The paradox of cancer genes in non-malignant conditions: implications for precision medicine.

Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activating KRAS mutations are discerned in endometriosis and in brain arteriovenous malformations, inactivating TP53 tumor suppressor mutations in rheumatoid arthritis synovium, and AKT, MAPK, and AMPK pathway gene alterations in the brains of Alzheimer's disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation of PIK3CA mutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate non-malignant illnesses and/or to prevent the emergence of cancer

Voltage gated inter-cation selective ion channels from graphene nanopores

With the ability to selectively control ionic flux, biological protein ion channels perform a fundamental role in many physiological processes. For practical applications that require the functionality of a biological ion channel, graphene provides a promising solid-state alternative, due to its atomic thinness and mechanical strength. Here, we demonstrate that nanopores introduced into graphene membranes, as large as 50 nm in diameter, exhibit inter-cation selectivity with a ~20x preference for K+ over divalent cations and can be modulated by an applied gate voltage. Liquid atomic force microscopy of the graphene devices reveals surface nanobubbles near the pore to be responsible for the observed selective behavior. Molecular dynamics simulations indicate that translocation of ions across the pore likely occurs via a thin water layer at the edge of the pore and the nanobubble. Our results demonstrate a significant improvement in the inter-cation selectivity displayed by a solid-state nanopore device and by utilizing the pores in a de-wetted state, offers an approach to fabricating selective graphene membranes that does not rely on the fabrication of sub-nm pores

IronNetInjector: Weaponizing .NET Dynamic Language Runtime Engines

As adversaries evolve their Tactics, Techniques, and Procedures (TTPs) to stay ahead of defenders, Microsoft’s .NET Framework emerges as a common component found in the tradecraft of many contemporary Advanced Persistent Threats (APTs), whether through PowerShell or C#. Because of .NET’s ease of use and availability on every recent Windows system, it is at the forefront of modern TTPs and is a primary means of exploitation. This article considers the .NET Dynamic Language Runtime as an attack vector, and how APTs have utilized it for offensive purposes. The technique under scrutiny is Bring Your Own Interpreter (BYOI), which is the ability of developers to embed dynamic languages into .NET using an engine. The focus of this analysis is an adversarial use case in which APT Turla utilized BYOI as an evasion technique, using an IronPython .NET Injector named IronNetInjector. This research analyzes IronNetInjector and how it was used to reflectively load .NET assemblies. It also evaluates the role of Antimalware Scan Interface (AMSI) in defending Windows. Due to AMSI being at the core of Windows malware mitigation, this article further evaluates the memory patching bypass technique by demonstrating a novel AMSI bypass method in IronPython using Platform Invoke (P/Invoke)

Increase in Pile Capacity with Time in Missouri River Alluvium

The data measured in this study suggest that the increase in compressive pile capacity for a 42-ft long, HP14x102 pile, in a predominantly fine-grained Missouri River alluvium soil profile, increases by about 16 percent from days seven to forty-four after driving. It appears evident that Davisson’s (1973) failure criteria seems to agree fairly well with the observed plunging failure of two compressive pile-load failure tests performed in Missouri River alluvium. By comparison of compressive proof and failure tests performed on day forty-four after driving, it appears that loading a pile to some degree prior to failure, and then reloading the pile, has almost no affect on the load-settlement relationship. Hence, proof loaded piles in Missouri River alluvium that pass should be allowed for use beneath the structure. Finally, comparisons of tension and compression pile load test data have lead to two possible conclusions. First, the estimation of tip load by tell-tale data may not be accurate, and may underestimate the amount of load actually transferred to the tip. And second, it seems viable that, at this site, the skin friction that can be counted on in design is perhaps 55 to 60 percent of that calculated for compression

The \u3cem\u3edapE\u3c/em\u3e-encoded \u3cem\u3eN\u3c/em\u3e-Succinyl-l,l-Diaminopimelic Acid Desuccinylase from \u3cem\u3eHaemophilus influenzae\u3c/em\u3e Is a Dinuclear Metallohydrolase

