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Abstract Saturn’s moon Titan was explored by the Cassini spacecraft from 2004 to 2017. While Cassini revealed a lot about this Earth-like world, its radar observations could only provide limited information about Titan’s liquid hydrocarbons seas Kraken, Ligeia and Punga Mare. Here, we show the results of the analysis of the Cassini mission bistatic radar experiments data of Titan’s polar seas. The dual-polarized nature of bistatic radar observations allow independent estimates of effective relative dielectric constant and small-scale roughness of sea surface, which were not possible via monostatic radar data. We find statistically significant variations in effective dielectric constant (i.e., liquid composition), consistent with a latitudinal dependence in the methane-ethane mixing-ratio. The results on estuaries suggest lower values than the open seas, compatible with methane-rich rivers entering seas with higher ethane content. We estimate small-scale roughness of a few millimeters from the almost purely coherent scattering from the sea surface, hinting at the presence of capillary waves. This roughness is concentrated near estuaries and inter-basin straits, perhaps indicating active tidal currents.

Abstract Unlike the intense research effort devoted to exploring the significance of heparanase in cancer, very little attention was given to Hpa2, a close homolog of heparanase. Here, we explored the role of Hpa2 in breast cancer. Unexpectedly, we found that patients endowed with high levels of Hpa2 exhibited a higher incidence of tumor metastasis and survived less than patients with low levels of Hpa2. Immunohistochemical examination revealed that in normal breast tissue, Hpa2 localizes primarily in the cell nucleus. In striking contrast, in breast carcinoma, Hpa2 expression is not only decreased but also loses its nuclear localization and appears diffuse in the cell cytoplasm. Importantly, breast cancer patients in which nuclear localization of Hpa2 is retained exhibited reduced lymph-node metastasis, suggesting that nuclear localization of Hpa2 plays a protective role in breast cancer progression. To examine this possibility, we engineered a gene construct that directs Hpa2 to the cell nucleus (Hpa2-Nuc). Notably, overexpression of Hpa2 in breast carcinoma cells resulted in bigger tumors, whereas targeting Hpa2 to the cell nucleus attenuated tumor growth and tumor metastasis. RNAseq analysis was performed to reveal differentially expressed genes (DEG) in Hpa2-Nuc tumors vs. control. The analysis revealed, among others, decreased expression of genes associated with the hallmark of Kras, beta-catenin, and TNF-alpha (via NFkB) signaling. Our results imply that nuclear localization of Hpa2 prominently regulates gene transcription, resulting in attenuation of breast tumorigenesis. Thus, nuclear Hpa2 may be used as a predictive parameter in personalized medicine for breast cancer patients.

Introduction: Heparan sulfate (HS) in the vascular endothelial glycocalyx (eGC) is a critical regulator of blood vessel homeostasis. Trauma results in HS shedding from the eGC, but the impact of trauma on HS structural modifications that could influence mechanisms of vascular injury and repair has not been evaluated. Moreover, the effect of eGC HS shedding on endothelial cell (EC) homeostasis has not been fully elucidated. The objectives of this work were to characterize the impact of trauma on HS sulfation and determine the effect of eGC HS shedding on the transcriptional landscape of vascular ECs.Methods: Plasma was collected from 25 controls and 49 adults admitted to a level 1 trauma center at arrival and 24 h after hospitalization. Total levels of HS and angiopoietin-2, a marker of pathologic EC activation, were measured at each time point. Enzymatic activity of heparanase, the enzyme responsible for HS shedding, was determined in plasma from hospital arrival. Liquid chromatography-tandem mass spectrometry was used to characterize HS di-/tetrasaccharides in plasma. In vitro work was performed using flow conditioned primary human lung microvascular ECs treated with vehicle or heparinase III to simulate human heparanase activity. Bulk RNA sequencing was performed to determine differentially expressed gene-enriched pathways following heparinase III treatment.Results: We found that heparanase activity was increased in trauma plasma relative to controls, and HS levels at arrival were elevated in a manner proportional to injury severity. Di-/tetrasaccharide analysis revealed lower levels of 3-O-sulfated tetramers with a concomitant increase in ΔIIIS and ΔIIS disaccharides following trauma. Admission levels of total HS and specific HS sulfation motifs correlated with 24-h angiopoietin-2 levels, suggesting an association between HS shedding and persistent, pathological EC activation. In vitro pathway analysis demonstrated downregulation of genes that support cell junction integrity, EC polarity, and EC senescence while upregulating genes that promote cell differentiation and proliferation following HS shedding.Discussion: Taken together, our findings suggest that HS cleavage associated with eGC injury may disrupt homeostatic EC signaling and influence biosynthetic mechanisms governing eGC repair. These results require validation in larger, multicenter trauma populations coupled with in vivo EC-targeted transcriptomic and proteomic analyses.

