Search

Abstract Combined molecular, physicochemical and chemical properties of electrophilic warheads can be applied to create covalent drugs with diverse facets. Here we study these properties in fluorinated diketones (FDKs) and their multicomponent equilibrium systems in the presence of protic nucleophiles, revealing the potential of the CF2(CO)2 group to act as a multifaceted warhead for reversible covalent drugs. The equilibria compositions of various FDKs in water/octanol contain up to nine species. A simultaneous direct species-specific 19F-NMR-based log P determination of these complex equilibria systems was achieved and revealed in some cases lipophilic to hydrophilic shifts, indicating possible adaptation to different environments. This was also demonstrated in 19F-MAS-NMR-based water-membrane partitioning measurements. An interpretation of the results is suggested by the aid of a DFT study and 19F-DOSY-NMR spectroscopy. In dilute solutions, a model FDK reacted with protected cysteine to form two hemi-thioketal regioisomers, indicating possible flexible regio-reactivity of CF2(CO)2 warheads toward cysteine residues.

Thin-film composite (TFC) polyamide (PA) RO membrane modified with a layer of tethered poly(acrylic acid) (PAA) chains displayed intrinsic rejections of nitrate, boron, As(III), and As(V) of 98.0%, 90.7%, 96%, and 99.6%, respectively. The solute permeability coefficients for nitrate, boron, As(III), and As(V) by the SNS-PAA-PA membrane were lower by 31–38%, 49–63%, 57–72% and 87–93% relative to tested commercial membranes. The above results indicate that the SNS-PAA-PA membrane should be suitable for purification of brackish source water contaminated with nitrate, boron, As(III), and As(V) to levels 1219 ppm, 2 ppm, 95 ppb, and 948 ppb, respectively. The study results suggest that there is merit in further exploration of the potential of the present approach for enhancing RO membranes performance for targeted solute removal.

Abstract An uncharged, water‐soluble per‐ethylene‐glycol pillar[5]arene derivative (1) was synthesized and its aggregation mode, host‐guest chemistry in water and extraction ability was explored. Compound 1 is a liquid at room temperature; in water, limited self‐aggregation occurred at high concentrations as deduced from diffusion NMR and dynamic light scattering. Compound 1 forms pseudo‐rotaxane‐like 1 : 1 host‐guest complexes with 1,ω‐di‐substituted alkanes with association constants on the order of 103–104 m−1. Interestingly, NMR experiments showed that the guest location relative to the host ring system differs among the different complexes. In proof‐of‐concept experiments, compound 1 was shown to extract structurally related organic compounds from benzene into water with significant selectivity. Compound 1, which is a liquid at room temperature and has only limited interactions with its side arms, can, in principle, be regarded as a complement to or as a kind of type I porous liquid.

Abstract FMR1 premutation (55–200 CGG repeats) results in fragile X-associated primary ovarian insufficiency (FXPOI). We evaluated expression levels of folliculogenesis-related mediators, follicle-stimulating hormone (FSH) receptor and anti-Mullerian hormone (AMH), to gain insights into the mechanisms underlying the reduced ovarian function. Mural granulosa cells (MGCs) were collected from FMR1 premutation carriers and noncarriers undergoing IVF treatments. At baseline, MGCs of carriers demonstrated significantly higher mRNA expression levels of AMH (3.5 ± 2.2, n = 12 and 0.97 ± 0.5, n = 17, respectively; p = 0.0003) and FSH receptor (5.6 ± 2.8 and 2.7 ± 2.8, respectively; p = 0.02) and higher AMH protein expression on immunostaining. Accordingly, FMR1 premutation-transfected COV434 cells exhibited higher AMH protein expression than COV434 cells transfected with 20 CGG repeats. We conclude that FMR1 premutation may lead to dysregulation of AMH expression levels, probably due to a compensatory mechanism. Elucidating the pathophysiology of FXPOI may help in early detection of ovarian dysfunction and tailoring IVF treatments to FMR1 premutation carriers.

Nanotechnology has enabled the discovery of a multitude of novel materials exhibiting unique physicochemical (PChem) properties compared to their bulk analogues. These properties have led to a rapidly increasing range of commercial applications; this, however, may come at a cost, if an association to long-term health and environmental risks is discovered or even just perceived. Many nanomaterials (NMs) have not yet had their potential adverse biological effects fully assessed, due to costs and time constraints associated with the experimental assessment, frequently involving animals. Here, the available NM libraries are analyzed for their suitability for integration with novel nanoinformatics approaches and for the development of NM specific Integrated Approaches to Testing and Assessment (IATA) for human and environmental risk assessment, all within the NanoSolveIT cloud-platform. These established and well-characterized NM libraries (e.g. NanoMILE, NanoSolutions, NANoREG, NanoFASE, caLIBRAte, NanoTEST and the Nanomaterial Registry (>2000 NMs)) contain physicochemical characterization data as well as data for several relevant biological endpoints, assessed in part using harmonized Organisation for Economic Co-operation and Development (OECD) methods and test guidelines. Integration of such extensive NM information sources with the latest nanoinformatics methods will allow NanoSolveIT to model the relationships between NM structure (morphology), properties and their adverse effects and to predict the effects of other NMs for which less data is available. The project specifically addresses the needs of regulatory agencies and industry to effectively and rapidly evaluate the exposure, NM hazard and risk from nanomaterials and nano-enabled products, enabling implementation of computational ‘safe-by-design’ approaches to facilitate NM commercialization.

