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Tauopathies comprise a spectrum of genetic and sporadic neurodegenerative diseases mainly characterized by the presence of hyperphosphorylated TAU protein aggregations in neurons or glia. Gene therapy, in particular adeno-associated virus (AAV)-based, is an effective medical approach for difficult-to-treat genetic diseases for which there are no convincing traditional therapies, such as tauopathies. Employing AAV-based gene therapy to treat, in particular, genetic tauopathies has many potential therapeutic benefits, but also drawbacks which need to be addressed in order to successfully and efficiently adapt this still unconventional therapy for the various types of tauopathies. In this Viewpoint, we briefly introduce some potentially treatable tauopathies, classify them according to their etiology, and discuss the potential advantages and possible problems of AAV-based gene therapy. Finally, we outline a future vision for the application of this promising therapeutic approach for genetic and sporadic tauopathies. [ABSTRACT FROM AUTHOR]

Recently safety concerns have been raised in connection with high doses of recombinant adeno-associated viruses (rAAV). Therefore, we undertook a series of experiments to test viral capsid (rAAV9 and rAAV-PHP.B), dose, and route of administration (intrastromal, intravitreal, and intravenous) focused on aniridia, a congenital blindness that currently has no cure. The success of gene therapy for aniridia may depend on the presence of functional limbal stem cells (LSCs) in the damaged aniridic corneas and whether rAAV can transduce them. Both these concerns were unknown, and thus were also addressed by our studies. For the first time, we report ataxia and lethality after intravitreal or intrastromal rAAV-PHP.B virus injections. We demonstrated virus escape from the eye and transduction of non-ocular tissues by rAAV9 and rAAV-PHP.B capsids. We have also shown that intrastromal and intravitreal delivery of rAAV9 can transduce functional LSCs, as well as all four PAX6-expressing retinal cell types in aniridic eye, respectively. Overall, lack of adverse events and successful transduction of LSCs and retinal cells makes it clear that rAAV9 is the capsid of choice for future aniridia gene therapy. Our finding of rAAV lethality after intraocular injections will be impactful for other researchers developing rAAV-based gene therapies., (© 2023. The Author(s).)

On August 16th, 2018, a Mw 5.1 earthquake struck the Molise region (central Italy), inducing 84 earthquake-triggered landslides that predominantly involved soil covers of clayey materials and flysch on gently dipping slopes. To quantify the spatiotemporal landslide activity in the months immediately after the earthquake, a differential SAR interferometry (DInSAR) analysis was performed for a time span from 2 years before to one year after the earthquake, recognising both first-time and reactivated landslides. The results showed a clear increase in landslide activity following the low-magnitude earthquake with respect to the activities recorded in the same months of the previous years. Several coherent landslides (earth slides and earth flows) were observed following seasonally recurrent rainfall events. Such increases were observed for both reactivated and first-time landslides, showing decreases in inactive periods and activity over longer periods. Furthermore, the spatial density distribution of the landslides was investigated in the postseismic time interval along transects perpendicular and parallel to the direction of the tectonic element responsible for the seismic event. An asymmetrical distribution was deduced parallel to the fault strike with a higher number of landslides located inside the compressional sector according to a strike-slip faulting mechanism. [ABSTRACT FROM AUTHOR]

This study describes a successful case of preimplantation genetic testing for the monogenic disease (PGT-M) of methylmalonic acidemia (MMA). To avoid the transmission of pathogenic mutations and unnecessary pregnancy termination we applied next-generation sequencing (NGS)-based haplotyping on a couple with a previously deceased MMA offspring. After embryo preparation, all samples were amplified successfully by whole genome amplification. We performed preimplantation genetic testing for aneuploidy (PGT-A) to determine the copy number of embryos' chromosomes. PGT-A results showed five blastocysts (2, 11, 14, 15 and 16) with balanced chromosomes (46, XN). Two techniques were used for PGT-M. Sanger sequencing was used to detect the mutations of MMUT gene directly, and NGS-based single nucleotide polymorphism (SNP) haplotyping was used to distinguish the chromosomes that carried the mutation. Sanger sequencing and NGS-based SNP haplotyping confirmed that samples 2 and 15 carried c.730insTT, samples 11 and 15 carried c.1105 C > T and samples 14 and 16 did not carry any mutation. Thus, blastocyst 14 was transferred into the mother's uterus. After prenatal diagnosis at 18 weeks of gestation, a healthy infant without MMUT mutation was born at full term. This study highlights the efficiency of NGS-based SNP haplotyping for PGT-M of MMA. Abbreviations: MMA: methylmalonic acidemia; MMUT: methylmalonyl-CoA mutase; PGT-M: preimplantation genetic testing for monogenic disease; PGD: preimplantation genetic diagnosis; IVF: in vitro fertilization; ADO: allele dropout; WGA: whole genome amplification; SNP: single nucleotide polymorphism; NGS: next-generation sequencing; PND: prenatal diagnosis; ICSI: intracytoplasmic sperm injection; TE: trophectoderm; DOP-PCR: degenerate oligonucleotide primed polymerase chain reaction; PGT-A: preimplantation genetic testing for aneuploidy; PCR: polymerase chain reaction. [ABSTRACT FROM AUTHOR]

Background: Methylmalonic aciduria and homocystinuria, CblC type (OMIM #277400) is the most common disorder of cobalamin intracellular metabolism, an autosomal recessive disease, whose biochemical hallmarks are hyperhomocysteinemia, methylmalonic aciduria and low plasma methionine. Despite being a well-recognized disease for pediatricians, there is scarce awareness of its adult presentation. A thorough analysis and discussion of cobalamin C defect presentation in adult patients has never been extensively performed. This article reviews the published data and adds a new case of the latest onset of symptoms ever described for the disease.Results: We present the emblematic case of a 45-year-old male, describing the diagnostic odyssey he ventured through to get to the appropriate treatment and molecular diagnosis. Furthermore, available clinical, biochemical and molecular data from 22 reports on cases and case series were collected, resulting in 45 adult-onset CblC cases, including our own. We describe the onset of the disease in adulthood, encompassing neurological, psychiatric, renal, ophthalmic and thromboembolic symptoms. In all cases treatment with intramuscular hydroxycobalamin was effective in reversing symptoms. From a molecular point of view adult patients are usually compound heterozygous carriers of a truncating and a non-truncating variant in the MMACHC gene.Conclusion: Adult onset CblC disease is a rare disorder whose diagnosis can be delayed due to poor awareness regarding its presenting insidious symptoms and biochemical hallmarks. To avoid misdiagnosis, we suggest that adult onset CblC deficiency is acknowledged as a separate entity from pediatric late onset cases, and that the disease is considered in the differential diagnosis in adult patients with atypical hemolytic uremic syndromes and/or slow unexplained decline in renal function and/or idiopathic neuropathies, spinal cord degenerations, ataxias and/or recurrent thrombosis and/or visual field defects, maculopathy and optic disc atrophy. Plasma homocysteine measurement should be the first line for differential diagnosis when the disease is suspected. To further aid diagnosis, it is important that genes belonging to the intracellular cobalamin pathway are included within gene panels routinely tested for atypical hemolytic uremic syndrome and chronic kidney disorders. [ABSTRACT FROM AUTHOR]