Neuromuscular junction (NMJ) dysfunction underlies several diseases, including congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular pathways governing NMJ stability are therefore of interest from both biological and therapeutic perspectives. Muscle-specific kinase (MuSK) is necessary for the formation and maintenance of post-synaptic elements of the NMJ, and downstream of tyrosine kinases 7 (DOK7) is crucial for activation of the MuSK pathway. Overexpression of DOK7 using AAV9 has been shown to ameliorate neuromuscular pathology in pre-clinical disease models of CMS and MND. However, long-term consequences of DOK7 expression have been sparsely investigated and targeted overexpression of DOK7 in skeletal muscle yet to be established. Here, we developed and characterized a novel AAV9-DOK7 facilitating forced expression of DOK7 under a skeletal muscle-specific promoter. AAV9-tMCK-DOK7 was systemically delivered to newborn mice that were monitored over 6 months. DOK7 overexpression was restricted to skeletal muscles. Body weight, blood biochemistry, and histopathological assessments were unaffected by AAV9-tMCK-DOK7 treatment. In contrast, forced expression of DOK7 resulted in enlargement of both the pre- and post-synaptic components of the NMJ, without causing denervation. We conclude that muscle-specific DOK7 overexpression can be achieved in a safe manner, with the capacity to target NMJs in vivo.

In a May 1995 issue of Christianity Today the Rev. Dr. Joe Samuel Ratliff, a leading pastor in the Southern Baptist Convention (SBC), stated: 'The Southern Baptist Convention's history speaks [...]

BackgroundClinical biomarkers for brain metastases remain elusive. Increased availability of genomic profiling has brought discovery of these biomarkers to the forefront of research interests.MethodIn this single institution retrospective series, 130 patients presenting with brain metastasis secondary to Non-Small Cell Lung Cancer (NSCLC) underwent comprehensive genomic profiling conducted using next generation circulating tumor deoxyribonucleic acid (DNA) (Guardant Health, Redwood City, CA). A total of 77 genetic mutation identified and correlated with nine clinical outcomes using appropriate statistical tests (general linear models, Mantel-Haenzel Chi Square test, and Cox proportional hazard regression models). For each outcome, a genetic signature composite score was created by summing the total genes wherein genes predictive of a clinically unfavorable outcome assigned a positive score, and genes with favorable clinical outcome assigned negative score.ResultsSeventy-two genes appeared in at least one gene signature including: 14 genes had only unfavorable associations, 36 genes had only favorable associations, and 22 genes had mixed effects. Statistically significant associated signatures were found for the clinical endpoints of brain metastasis velocity, time to distant brain failure, lowest radiosurgery dose, extent of extracranial metastatic disease, concurrent diagnosis of brain metastasis and NSCLC, number of brain metastases at diagnosis as well as distant brain failure. Some genes were solely associated with multiple favorable or unfavorable outcomes.ConclusionGenetic signatures were derived that showed strong associations with different clinical outcomes in NSCLC brain metastases patients. While these data remain to be validated, they may have prognostic and/or therapeutic impact in the future.Statement of translation relevanceUsing Liquid biopsy in NSCLC brain metastases patients, the genetic signatures identified in this series are associated with multiple clinical outcomes particularly these ones that lead to early or more numerous metastases. These findings can be reverse-translated in laboratory studies to determine if they are part of the genetic pathway leading to brain metastasis formation.