The gypsum and calcite scaling propensities of the thin-film composite polyamide (PA-TFC) reverse osmosis (RO) membrane, modified with a tethered surface layer of polyacrylic acid (PAA) chains, was evaluated and compared to the scaling of selected commercial RO membranes. The tethered PAA layer was synthesized onto a commercial polyamide membrane (i.e., base-PA) via atmospheric pressure plasma-induced graft polymerization (APPIGP). The PAA nano-structured (SNS) base-PA membrane (SNS-PAA-PA) was scaled to a lesser degree, as quantified by a lower permeate flux decline and surface imaging, relative to the tested commercial membranes (Dow SW30, Toray SWRO, and BWRO). The cleaning of gypsum-scaled membranes with D.I. water flushing achieved 100% water permeability recovery for both the SNS-PAA-PA and Dow SW30 membranes, relative to 92–98% permeability restoration for the Toray membranes. The calcium carbonate scaling of SNS-PAA-PA membranes was also lower relative to the commercial membranes, but permeability recovery after D.I. water cleaning was somewhat lower (94%) but consistent with the level of surface scale coverage. In contrast, the calcite and gypsum-scaled membrane areas of the commercial membranes post-cleaning were significantly higher than for the SNS-PAA-PA membrane but with 100% permeability recovery, suggesting the potential for membrane damage when mineral scaling is severe.

In this paper we present a new method for automatic transliteration and segmentation of Unicode cuneiform glyphs using Natural Language Processing (NLP) techniques. Cuneiform is one of the earliest known writing system in the world, which documents millennia of human civilizations in the ancient Near East. Hundreds of thousands of cuneiform texts were found in the nineteenth and twentieth centuries CE, most of which are written in Akkadian. However, there are still tens of thousands of texts to be published. We use models based on machine learning algorithms such as recurrent neural networks (RNN) with an accuracy reaching up to 97% for automatically transliterating and segmenting standard Unicode cuneiform glyphs into words. Therefore, our method and results form a major step towards creating a human-machine interface for creating digitized editions. Our code, Akkademia, is made publicly available for use via a web application, a python package, and a github repository.

The potential environmental impact of nanomaterials is a critical concern and the ability to assess these potential impacts is top priority for the progress of sustainable nanotechnology. Risk assessment tools are needed to enable decision makers to rapidly assess the potential risks that may be imposed by engineered nanomaterials (ENMs), particularly when confronted by the reality of limited hazard or exposure data. In this review, we examine a range of available risk assessment frameworks considering the contexts in which different stakeholders may need to assess the potential environmental impacts of ENMs. Assessment frameworks and tools that are suitable for the different decision analysis scenarios are then identified. In addition, we identify the gaps that currently exist between the needs of decision makers, for a range of decision scenarios, and the abilities of present frameworks and tools to meet those needs.

The data presented are supplementary to an article [Kim et al., 2019] on synthesis and surface characterization of tethered polyacrylic acid (PAA) layers on polysulfone (PSf) film/membrane surfaces via atmospheric pressure plasma-induced graft polymerization (APPIGP). Data on surface characterization of the synthesized tethered PAA layers includes: AFM topographic surface images and height distributions of surface features, dry layer thickness, chain rupture length distributions determined via AFM based force spectroscopy (AFM-FS), in addition to measurements of water contact angles. Fouling propensity data for ultrafiltration of alginic acid as a model foulant are also provided for native and PAA grafted PSf ultrafiltration (UF) membranes.