In regions of infrequent but potentially damaging seismicity, modern earthquake inventories may be insufficient to provide inputs to seismic hazard analyses (i.e., fault locations and magnitude–frequency relations). As a result, analysis of paleoseismic evidence, such as coseismic landsliding, is commonly used to help elucidate the seismic record, thereby reducing seismic hazard uncertainty. However, while paleolandslides have been investigated widely, existing inverse-analysis techniques (i.e., to constrain the causative earthquake magnitude and/or ground motions) have several shortcomings, namely, they (i) require the location of the causative earthquake to be known, (ii) provide only a lower-bound estimate of seismic parameters, and (iii) are deterministic in nature. Accordingly, this paper proposes a flexible inversion framework that probabilistically constrains seismic source parameters from regional paleolandslide evidence. The outputs of this framework are (i) a geospatial likelihood surface that constrains the location of fault rupture and (ii) a probability distribution of the rupture magnitude. Simulated paleolandslide studies are performed on modern earthquakes with known parameters. These examples demonstrate the framework's provocative potential as well as important lessons for implementation. The proposed framework has the potential to extract new insights from relic landslide evidence in seismic zones worldwide. [ABSTRACT FROM AUTHOR]

Cobalamin C disease is the most common complementation class of cobalamin disorders. Here, we present a case of a 14-yr-old male with early-onset cblC disease and autism spectrum disorder (ASD) admitted to our inpatient medical service for behavioral decompensation. We use this case to highlight key aspects of the neurodevelopmental and neuropsychiatric disorders associated with cblC disease. By incorporating a comprehensive review of existing literature, we highlight salient domains of psychological impairment in cblC disease, discuss the full range of neuropsychiatric presentations, and review clinical management implications unique to cblC disease. [ABSTRACT FROM AUTHOR]

On 7th of August 2020, a Mw = 4.9 earthquake occurred in Mila province (Northeast Algeria). Consequently, more than 2000 houses were indirectly affected (partially damaged or collapsed) within 10 km from the earthquake's epicenter, in the locality of El Kherba. According to field surveys conducted 3 days after the earthquake, damages and casualties were directly linked to an earthquake-induced landslide that occurred after the main shock. This was evidenced by numerous cracks in the site's soil mainly perpendicular to the landslide direction. Local characteristics (i.e., geology, geomorphology) and anthropogenic activities expose this area to landslide hazard. This study shows the reliability of the ambient noise horizontal to vertical spectral ratio (HVSR) method in the characterization of an active landslide. Ambient noise records were processed through spectral ratio techniques to identify the landslide's geometry based on spectral responses analysis. The obtained results allowed the landslide's slip surface mapping and boundary delineation, which correlates well with the field observations. After the rotation of the signal's horizontal components, large variations in the experimental spectral ratios, in both amplitude and direction, revealed site effects (soil remoulding, crack network) on the soil dynamic behavior. [ABSTRACT FROM AUTHOR]

Earthquake-triggered landslides are common disasters of active mountain belts. Due to the lack of earthquake-triggered landslide inventory in Taiwan, it is not intuitive to observe spatial relationships and discover unique patterns between landslides and essential triggers. We examined strong earthquake events in Taiwan after the 1999 Mw7.6 Chi-Chi earthquake and targeted the 2013 ML6.5 Nantou earthquake to create the landslide inventory. We adopted two Landsat-8 satellite images before and after the event to detect landslides, and incorporated a 20-m DEM and rock type data of Taiwan to represent key factors triggering earthquake-induced landslides such as peak ground acceleration (PGA), lithology, slope roughness, slope, and aspect. Based on the analysis of the density of landslides, there are strong correlations between the landslide occurrence and seismic and geomorphic factors. Furthermore, we noticed that the landslide aspects have a systematic tendency towards the northeast, which is not correlated with the dip directions and wave propagation directions. Instead, we found that the northeastward landslide aspect is more associated with the westward–southwestward surface movement at the landslides. We found that the included angles between the landslide aspects and the displacement directions for all the landslides are ~ 100°–180°. The relationship indicated that the coseismic deformation of the Nantou earthquake may play a role in the landslide distribution. [ABSTRACT FROM AUTHOR]

Tailings ponds are composed of residual mining sediments and represent a high risk due to their mechanical instability. A tailings dam break can cause extensive damage to the safety of downstream residents and the surrounding environment. This paper introduces a collapse of the tailings dam that occurred in Tonglüshan, Daye, Hubei, China. To examine the rheological properties and evolutionary mechanism of the tailings slurry from initiation to run-out, a numerical simulation was conducted through a dynamic model (DAN3D) to simulate the run-out behaviors of the tailings slurry based on the models and parameters obtained from the rheology tests. The results indicate that the slurry properties are highly consistent with the Bingham model during the movement process, and the rheological parameters of a slurry with a solid mass concentration of 74% provide the best performance in simulating this catastrophe. During the process of the Tonglüshan tailings dam break, the duration of the movement is estimated at approximately 100 s, with a maximum velocity of 22 m/s. The final distribution of the tailings deposit obtained from simulated results is in good agreement with the actual situation, indicating the validity of the selected rheological models and parameters. It is expected that the method of combining the DAN3D model with rheology tests could help clarify the propagation process of the similar tailings dam break and thus improve the accuracy of hazard prediction. [ABSTRACT FROM AUTHOR]