Alfredo Berrettini,1 Irene Paraboschi,1 Massimo Di Grazia,1 Michele Gnech,1 Guglielmo Mantica,2 Dario Guido Minoli,1 Erika Adalgisa De Marco,1 Gianantonio Manzoni,1 Marco Capece,3 Alessandro Palmieri,3 David Ralph,3 Vincenzo Mirone3 1Department of Pediatric Urology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; 2Department of Urology, IRCCS Ospedale Policlinico San Martino, Genova, Italy; 3Department of Urology, Azienda Ospedaliera Universitaria “Federico II”, Napoli, ItalyCorrespondence: Irene Paraboschi, Department of Pediatric Urology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milano, Italy, Tel +393313229495, Email irene.paraboschi01@gmail.comAbstract: We present the first case of a patient born with congenital fusiform megalourethra who underwent the successful placement of an inflatable penile prosthesis (IPP) and mesh phalloplasty due to primary erectile dysfunction (ED). After an extensive psychosexual assessment and a preoperative MRI scan, an IPP was successfully implanted. The procedure was carried out through a penoscrotal approach, which offered excellent exposure to the crura and the proximal ends of the corpora cavernosa. Following the incision and the dilatation of both corpora cavernosa, the penile cylinders were inserted and a mesh phalloplasty was performed, to replace the erectile tissues lacking in the distal corpora cavernosa. After reservoir and pump placement, the device was tested, and no mechanical issues were recorded. The postoperative course was uneventful, and, at the 2-year follow-up, the patient reported highly satisfactory results, with valid functional erections.Keywords: congenital fusiform megalourethra, inflatable penile prosthesis, phalloplasty, erectile dysfunction

What motivates the voluntary suffering of training for a long-distance run – or any other difficult athletic skill? Long-term pleasure cannot adequately explain this seemingly masochistic activity. On the contrary, I argue that pleasure, or “reinforcement,” is not the only ultimate motivator of behavior. Each of the emotion systems defines its own intrinsic values, including an innate “play” system and an innate “exploratory drive” that is included in what neuropsychologist Jaak Panksepp calls the “SEEKING system” of the emotional brain. Panksepp’s description of the conscious dimension of SEEKING is remarkably similar to Otto Rank’s descriptions of his “love of life” dimension of motivation, which actually conflicts with the pleasure principle. The desire for pleasure is a desire to reduce consummatory drives, which means reducing the energy level of our bodily systems. Complete reduction would be death. If there were no competing motivation in the other direction, there would be nothing to keep us alive. The SEEKING system is what does that. It motivates a higher energy level. In the case of athletic training, we do not have to “force ourselves” to this higher energy level. The SEEKING system is an innate natural drive. If we were to deliberately try to just sit on a couch indefinitely, at some point we would fail.