Introduction: Fragile X syndrome (FXS) is a common form of X-linked intellectual and developmental disability with a prevalence of 1/4000–5000 in males and 1/6000–8000 in females. Most cases of the syndrome result from expansion of a premutation (55–200 CGGs) to a full mutation (>200 CGGs) repeat located in the 5′ untranslated region of the fragile X mental retardation (FMR1) gene. The risk for full mutation expansions increases dramatically with increasing numbers of CGG repeats. Recent studies, however, revealed AGG interruptions within the repeat area function as a “protective factor” decreasing the risk of intergenerational expansion.Materials and Methods: This study was conducted to validate the relevance of AGG analysis for the ethnically diverse Israeli population. To increase the accuracy of our results, we combined results from Israel with those from the New York State Institute for Basic Research in Developmental Disabilities (IBR). To the best of our knowledge this is the largest cohort of different ethnicities to examine risks of unstable transmissions and full mutation expansions among FMR1 premutation carriers.Results: The combined data included 1471 transmissions of maternal premutation alleles: 369 (25.1%) stable and 1,102 (74.9%) unstable transmissions. Full mutation expansions were identified in 20.6% (303/1471) of transmissions. A total of 97.4% (388/397) of transmissions from alleles with no AGGs were unstable, 79.6% (513/644) in alleles with 1 AGG and 46.7% (201/430) in alleles with 2 or more AGGs. The same trend was seen with full mutation expansions where 40% (159/397) of alleles with no AGGs expanded to a full mutation, 20.2% (130/644) for alleles with 1 AGG and only 3.2% (14/430) in alleles with 2 AGGs or more. None of the alleles with 3 or more AGGs expanded to full mutations.Conclusion: We recommend that risk estimates for FMR1 premutation carriers be based on AGG interruptions as well as repeat size in Israel and worldwide.

Abnormalities in the X-linked FMR1 gene are associated with a constellation of disorders, which have broad and profound implications for the person first diagnosed, and extended family members of all ages. The rare and pleiotropic nature of the associated disorders, both common and not, place great burdens on (1) the affected families, (2) their care providers and clinicians, and (3) investigators striving to conduct research on the conditions. Fragile X syndrome, occurring more severely in males, is the leading genetic cause of intellectual disability. Fragile X associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disorder seen more often in older men. Fragile X associated primary ovarian insufficiency (FXPOI) is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: (1) depression and anxiety related to the loss of reproductive hormones and infertility; (2) reduced bone mineral density; and (3) increased risk of cardiovascular disease related to estrogen deficiency. Here we report the case of a young woman who never established regular menses and yet experienced a 5-year diagnostic odyssey before establishing a diagnosis of FXPOI despite a known family history of fragile X syndrome and early menopause. Also, despite having clearly documented FXPOI the woman conceived spontaneously and delivered two healthy children. We review the pathophysiology and management of FXPOI. As a rare disease, the diagnosis of FXPOI presents special challenges. Connecting patients and community health providers with investigators who have the requisite knowledge and expertise about the FMR1 gene and FXPOI would facilitate both patient care and research. There is a need for an international natural history study on FXPOI. The effort should be coordinated by a global virtual center, which takes full advantage of mobile device communication systems.

The impact of ZnO and TiO2 manufactured nanoparticles (MNPs) on soil bacterial communities for different exposure periods and MNP doses was explored via data visualization techniques. Interrelationships between MNP treatments and responses of bacterial taxa were illustrated by bipartite graphs, allowing fast identification of important soil bacterial taxa that are susceptible to MNPs. Contribution biplots with subcompositional coherence property were generated via log-ratio analysis (LRA), which jointly display the treatment distribution and the variance (contribution) of bacterial taxa. The LRA contribution biplots and nonmetric multi-dimensional scaling (NMDS) of the dataset, along with hierarchical clustering, demonstrated that high doses of ZnO and TiO2 MNPs caused significant compositional changes in soil bacterial communities. The suitability of family level for MNP taxonomic impact assessment was demonstrated by both the LRA biplots and simplified NMDSs with quantification provided by the distance correlation between MNP impacts summarized at different taxonomic levels. The present study demonstrates that visual exploration could potentially assist in knowledge discovery and interpretation of data on soil bacterial communities exposed to MNPs and thus evaluate the potential for environmental impacts.

An integrated simulation tool was developed for assessing the potential release and environmental distribution of nanomaterials (RedNano) based on a life cycle assessment approach and multimedia compartmental modeling coupled with mechanistic intermedia transport processes. The RedNano simulation tool and its web-based software implementation enables rapid “what-if?” scenario analysis, in order to assess the response of an environmental system to various release scenarios of engineered nanomaterials (ENMs). It also allows for the investigation of the impact of geographical and meteorological parameters on ENM distribution in the environment, comparison of the impact of ENM production and potential releases on different regions, and estimation of source release rates based on monitored ENM concentrations. Moreover, the RedNano simulation tool is suitable for research, academic, and regulatory purposes. Specifically, it has been used in environmental multimedia impact assessment courses at both the undergraduate and graduate levels. The RedNano simulation tool can also serve as a decision support tool to rapidly and critically assess the potential environmental implications of ENMs and thus ensure that nanotechnology is developed in a productive and environmentally responsible manner.