A hypoplastic constitutive model is proposed to model the cementation-induced enhanced stiffness, strength and dilative behavior of cemented sand and gravel materials. The model is based on the original equations proposed by Gudehus and Bauer (1996) and is extended on the basis of the concept of geometrical constraints due to cementation. The novelty of the model is twofold. First, a damage-dependent additional void ratio term is added to the original equations for the maximum, minimum and critical void ratios to account for the geometrical constraints. As a result, the two-dimensional characteristic state lines are extended to three-dimensional characteristic state surfaces. Second, a new damage factor is introduced to the constitutive equation to reflect the effect of cementation on the peak strength, and the so-called barotropy component of the stiffness factor is reformulated. Both the additional void ratio and the damage factor are related to the damage process of the inter-particle bonds, and a strain-driven damage equation is proposed based on the results of previous discrete element simulations. The model is used to reproduce triaxial experiments on a cemented dense gravel and a cemented loose sand. It is capable of capturing most of the important features of cemented granular materials. The work described in this study demonstrates the capability of hypoplasticity in modeling the complex behavior of structured soils. [ABSTRACT FROM AUTHOR]

The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington's disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells' substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic. [ABSTRACT FROM AUTHOR]

Sequencing of the human genome and numerous advances in molecular techniques have launched the era of genetic medicine. Increasingly precise technologies for genetic modification, manufacturing, and administration of pharmaceutical-grade biologics have proved the viability of in vivo gene therapy (GTx) as a therapeutic modality as shown in several thousand clinical trials and recent approval of several GTx products for treating rare diseases and cancers. In recognition of the rapidly advancing knowledge in this field, the regulatory landscape has evolved considerably to maintain appropriate monitoring of safety concerns associated with this modality. Nonetheless, GTx safety assessment remains complex and is designed on a case-by-case basis that is determined by the disease indication and product attributes. This article describes our current understanding of fundamental biological principles and possible procedures (emphasizing those related to toxicology and toxicologic pathology) needed to support research and development of in vivo GTx products. This article is not intended to provide comprehensive guidance on all GTx modalities but instead provides an overview relevant to in vivo GTx generally by utilizing recombinant adeno-associated virus-based GTx—the most common in vivo GTx platform—to exemplify the main points to be considered in nonclinical research and development of GTx products. [ABSTRACT FROM AUTHOR]

Creep or secondary consolidation of the clayey soil is critical and should be investigated. In this study, the creep behaviour of a clayey soil was investigated in the laboratory by conducting long-term oedometer tests. Standard loading and unloading procedures were followed to investigate creep for more than 1 year. The results confirmed the high creep potential of the clayey soil. Furthermore, the creep strain rate did not always increase with the load level because of the oedometric modulus hardening effect, which could be closely related to the rearrangement of the soil particles produced by secondary consolidation. A relationship existed between the compression index and the secondary consolidation coefficient, and their ratio was constant at approximately 0.026. The permeability approximately linearly increased with the void ratio. The difference in the creep behaviour at the same loading or unloading load levels indicated that the creep of the clayey soil was essentially stress-path dependent. [ABSTRACT FROM AUTHOR]

When an active landslide is first identified in an artificial reservoir, a comprehensive study has to be quickly conducted to analyse the possible hazard that it may represent to such a critical infrastructure. This paper presents the case of the El Arrecife Landslide, located in a slope of the Rules Reservoir (Southern Spain), as an example of geological and motion data integration for elaborating a preliminary hazard assessment. For this purpose, a field survey was carried out to define the kinematics of the landslide: translational in favour of a specific foliation set, and rotational at the foot of the landslide. A possible failure surface has been proposed, as well as an estimation of the volume of the landslide: 14.7 million m3. At the same time, remote sensing and geophysical techniques were applied to obtain historical displacement rates. A mean subsidence rate of the landslide around 2 cm/year was obtained by means of synthetic aperture radar interferometry (InSAR) and ground-penetrating radar (GPR) data, during the last 5 and 22 years, respectively. The structure-from-motion (SfM) technique provided a rate up to 26 cm/year during the last 14 years of a slag heap located within the foot of the landslide, due to compaction of the anthropical deposits. All of this collected information will be valuable to optimise the planning of future monitoring surveys (i.e. differential global positioning systems, inclinometers, ground drilling, and InSAR) that should be applied in order to prevent further damage on the reservoir and related infrastructures. [ABSTRACT FROM AUTHOR]

The specimen preparation method for saturated soils is crucial in soil element tests. Soil structure variations induced by different specimen preparation methods account for the different deformation characteristics and strength characteristics. In this paper, a detailed literature survey is conducted on the effects of specimen preparation methods and strain rate effects on the mechanical responses of a wide range of soil types. A series of consolidated undrained compression tests with different strain rates were carried out on clayey loess specimens made by three different remolding methods: dynamic compaction, static compaction, and reconstitution from slurry. The intertwined effects of specimen preparation methods and strain rates on stress–strain relationship, effective stress path, excess pore water pressure, and undrained strength were examined. The experimental results show that for the three orders of strain rates investigated, the dynamically compacted samples have the largest peak strength and the smallest critical state strength, while the reconstituted samples have the smallest peak strength and the largest critical state strength. The strength and the excess pore water pressure of reconstituted specimens show a correlation in regard to strain rate effect. The strain at peak deviator stress, εf, increased as the strain rate decreased. For the strain rates from 0.1%/min to 1%/min, dynamic compaction method exhibited the strongest strain rate effect, followed by the static compaction method and the reconstitution method. The above findings form an important reference for the selection of specimen preparation methods in the geotechnical laboratory testing and the engineering investigation of soil properties. [ABSTRACT FROM AUTHOR]

Soil structure is an important mechanics property which has drawn much attention from researchers. A piecewise‐linear numerical model, called SCS, is developed to investigate the large strain consolidation of structured soils. SCS accommodates large strain, soil self‐weight, vertical flows, time‐dependent loading, unloading/reloading, seepage force, soil heterogeneity, and soil structure. A three‐stage formulation is proposed to specify the compressibility behaviors of structured soils in SCS. The accuracy of SCS in the cases of small strain and large strain is checked comparing with analytical solutions and numerical solutions respectively. The effect of the main factors impacting soil structure on the consolidation processes of structured soils is investigated using several SCS simulations. Finally, a few SCS simulations with multiple structured soil layers are conducted. [ABSTRACT FROM AUTHOR]