Introduction: Heparan sulfate (HS) in the vascular endothelial glycocalyx (eGC) is a critical regulator of blood vessel homeostasis. Trauma results in HS shedding from the eGC, but the impact of trauma on HS structural modifications that could influence mechanisms of vascular injury and repair has not been evaluated. Moreover, the effect of eGC HS shedding on endothelial cell (EC) homeostasis has not been fully elucidated. The objectives of this work were to characterize the impact of trauma on HS sulfation and determine the effect of eGC HS shedding on the transcriptional landscape of vascular ECs. Methods: Plasma was collected from 25 controls and 49 adults admitted to a level 1 trauma center at arrival and 24 h after hospitalization. Total levels of HS and angiopoietin-2, a marker of pathologic EC activation, were measured at each time point. Enzymatic activity of heparanase, the enzyme responsible for HS shedding, was determined in plasma from hospital arrival. Liquid chromatography-tandem mass spectrometry was used to characterize HS di-/ tetrasaccharides in plasma. In vitro work was performed using flow conditioned primary human lung microvascular ECs treated with vehicle or heparinase III to simulate human heparanase activity. Bulk RNA sequencing was performed to determine differentially expressed gene-enriched pathways following heparinase III treatment. Results: We found that heparanase activity was increased in trauma plasma relative to controls, and HS levels at arrival were elevated in a manner proportional to injury severity. Di-/tetrasaccharide analysis revealed lower levels of 3-O-sulfated tetramers with a concomitant increase in ΔIIIS and ΔIIS disaccharides following trauma. Admission levels of total HS and specific HS sulfation motifs correlated with 24-h angiopoietin-2 levels, suggesting an association between HS shedding and persistent, pathological EC activation. In vitro pathway analysis demonstrated downregulation of genes that support cell junction integrity, EC polarity, and EC senescence while upregulating genes that promote cell differentiation and proliferation following HS shedding. Discussion: Taken together, our findings suggest that HS cleavage associated with eGC injury may disrupt homeostatic EC signaling and influence biosynthetic mechanisms governing eGC repair. These results require validation in larger, multicenter trauma populations coupled with in vivo EC-targeted transcriptomic and proteomic analyses. [ABSTRACT FROM AUTHOR]

Products from many domains (art, music, engineering design, literature, etc.) are considered to be creative works, but there is a misconception that computer programs are limited by set expressions and thus have no room for creativity. To determine whether computer programs are creative works, we collected programs from 23 advanced graduate students that were written to solve simple and complex bioinformatics problems. These programs were assessed for their variability of expression using a new measurement that we designed. They were also evaluated on several elements of their creativity using a version of Cropley and Kaufman's (2012) Creative Solution Diagnosis Scale that was modified to refer to programming. We found a high degree of variation in the programs that were produced, with 11 unique solutions for the simple problem and 20 unique solutions for the complex problem. We also found higher ratings of propulsion-genesis and problematization for the complex problem than for the simple problem. This combination of variation in expression and differences in level of creativity based on program complexity suggests that computer programs, like many other products, count as creative works. Implications for the creativity literature, computer science education, and intellectual property law, particularly copyright, are discussed. [ABSTRACT FROM AUTHOR]

Angiopoietin-2 (Ang-2) is a key mediator of vascular disease during sepsis, and elevated plasma levels of Ang-2 are associated with organ injury scores and poor clinical outcomes. We have previously observed that biomarkers of endothelial glycocalyx (EG) damage correlate with plasma Ang-2 levels, suggesting a potential mechanistic linkage between EG injury and Ang-2 expression during states of systemic inflammation. However, the cell signaling mechanisms regulating Ang-2 expression following EG damage are unknown. In the current study, we determined the temporal associations between plasma heparan sulfate (HS) levels as a marker of EG erosion and plasma Ang-2 levels in children with sepsis and in mouse models of sepsis. Second, we evaluated the role of shear stress–mediated 5′-adenosine monophosphate–activated protein kinase (AMPK) signaling in Ang-2 expression following enzymatic HS cleavage from the surface of human primary lung microvascular endothelial cells (HLMVECs). We found that plasma HS levels peaked before plasma Ang-2 levels in children and mice with sepsis. Further, we discovered that impaired AMPK signaling contributed to increased Ang-2 expression following HS cleavage from flow-conditioned HLMVECs, establishing a paradigm by which Ang-2 may be upregulated during sepsis.

NEW NETHERLAND People of African descent were among the earliest inhabitants of the Dutch colony of New Netherland. (2) Initiated in 1624, the colony's population also included English, French, German, [...]