The Zn K-edge extended X-ray absorption fine structure (EXAFS) spectra, of the dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) from Haemophilus influenzae have been recorded in the presence of one or two equivalents of Zn(II) (i.e. [Zn_(DapE)] and [ZnZn(DapE)]). The Fourier transforms of the Zn EXAFS are dominated by a peak at ca. 2.0 Å, which can be fit for both [Zn_(DapE)] and [ZnZn(DapE)], assuming ca. 5 (N,O) scatterers at 1.96 and 1.98 Å, respectively. A second-shell feature at ca. 3.34 Å appears in the [ZnZn(DapE)] EXAFS spectrum but is significantly diminished in [Zn_(DapE)]. These data show that DapE contains a dinuclear Zn(II) active site. Since no X-ray crystallographic data are available for any DapE enzyme, these data provide the first glimpse at the active site of DapE enzymes. In addition, the EXAFS data for DapE incubated with two competitive inhibitors, 2-carboxyethylphosphonic acid and 5-mercaptopentanoic acid, are also presented

Constraints on Mars Aphelion Cloud Belt Phase Function and Ice Crystal Geometries

This study constrains the lower bound of the scattering phase function of Martian water ice clouds (WICs) through the implementation of a new observation aboard the Mars Science Laboratory (MSL). The Phase Function Sky Survey (PFSS) was a multiple pointing all-sky observation taken with the navigation cameras (Navcam) aboard MSL. The PFSS was executed 35 times during the Aphelion Cloud Belt (ACB) season of Mars Year 34 over a solar longitude range of L_s=61.4{\deg}-156.5{\deg}. Twenty observations occurred in the morning hours between 06:00 and 09:30 LTST, and 15 runs occurred in the evening hours between 14:30 and 18:00 LTST, with an operationally required 2.5 hour gap on either side of local noon due the sun being located near zenith. The resultant WIC phase function was derived over an observed scattering angle range of 18.3{\deg} to 152.61{\deg}, normalized, and compared with 9 modeled phase functions: seven ice crystal habits and two Martian WIC phase functions currently being implemented in models. Through statistical chi-squared probability tests, the five most probable ice crystal geometries observed in the ACB WICs were aggregates, hexagonal solid columns, hollow columns, plates, and bullet rosettes with p-values greater than or equal to 0.60, 0.57,0.56,0.56, and 0.55, respectively. Droxtals and spheres had p-values of 0.35, and 0.2, making them less probable components of Martian WICs, but still statistically possible ones. Having a better understanding of the ice crystal habit and phase function of Martian water ice clouds directly benefits Martian climate models which currently assume spherical and cylindrical particles.Comment: Accepted Manuscript by Planetary and Space Scienc

ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders

This is the peer reviewed version of the following article: Steinle, J, Hossain, WA, Lovell, S, Veatch, OJ, Butler, MG. ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders. Am J Med Genet Part A. 2021; 185A: 743– 752. https://doi.org/10.1002/ajmg.a.62030, which has been published in final form at https://doi.org/10.1002/ajmg.a.62030. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.Ehlers-Danlos syndrome (EDS) consists of a heterogeneous group of genetically inherited connective tissue disorders. A family with three affected members over two generations with features of Dermatosparaxic EDS (dEDS) autosomal dominant transmission was reported by Desai et al. and having a heterozygous nonsynonymous missense variant of ADAMTSL2 (c.1261G > A; p. Gly421Ser). Variation in this gene is also reported to cause autosomal recessive geleophysic dysplasia. We report five unrelated patients with the Gly421Ser variant identified from a large series of patients presenting with features of connective tissue disorders, each with a positive family history consistent with autosomal dominant transmission. Clinical features of a connective tissue disorder included generalized joint hypermobility and pain with fragility of internal and external tissues including of skin, dura, and arteries. Overall, our analyses including bioinformatics, protein modeling, and gene-protein interactions with the cases described would add evidence for the Gly421Ser variant in ADAMTSL2 as causative for variable expressivity of autosomal dominant connective tissue disorders