Background: Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in only a few populations. AAV infection and host genome integration in another type of liver cancer, cholangiocarcinoma (CCA), has been studied only in one cohort. All reported oncogenic AAV integrations in HCC come from strains resembling the fully sequenced AAV2 and partly sequenced AAV13. When AAV integration occurs, only a fragment of the AAV genome is detectable in later DNA or RNA sequencing. The integrated fragment is typically from the 3' end of the AAV genome, and this positional bias has been only partly explained. Three research groups searched for evidence of AAV integration in HCC RNAseq samples in the Cancer Genome Atlas (TCGA) but reported conflicting results. Results: We collected and analyzed whole transcriptome and viral capture DNA sequencing in paired tumor and non-tumor samples from two liver cancer Asian cohorts from Thailand (N = 147, 47 HCC and 100 intrahepatic cholangiocarcinoma (iCCA)) and Mongolia (N = 70, all HCC). We found only one HCC patient with a potentially oncogenic integration of AAV, in contrast to higher frequency reported in European patients. There were no oncogenic AAV integrations in iCCA patients. AAV genomic segments are present preferentially in the non-tumor samples of Thai patients. By analyzing the AAV genome positions of oncogenic and non-oncogenic integrated fragments, we found that almost all the putative oncogenic integrations overlap the X gene, which is present and functional only in the strain AAV2 among all fully sequenced strains. This gene content difference could explain why putative oncogenic integrations from other AAV strains have not been reported. We resolved the discrepancies in previous analyses of AAV presence in TCGA HCC samples and extended it to CCA. There are 12 TCGA samples with an AAV segment and none are in Asian patients. AAV segments are present in preferentially in TCGA non-tumor samples, like what we observed in the Thai patients. Conclusions: Our findings suggest a minimal AAV risk of hepatocarcinogenesis in Asian liver cancer patients. The partial genome presence and positional bias of AAV integrations into the human genome has complicated analysis of possible roles of AAV in liver cancer. [ABSTRACT FROM AUTHOR]

Multi-pathway approaches for the treatment of complex polygenic disorders are emerging as alternatives to classical monotarget therapies and microRNAs are of particular interest in that regard. MicroRNA research has come a long way from their initial discovery to the cumulative appreciation of their regulatory potential in healthy and diseased brain. However, systematic interrogation of putative therapeutic or toxic effects of microRNAs in (models of) Alzheimer's disease is currently missing and fundamental research findings are yet to be translated into clinical applications. Here, we review the literature to summarize the knowledge on microRNA regulation in Alzheimer's pathophysiology and to critically discuss whether and to what extent these increasing insights can be exploited for the development of microRNA-based therapeutics in the clinic. [ABSTRACT FROM AUTHOR]

Mitochondria—the intracellular powerhouse in which nutrients are converted into energy in the form of ATP or heat—are highly dynamic, double-membraned organelles that harness a plethora of cellular functions that sustain energy metabolism and homeostasis. Exciting new discoveries now indicate that the maintenance of this ever changing and functionally pleiotropic organelle is particularly relevant in terminally differentiated cells that are highly dependent on aerobic metabolism. Given the central role in maintaining metabolic and physiological homeostasis, dysregulation of the mitochondrial network might therefore confer a potentially devastating vulnerability to high-energy requiring cell types, contributing to a broad variety of hereditary and acquired diseases. In this Review, we highlight the biological functions of mitochondria-localized enzymes from the perspective of understanding—and potentially reversing—the pathophysiology of inherited disorders affecting the homeostasis of the mitochondrial network and cellular metabolism. Using methylmalonic acidemia as a paradigm of complex mitochondrial dysfunction, we discuss how mitochondrial directed-signaling circuitries govern the homeostasis and physiology of specialized cell types and how these may be disturbed in disease. This Review also provides a critical analysis of affected tissues, potential molecular mechanisms, and novel cellular and animal models of methylmalonic acidemia which are being used to develop new therapeutic options for this disease. These insights might ultimately lead to new therapeutics, not only for methylmalonic acidemia, but also for other currently intractable mitochondrial diseases, potentially transforming our ability to regulate homeostasis and health. [ABSTRACT FROM AUTHOR]

Due to complications in describing and analysing the behaviour of earth materials resulting from alteration of rocks, detailed laboratory and empirical studies of their geochemical, geological, and mechanical properties are very essential and require great attention. In this work, geochemical indices have been used as an important tool in characterising tropical clays and mechanical behaviour has been predicted using different techniques. This was achieved by using a scanning electron microscope equipped with an electron dispersive spectrometer and conducting statistical analysis on tropical clays, materials that are frequently encountered by practising engineers. The mechanical behaviour considered were inherent (in situ specific volume), compression (compression index and intercept), and strength (uniaxial compressive strength), and the indices used were physical (e.g. fines content), mineralogical (e.g. quartz), and chemical indices (e.g. silica-to-alumina ratio). Tropical clay can be characterised by relating chemical indices with both depth and in situ specific volume, and the most appropriate chemical indices are alumina-titania index (ATI), silica-titania index (STI), and silica-to-alumina ratio (SA). The in situ specific volume will be satisfactorily predicted by the coefficient of uniformity (Cu), ATI, STI, and SA. The fines content (Fc), Cu, quartz, and the SA are the most suitable predictor for the compression behaviour. The strength will be successfully predicted by Fc. Physical, mineralogical, and chemical indices can be used to predict mechanical behaviour, and they are recommended for practitioners working on these materials depending on the properties required. [ABSTRACT FROM AUTHOR]

A series of one-dimensional consolidation tests was conducted on reconstituted soil mixtures with different mineral compositions. Test groups were prepared by mixing various proportions of kaolinite, quartz, and montmorillonite in which the initial water contents were equal to the liquid limits of the soils. The focus was on the compression behavior of reconstituted clay mixtures, including the rarely reported triple mixtures, as well as establishing a link between the liquid limit and the clay mineral ratio of the specimens. The intrinsic compression indexes of the soils were highly dependent on the composition of the soils and the initial water contents. New equations were proposed to estimate the compression index based on the clay mineral content, liquid limit, plasticity index, and initial void ratio. A triangular chart was proposed to estimate the compression indexes of reconstituted soils. A simple way to determine the virgin compression lines of reconstituted specimens is described. [ABSTRACT FROM AUTHOR]

