy.
The large-scale analyses of CNV-drug screening provides a platform to evaluate genetic alterations across aggressive pediatric sarcomas. Additionally, this study provides novel insights into the potential utilization of CNVs as not only prognostic but also as predictive biomarkers of therapeutic response. Information obtained in this study may help guide and prioritize patient-specific therapeutic options in pediatric bone and soft-tissue sarcomas.
Abstract
People in urban areas appreciate and enjoy the beauty of nature as carefully manicured grass and flowers in public gardens. Senior citizens find this place best for their social networking, ...while children enjoy their recreational activities here. Botanical garden generally refers to a place where, variety of flora species are planted and grown for the purpose of scientific study. Maintaining a garden or botanical garden takes lot of maintenance effort along with monitoring various parameters such as moisture and light; ambient factors like temperature and humidity of air are also important factors. The focus of this paper is to demonstrate and implement a cost-effective way to monitor and control soil moisture, ambient air temperature and humidity in such gardens by means of controlling drip irrigation pumps and water sprinklers.
Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant ...transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794-0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4-9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.
•After yoga, stress was reduced, and mood improved for four populations including people who were incarcerated, people in treatment for substance use, veterans, and youth.•Across multiple sessions ...both the largest decreases in stress and greatest increase in mood occurred after participant in the first session.•A specific exploration of curriculum class impact by theme for participants who were incarcerated indicated no difference in impact by theme.•For individuals in treatment for substance use, reductions in systolic blood pressure occurred immediately after the first curriculum session, and diastolic blood pressure reduced over three consecutive sessions.
Individuals with trauma experience negative mental health impacts and are at risk of poor cardiovascular outcomes. Unmanaged, these conditions may worsen, compromising healing and wellbeing. Yoga, particularly trauma-informed, may improve outcomes. The current pilot study explores the impact of a novel trauma-informed yoga and mindfulness curriculum on wellbeing in two parts. The first examined mental health (stress, mood) outcomes in four trauma-impacted populations: adults who were incarcerated (INC), individuals in recovery from substance use disorders (SU), veterans (VA), and vulnerable youth (YTH) assessing both the impact of individual class participation and impact of attending at least four curriculum sessions. For the subgroup of incarcerated individuals, impact by theme was examined. After curriculum sessions, stress was reduced, and mood improved. Across multiple sessions both the largest decreases in stress and greatest increase in mood occurred after participant in the first session. Further, a specific exploration of curriculum class impact by theme for participants who were incarcerated indicated no difference in impact by theme. The second part of this study explored cardiovascular outcomes for the population of those in recovery from substance use. Reductions in systolic blood pressure occurred immediately after the first curriculum session, and diastolic blood pressure reduced over three consecutive sessions.
A new heterocyclic framework of 2-(4-{(2-oxo-2
H
-chromen-4-yl)oxymethyl}-1
H
-1,2,3-triazol-1-yl)-
N
-4-(3-oxomorpholino)phenylacetamide was constructed using the copper-catalyzed click chemistry ...tool as a key reaction. The synthesized compounds were subjected to
in vitro
antimicrobial activity against gram-positive (
S. aureus
,
S. pyogenes
), gram-negative (
E. coli, P. aeruginosa
), and fungal strains (
C. albicans
,
A. clavatus,
and
A. niger
) concerning standard drugs. The screened compounds show moderate to good activity against various bacteria and fungi. The compounds were also studied for
in silico
molecular docking with the target protein of bacteria and fungi to investigate potential inhibition properties. The study suggests that compounds some have the potential and, after other detailed studies, may be useful for medicinal purposes.
This paper presents a fault diagnosis technique based on acoustic emission (AE) analysis with the Hilbert–Huang Transform (HHT) and data mining tool. HHT analyzes the AE signal using intrinsic mode ...functions (IMFs), which are extracted using the process of Empirical Mode Decomposition (EMD). Instead of time domain approach with Hilbert transform, FFT of IMFs from HHT process are utilized to represent the time frequency domain approach for efficient signal response from rolling element bearing. Further, extracted statistical and acoustic features are used to select proper data mining based fault classifier with or without filter. K-nearest neighbor algorithm is observed to be more efficient classifier with default setting parameters in WEKA. APF-KNN approach, which is based on asymmetric proximity function with optimize feature selection shows better classification accuracy is used. Experimental evaluation for time frequency approach is presented for five bearing conditions such as healthy bearing, bearing with outer race, inner race, ball and combined defect. The experimental results show that the proposed method can increase reliability for the faults diagnosis of ball bearing.
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