Cystathionine β‐synthase (CBS) deficiency is a recessive inborn error of sulfur metabolism characterized by elevated blood levels of total homocysteine (tHcy). Patients diagnosed with CBS deficiency are currently treated by a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine, but the effectiveness of this therapy is limited due to poor compliance. A mouse model for CBS deficiency (Tg‐I278T Cbs−/−) was used to evaluate a potential gene therapy approach to treat CBS deficiency utilizing an AAVrh.10‐based vector containing the human CBS cDNA downstream of the constitutive, strong CAG promoter (AAVrh.10hCBS). Mice were administered a single dose of virus and followed for up to 1 year. The data demonstrated a dose‐dependent increase in liver CBS activity and a dose‐dependent decrease in serum tHcy. Liver CBS enzyme activity at 1 year was similar to Cbs+/− control mice. Mice given the highest dose (5.6 × 1011 genomes/mouse) had mean serum tHcy decrease of 97% 1 week after injection and an 81% reduction 1 year after injection. Treated mice had either full‐ or substantial correction of alopecia, bone loss, and fat mass phenotypes associated with Cbs deficiency in mice. Our findings show that AAVrh.10‐based gene therapy is highly effective in treating CBS deficiency in mice and supports additional pre‐clinical testing for eventual use human trials. [ABSTRACT FROM AUTHOR]

Bored-in-place piles in the loess area are mostly friction piles with a large aspect ratio. In order to study the influence of length diameter ratio on the value of pile side friction in loess area, this paper studied the load-settlement characteristics, the variation of pile axial force, and pile side friction characteristics of three test piles with different length diameter ratio through indoor tests. At the same time, ABAQUS software was used to simulate the model test to verify model test results. The results all show that the side friction in the upper part of the pile gives priority to give full play to the role, and then the side friction in the lower part of the pile begins to bear the load. With the increase of length diameter ratio, the proportion of pile end resistance to load gradually decreases, and with the pile side friction reaches the limit value, the displacement gradually moves down, and the value decreases. In order to study the value of pile side friction in loess area, a single pile load transfer model was established based on the load transfer method. Through theoretical analysis and by fitting measured soil data, the hyperbolic function parameters a and b were deduced. Hyperbolic function was subsequently used to calculate the indoor experiment pile side friction done within potting soil. The error between the measured and theoretical results was less, which indicated that the hyperbolic function method could be applied to calculate the standard value of lateral friction of pile foundations in the loess area. Combined with two example projects, the pile side friction of loess-like soil and old loess was solved by using the derived hyperbolic function method. Finally, it is concluded that the recommended value of lateral friction of loess-like soil is in the range of 40–60kPa and that of old loess is in the range of 55–80kPa.These research results can provide a reference for the determination of the standard value of lateral friction resistance of bored piles in the loess area. [ABSTRACT FROM AUTHOR]

Cardiometabolic disease (CMD) is a leading cause of death worldwide and encompasses the inflammatory metabolic disorders of obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. Flavonoids are polyphenolic plant metabolites that are abundantly present in fruits and vegetables and have biologically relevant protective effects in a number of cardiometabolic disorders. Several epidemiological studies underscored a negative association between dietary flavonoid consumption and the propensity to develop CMD. Recent studies elucidated the contribution of the gut microbiota in metabolizing dietary intake as it relates to CMD. Importantly, the biological efficacy of flavonoids in humans and animal models alike is linked to the gut microbial community. Herein, we discuss the opportunities and challenges of leveraging flavonoid intake as a potential strategy to prevent and treat CMD in a gut microbe–dependent manner, with special emphasis on flavonoid-derived microbial metabolites. [ABSTRACT FROM AUTHOR]

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Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disease caused by biallelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is characterized by motor neuron degeneration, resulting in progressive muscle atrophy and weakness. Before the emergence of disease‐modifying therapies, children with the most severe form of SMA would never achieve the ability to sit independently. Only 8% survived beyond 20 months of age without permanent ventilator support. One such therapy, onasemnogene abeparvovec, an adeno‐associated virus–based gene replacement therapy, delivers functional human SMN through a one‐time intravenous infusion. In addition to substantially improving survival, onasemnogene abeparvovec was found to increase motor milestone attainment and reduce the need for respiratory or nutritional support in many patients. This expert opinion provides recommendations and practical considerations on the patient‐centered decisions to use onasemnogene abeparvovec. Recommendations include the need for patient‐centered multidisciplinary care and patient selection to identify those with underlying medical conditions or active infections to reduce risks. We also describe the importance of retesting patients with elevated anti–adeno‐associated virus serotype 9 antibodies. Recommendations for prednisolone tapering and monitoring for potential adverse events, including hepatotoxicity and thrombotic microangiopathy, are described. The need for caregiver education on managing day‐to‐day care at time of treatment and patient‐ and family‐centered discussions on realistic expectations are also recommended. We detail the importance of following standard‐of‐care guidance and long‐term monitoring of all children with SMA who have received one or more disease‐modifying therapy using registries. We also highlight the need for presymptomatic or early symptomatic treatment of this disorder. [ABSTRACT FROM AUTHOR]

Empirical correlations provide valuable information in early design stages, and they help to validate or discard single values from site investigations. This paper presents a multivariate database from commercial projects consisting of evaluated shear strengths obtained from direct simple shear tests and fall cone tests (which are calibrated to the field vane test), including index tests. The multivariate database is used to investigate the performance of common transformation models and to test the recommended correction for fall cone tests. It is found that the measured normalised shear strength evaluated from direct simple shear tests and fall cone tests is correlated to the liquid limit and that the results conform to Swedish and Norwegian recommendations. However, the scatter is large, more for fall cone tests than for direct simple shear tests, which is thought to depend mainly on sample disturbance. It can however be concluded that the trend of normalised shear strengths increases with increasing plasticity. [ABSTRACT FROM AUTHOR]

Slow-moving landslides, often with nearly imperceptible creeping motion, are an important landscape shaper and a dangerous natural hazard across the globe, yet their spatial distribution and geologic controls are still poorly known owing to a paucity of detailed, large-area observations. Here, we use interferometry of L-band satellite radar images to reveal 617 spatially large (4 × 104–13 × 106 m2) and presently active (2007–2019) slow-moving landslides near the populous US West Coast (only 4.6% of these slides were previously known) and provide evidence for their fundamental controls by bedrock lithology and vertical land motion. We found that slow-moving landslides are generally larger and more spatially frequent in homogeneous bedrock with low rock strength, and they are preferentially located on hillslopes with geologically recent uplift. Notably, landslide size and spatial density in the relatively weak metamorphic rocks and mélange (due to pervasive tectonically sheared discontinuities, foliation, and abundant clay minerals) were two times larger than those in sedimentary and igneous rocks, and the hillslopes with landslides were found to be uplifting approximately three times faster than the average for the whole region. These results suggest that slow-moving landslides can be effectively uncovered by satellite radar imagery and their occurrence and character may be anticipated from vertical land uplift and bedrock lithology. Hence, our study provides understanding critical for reducing landslide hazards and quantifying landslide impacts on landscape change. [ABSTRACT FROM AUTHOR]

Mainstay haemophilia treatment, namely intravenous factor replacement, poses several clinical challenges including frequent injections due to the short half-life of recombinant factors, intravenous administration (which is particularly challenging in those with difficult venous access), and the risk of inhibitor development. These impact negatively upon quality of life and treatment compliance, highlighting the need for improved therapies. Several novel pharmacological therapies developed for haemophilia aim to rebalance the clotting cascade and potentially circumvent the aforementioned challenges. These therapies utilise a range of different mechanisms, namely: the extension of the circulating half-life of standard recombinant factors; the mimicking of factor VIII cofactor activity; rebalancing of coagulation through targeting of natural anticoagulants such as antithrombin and tissue factor pathway inhibitor; and inducing the production of endogenous factors with gene therapy. These therapies carry the potential of revolutionising haemophilia treatment by alleviating the current challenges presented by mainstay factor replacement. This review will provide an overview of the key trial findings related to novel therapies based on the mechanisms described above. [ABSTRACT FROM AUTHOR]

Red clay has the characteristics of high water content, high porosity ratio, and complex inverse profile, which can hardly meet the requirement strength and is of most importance in the prevision of foundation or landslides which are mainly controlled by the red clay of geotechnical properties. Hence, the X-ray diffraction test, oedometer test, triaxial un-drained (CU) test, and scanning electronic microscope test are conducted to study the geotechnical properties of intact red clay. In this paper, firstly, the effect of depth on the properties of intact specimens is investigated, including mineral component, dry density, free swell ratio, water content, void ratio, and grain size distribution. Then, the characteristics of compression behavior and its development with depth are investigated. A normalization method is carried, considering the effect of structure. Secondly, CU test is performed to analyze the mechanical behavior and strength parameters of intact, reconstructed, and slurry specimens. In addition, the classification of intact red clay is used to characterize the compression behavior. The intact specimens can be classed as structural un-compacted and structural over-consolidation soil. Moreover, an attempt is made to explain the mechanism of structural strength enhancement in intact red clay, involving interlocking strength, bonding strength, and compaction strength. [ABSTRACT FROM AUTHOR]

Background: Various stimuli, including Clonorchis sinensis infection, can cause liver fibrosis. Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs) with massive production of extracellular matrix (ECM). Our previous study showed that the TGF-β1-induced Smad signaling pathway played a critical role in the activation of HSCs during liver fibrosis induced by worm infection; however, the mechanisms that modulate the TGF-β/Smad signaling pathway are still poorly understood. Accumulating evidence demonstrates that miRNAs act as an important regulator of activation of HSCs during liver fibrosis. Methods: The target of miR-497 was determined by bioinformatics analysis combined with a dual-luciferase activity assay. LX-2 cells were transfected with miR-497 inhibitor and then stimulated with TGF-β1 or excretory/secretory products of C. sinensis (CsESPs), and activation of LX-2 was assessed using qPCR or western blot. In vivo, the mice treated with CCl4 were intravenously injected with a single dose of adeno-associated virus serotype 8 (AAV8) that overexpressed anti-miR-497 sequences or their scramble control for 6 weeks. Liver fibrosis and damage were assessed by hematoxylin and eosin (H&E) staining, Masson staining, and qPCR; the activation of the TGF-β/Smad signaling pathway was detected by qPCR or western blot. Results: In the present study, the expression of miR-497 was increased in HSCs activated by TGF-β1 or ESPs of C. sinensis. We identified that Smad7 was the target of miR-497 using combined bioinformatics analysis with luciferase activity assays. Transfection of anti-miR-497 into HSCs upregulated the expression of Smad7, leading to a decrease in the level of p-Smad2/3 and subsequent suppression of the activation of HSCs induced by TGF-β1 or CsESPs. Furthermore, miR-497 inhibitor delivered by highly-hepatotropic (rAAV8) inhibited TGF-β/smads signaling pathway by targeting at Smad7 to ameliorate CCL4-induced liver fibrosis. Conclusions: The present study demonstrates that miR-497 promotes liver fibrogenesis by targeting Smad7 to promote TGF-β/Smad signaling pathway transduction both in vivo and in vitro, which provides a promising therapeutic strategy using anti-miR-497 against liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: Methylmalonic acidemia is an organic acid metabolism disorder that usually has nonspecific clinical manifestations.Case Presentation: A 3-month-old female infant was admitted to the hospital for developmental retardation. Her prenatal and birth history was unremarkable. After admission, she developed dyspnea and severe anemia and was subsequently transferred to the intensive care unit. Magnetic resonance imaging of her brain showed a Dandy-Walker malformation, and metabolic screening indicated methylmalonic acidemia. Thus, she was diagnosed with methylmalonic acidemia and Dandy-Walker malformation. The patient underwent treatment including acidosis correction, blood transfusion, antibiotics, mechanical ventilation and heat preservation. Unfortunately, her condition progressively worsened and she died of metabolic crisis.Conclusions: Dandy-Walker malformation may be a clinical manifestation of methylmalonic acidemia. Additionally, the co-existence of methylmalonic acidemia and Dandy-Walker malformation may be an uncharacterized syndrome which needs to be studied further. [ABSTRACT FROM AUTHOR]

Relationships are important to quality of life after traumatic brain injury (TBI). However, there has been limited research into how to support dating skills or how professionals view this area. An online 52-item survey was developed and sent to professionals in the UK involved in rehabilitation after TBI. Recruitment was through professional networks, special interest groups and social media. 125 participants from a range of professions completed the survey. Many agreed that dating skills are important in rehabilitation (81.6%), but fewer (51.2%) reported engaging in this work. Psychologists, SLTs and OTs were identified as well placed to address dating skills. Case managers also appeared aware of this work. Participants reported using a range of activities to address dating skills, including managing disinhibited behavior and teaching interaction skills. Perceived barriers were both personal and professional, including lack of resources and feeling embarrassed. This study has highlighted an awareness of the importance of dating in brain injury, but professionals face multiple barriers to supporting dating skills. It is possible to draw on recommendations from related areas, including rehabilitation for cognitive communication difficulties and sexual dysfunction with further research to specifically link these areas to dating skills. [ABSTRACT FROM AUTHOR]

Abbreviations AADC Aromatic l -amino acid decarboxylase AAV Adeno-associated virus ASO Antisense oligonucleotide MPS Mucopolysaccharidosis rAAV Recombinant adeno-associated virus The impact of genome and exome sequencing has led to an unprecedented rise in diagnoses of genetic paediatric neurological diseases.1 This provides an opportunity to understand disease mechanisms and to develop novel therapeutic approaches for significant unmet clinical needs. Managed access agreements for access to Spinraza are available on public healthcare in more than 40 countries as of August 2019.29 This success stimulated the development of a personalized ASO (Milasen) for a patient with Batten disease.30 Viral gene therapy for spinal muscular atrophy type 1 has resulted in a fundamental change in rAAV gene therapy. The first was ornithine transcarbamylase deficiency gene therapy delivered by intrahepatic infusion of wild-type adenovirus that resulted in vector-related immune response, multi-organ failure, and death.4 The second was gamma retroviral correction of X-linked severe combined immunodeficiency, which reconstituted immunity but vector-related leukaemia consequently developed.5 These highlighted an inadequate understanding of vector properties, and gene therapists have worked tirelessly to engineer recombinant viral vectors to improve safety and efficiency. Lentivirus-based gene therapies are used for X-linked adrenoleukodystrophy and metachromatic leukodystrophy.26,27 In 2018, Lenti-D, an investigational gene therapy lentivirus, was granted US Food and Drug Administration "breakthrough therapy" designation and used to treat 17 patients with X-linked adrenoleukodystrophy. [Extracted from the article]

Mucopolysaccharidoses type I (MPS I) is an inherited metabolic disease characterized by a malfunction of the α‐l‐iduronidase (IDUA) enzyme leading to the storage of glycosaminoglycans in the lysosomes. This disease has longtime been studied as a therapeutic target for those studying gene therapy and many studies have been done using various vectors to deliver the IDUA gene for corrective treatment. Many vectors have difficulties with efficacy and insertional mutagenesis concerns including adeno‐associated viral (AAV) vectors. Studies of AAV vectors treating MPS I have seemed promising, but recent deaths in gene therapy clinical trials for other inherited diseases using AAV vectors have left questions about their safety. Additionally, the recent modifications to adenoviral vectors leading them to target the vascular endothelium minimizing the risk of hepatotoxicity could lead to them being a viable option for MPS I gene therapy when coupled with gene editing technologies like CRISPR/Cas9. [ABSTRACT FROM AUTHOR]

Many people with intellectual disability experience digital inequality due to a lack of Internet access; this is known as the digital divide. Digital inequality is also apparent when people with intellectual disability have Internet access, but only use it for a small number of applications (e.g., watching videos and playing games). Recently, it has been suggested that digital inequality also occurs in situations where some Internet users are less likely than others to translate their online activities to offline resources, including educational outcomes and social capital. The extent to which people with intellectual disability are translating their online activities to offline resources has not been examined. We conducted a systematic and critical review using PRISMA guidelines. The search strategy terms "intellectual disability" and "Internet use" were used to search the databases: Scopus; Wiley Online Library; Psychiatry Online; Web of Science; CINAHL; and PubMed. Twenty-four studies were found, which described 53 types of Internet use, 48 risks of Internet use, and 28 benefits of Internet use. The data were identified thematically and categorized to facilitate comparisons. The most frequently reported types of Internet use were in the category of social media/social networking (23%), the most common Internet risks were in the category of emotional distress (24%), and the most often reported benefits were in the category of friendships and social connection (33%). The findings indicate that the benefits of Internet use for people with intellectual disability have received much less attention than the risks. [ABSTRACT FROM AUTHOR]

Founded on understanding of a slope's likely failure mechanism, an early warning system for instability should alert users of accelerating slope deformation behaviour to enable safety-critical decisions to be made. Acoustic emission (AE) monitoring of active waveguides (i.e. a steel tube with granular internal/external backfill installed through a slope) is becoming an accepted monitoring technology for soil slope stability applications; however, challenges still exist to develop widely applicable AE interpretation strategies. The objective of this study was to develop and demonstrate the use of machine learning (ML) approaches to automatically classify landslide kinematics using AE measurements, based on the standard landslide velocity scale. Datasets from large-scale slope failure simulation experiments were used to train and test the ML models. In addition, an example field application using data from a reactivated landslide at Hollin Hill, North Yorkshire, UK, is presented. The results show that ML can automatically classify landslide kinematics using AE measurements with the accuracy of more than 90%. The combination of two AE features, AE rate and AE rate gradient, enable both velocity and acceleration classifications. A conceptual framework is presented for how this automatic approach would be used for landslide early warning in the field, with considerations given to potentially limited site-specific training data. [ABSTRACT FROM AUTHOR]

Objective: Methylmalonic acidemia (MMA) is the most common organic acidemia in children. Many patients with MMA suffered from cognitive impairments. The aim of this study was to identify the significance of cytokines and oxidative stress biomarkers in MMA-induced cognitive impairment. Methods: We enrolled 64 children with combined MMA and homocystinuria and 64 age- and sex-matched healthy volunteers. Participants were subsequently classified as with or without cognitive impairments using a uniform neuropsychological assessment test. Serum samples were collected. The serum levels of cytokines and oxidative stress biomarkers were measured using the ELISA or chemical methods. Results: Compared to control group, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, malondialdehyde (MDA), and nitric oxide (NO) in the MMA patients increased markedly (p < 0.05); glutathione (GSH) and superoxide dismutase (SOD) decreased obviously (p < 0.01). The levels of IL-6, TNF-α, NO, and MDA in the serum were negatively associated with DQ or IQ scores. The levels of GSH and SOD in the serum were positively correlated with DQ or IQ scores. After receiver operating characteristic curve analysis, NO was the most useful individual marker for distinguishing the cognitive dysfunction, corresponding to the area under ROC curve (AUC) of 0.82 (95% CI, 0.74–0.91), sensitivity of 76.60%, and specificity of 80.25%. GSH and MDA were also useful for diagnosis of MMA-induced cognitive dysfunction, corresponding to the AUC of 0.80 (95% CI, 0.70–0.89), and 0.73 (95% CI, 0.63–0.82), respectively. The sensitivity and specificity of GSH were 72.34 and 80.25%, respectively. The sensitivity and specificity of MDA were 85.11 and 51.85%, respectively. Conclusions: The high-concentration methylmalonic acid in the blood induced immune cells to release pro-inflammatory cytokines such as TNF-α and IL-6. These cytokines and high-concentration methylmalonic acid stimulated the immune cells to produce reactive oxygen species (ROS) and reactive nitrogen species (RNS). The serum methylmalonic acid, cytokines, ROS, and RNS were across the blood-brain barrier and induced cognitive impairment. The small molecule substances such as serum NO, MDA, and GSH participated in the process of neuroinflammation and oxidative stress injury induced by MMA and could be useful for distinguishing the cognitive impairment. [ABSTRACT FROM AUTHOR]

Our ability to unravel the mysteries of human health and disease have changed dramatically over the past 2 decades. Decoding health and disease has been facilitated by the recent availability of high-throughput genomics and multi-omics analyses and the companion tools of advanced informatics and computational science. Understanding of the human genome and its influence on phenotype continues to advance through genotyping large populations and using "light phenotyping" approaches in combination with smaller subsets of the population being evaluated using "deep phenotyping" approaches. Using our capability to integrate and jointly analyze genomic data with other multi-omic data, the knowledge of genotype-phenotype relationships and associated genetic pathways and functions is being advanced. Understanding genotype-phenotype relationships that discriminate human health from disease is speculated to facilitate predictive, precision health care and change modes of health care delivery. The American Association for Dental Research Fall Focused Symposium assembled experts to discuss how studies of genotype-phenotype relationships are illuminating the pathophysiology of craniofacial diseases and developmental biology. Although the breadth of the topic did not allow all areas of dental, oral, and craniofacial research to be addressed (e.g., cancer), the importance and power of integrating genomic, phenomic, and other -omic data are illustrated using a variety of examples. The 8 Fall Focused talks presented different methodological approaches for ascertaining study populations and evaluating population variance and phenotyping approaches. These advances are reviewed in this summary. [ABSTRACT FROM AUTHOR]

Background: The role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported. Methods: We report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients. Results: All patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient's fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients. Conclusions: We provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria. [ABSTRACT FROM AUTHOR]

The strength recovery (healing) of the shear zone soil of a landslide during the dormant phase after the sliding affects the reactivation of the landslide, and may play a key role in determining the stability of the landslide. In this paper, we report the laboratory measurements of frictional strengthening characteristics of a red-bed landslide soil. Slide-hold-slide (SHS) experiments and ultrasonic tests are performed on soil samples under natural moisture content and saturated conditions. The roles of holding time, normal stress, and drainage conditions in friction enhancement are evaluated. All the experiments are performed under room temperature. The saturated soil samples show the lowest recovery value of shear strength. It is found that red-bed landslides have obvious healing properties. The recovery value log-linear depends on the holding time and proportional to the normal stress, and the better the drainage condition is, the more obvious the recovery. Ultrasonic tests show that the wave speed difference of soil sample before and after holding is proportional to the holding time. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a debilitating disorder characterized by degeneration of large motor neurons. It is a heterogeneous group of disorders caused by a homozygous deletion in the survival motor neuron (SMN) gene on chromosome 5, resulting in a SMN protein deficiency. Small amounts of SMN protein are also produced by the SMN2 gene, which that differs from SMN1 by a single nucleotide. Spinal muscular atrophy types and phenotypic severity depend on the number of variations of the SMN2 gene and the amount of SMN2 protein produced. Because the SMN protein deficiency is the root cause of the disease, treatment strategies for SMA revolve around increasing SMN protein production. Nusinersen (Spinraza, Biogen, Cambridge, MA) was the only treatment option available for SMA until the FDA approved onasemnogene abeparvovec-xioi (Zolgensma, AveXis Inc, Bannockburn, IL), a one-time-administered adeno-associated viral vector-based gene therapy that delivers the SMN gene to the motor neuron cells. Data from clinical studies show significant improvement in motor milestone achievements and ventilatorfree survival but are limited by approximately 5 years' worth of results. This one-time intravenous injection of this new gene therapy also bears a hefty price tag; however, it may be more cost effective in the long run versus the multiple intrathecal administrations needed with nusinersen. Drug access and use are hindered by drug cost, payer reimbursement issues, and lack of long-term data from clinical studies. Questions also remain regarding the safety and efficacy of repeated drug administration for patients with advanced disease. [ABSTRACT FROM AUTHOR]

The island of Lefkada, Greece periodically suffered environmental and structural damages induced by earthquakes. During the twenty-first century, two moderate events of magnitude M > 6 occurred in 2003 and 2015 (M6.2 and M6.5, respectively). The dominant type of the earthquake-induced environmental failures was rock falls and slides that were widespread at the western part of the island. The goal of this study is to assess the earthquake-induced landslide susceptibility in the island of Lefkada and to compile a relevant susceptibility map. To achieve this, we took into account the inventories of coseismic slope failures, that were compiled for the 2003 and 2015 events. The spatial distribution of landslides in relation to the causal factors of geology and topography-oriented parameters were statistically analyzed based on the landslide susceptibility index LSI and the Likelihood ratio LR methods. In order to be able to validate the developed map, the dataset of slope failures was separated into two groups: training set (inventory of 2015 event) and testing one (inventory of 2003 earthquake). The outcome arisen by these analyses is that the geological formation of limestones of Paxos zone and the northwest-facing slopes are considered as the most causal factors for the triggering of slope failures. Considering the factor of slope angle, the LSI-based method shows that the highest frequency of slope failures is related to slope angles between 40° and 50° while the LR approach indicates the areas of high-angle slopes (60°–80°) as the most susceptible one. Taking into consideration that the susceptibility map is compiled based on the spatial distribution of coseismic slope failures triggered by earthquakes occurred both on the northern (2003 event) and southern part (2015 event) of the Lefkada segment of the Cephalonia Transform Fault (CTF), it can be characterized as a complete susceptibility map. Therefore, it is believed that can be used by public agencies and civil protection authorities since the locations of the slope failures triggered by future earthquakes are shown and consequently the elements of the manmade environment, e.g. road network that will be disrupted due to coseismic slope failures could be forecasted. [ABSTRACT FROM AUTHOR]