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Aims To determine long-term safety and efficacy outcomes of a subretinal gene therapy for CNGA3-associated achromatopsia. We present data from an open-label, nonrandomised controlled trial (NCT02610582). Methods Details of the study design have been previously described. Briefly, nine patients were treated in three escalating dose groups with subretinal AAV8. CNGA3 gene therapy between November 2015 and October 2016. After the first year, patients were seen on a yearly basis. Safety assessment constituted the primary endpoint. On a secondary level, multiple functional tests were carried out to determine efficacy of the therapy. Results No adverse or serious adverse events deemed related to the study drug occurred after year 1. Safety of the therapy, as the primary endpoint of this trial, can, therefore, be confirmed. The functional benefits that were noted in the treated eye at year 1 were persistent throughout the following visits at years 2 and 3. While functional improvement in the treated eye reached statistical significance for some secondary endpoints, for most endpoints, this was not the case when the treated eye was compared with the untreated fellow eye. Conclusion The results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor. [ABSTRACT FROM AUTHOR]

Distributed widely in structured marine clay, intra- and inter-particle pores significantly influence the physical properties, hydraulic conductivity, and mechanical behavior of such soil. However, the distribution and morphology characteristics of these pores cannot be quantified through particular single method, and instead, a combination of techniques with different measuring ranges is required. This paper focuses on natural marine clay retrieved from Zhanjiang, China (ZJ clay), this being a typically structured clay with cementation bonding. In this study, the methods of scanning electron microscopy (SEM), mercury intrusion porosimetry (MIP), and nitrogen gas adsorption (NGA) were applied in combination to (i) analyze the microscopic characteristics of the pores in natural ZJ clay and the factors influencing the evolution of those pores and (ii) establish the relationship between the microstructural characteristics and macroscopic performance (including both physical and mechanical behaviors) of ZJ clay. The test results show that natural ZJ clay is featured by a randomly oriented open-flocculated structure with cementation bonding and the particles within this clay are interconnected by edge-to-face or edge-to-edge contacts, which contributed to the high structural strength and stability. The hysteresis loops in both the extrusion curves from the MIP tests and the desorption isotherms from the NGA tests indicate the existence of ink-bottle pores in ZJ clay. Through the test results of SEM, MIP, and NGA, further qualitative and quantitative analyses of the complete pore size distribution characteristics of marine clay were allowed. This study enhances the comprehension of pore characteristics of natural structured clays from a microscopic perspective. [ABSTRACT FROM AUTHOR]

A large landslide (frozen debris avalanche) occurred at Assapaat on the south coast of the Nuussuaq Peninsula in Central West Greenland on June 13, 2021, at 04:04 local time. We present a compilation of available data from field observations, photos, remote sensing, and seismic monitoring to describe the event. Analysis of these data in combination with an analysis of pre- and post-failure digital elevation models results in the first description of this type of landslide. The frozen debris avalanche initiated as a 6.9 * 106 m3 failure of permafrozen talus slope and underlying colluvium and till at 600–880 m elevation. It entrained a large volume of permafrozen colluvium along its 2.4 km path in two subsequent entrainment phases accumulating a total volume between 18.3 * 106 and 25.9 * 106 m3. About 3.9 * 106 m3 is estimated to have entered the Vaigat strait; however, no tsunami was reported, or is evident in the field. This is probably because the second stage of entrainment along with a flattening of slope angle reduced the mobility of the frozen debris avalanche. We hypothesise that the initial talus slope failure is dynamically conditioned by warming of the ice matrix that binds the permafrozen talus slope. When the slope ice temperature rises to a critical level, its shear resistance is reduced, resulting in an unstable talus slope prone to failure. Likewise, we attribute the large-scale entrainment to increasing slope temperature and take the frozen debris avalanche as a strong sign that the permafrost in this region is increasingly at a critical state. Global warming is enhanced in the Arctic and frequent landslide events in the past decade in Western Greenland let us hypothesise that continued warming will lead to an increase in the frequency and magnitude of these types of landslides. Essential data for critical arctic slopes such as precipitation, snowmelt, and ground and surface temperature are still missing to further test this hypothesis. It is thus strongly required that research funds are made available to better predict the change of landslide threat in the Arctic. [ABSTRACT FROM AUTHOR]

Methylmalonic acidemia is a neurometabolic disorder biochemically characterized by the accumulation of methylmalonic acid (MMA) in different tissues, including the central nervous system (CNS). In this sense, it has been shown that high levels of this organic acid have a key role in the progressive neurological deterioration in patients. Astroglial cells actively participate in a wide range of CNS functions, such as antioxidant defenses and inflammatory response. Considering the role of these cells to maintain brain homeostasis, in the present study, we investigated the effects of MMA on glial parameters, focusing on redox homeostasis and inflammatory process, as well as putative mediators of these events in C6 astroglial cells. MMA decreased cell viability, glutathione levels, and antioxidant enzyme activities, increased inflammatory response, and changed the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NFκB), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and adenosine receptors, suggesting that these transcriptional factors and proteins may underlie the glial responses induced by MMA. Moreover, we also demonstrated the protective roles of melatonin and resveratrol against MMA-induced inflammation and decrease in glutathione levels. In summary, our findings support the hypothesis that astroglial changes are associated with pathogenesis of methylmalonic acidemia. In addition, we showed that these cells might be potential targets for preventive/therapeutic strategies by using molecules, such as melatonin and resveratrol, which mediated glioprotection in this inborn error of metabolism. [ABSTRACT FROM AUTHOR]

Discovered as a contaminant of adenovirus stocks in the 1960s, adeno-associated virus (AAV) is a mono-stranded DNA virus that depends on helper factors to replicate. Even though AAV is endemic in the human population (35–80%), it is remarkable that many issues concerning the natural infection by this virus remain unanswered. In this study, we reflect on the main basic aspects of AAV biology and provide an overview of the studies exploring the impact of AAV infection on human health, focusing on three major research areas including, (i) cervical and (ii) liver cancer, and (iii) reproductive system disorders. Conflicting results have been obtained into the association of AAV infection with the occurrence of adverse reproductive outcomes, such as placental complications, spontaneous abortion, and fertility disorders, or with a protective role in HPV-related cervical carcinogenesis. Noteworthy, recent reports have identified AAV insertional mutagenesis as a novel risk factor for the development of hepatocellular carcinoma. This latest finding raises concern regarding the widespread usage of AAV vectors in liver-targeted gene therapy. [ABSTRACT FROM AUTHOR]

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies. Combined methylmalonic acidemia (MMA) and hyperhomocysteinemias are inborn errors of vitamin B12 metabolism, and mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) underlie some forms of these disorders. Here the authors generated mouse models of a human syndrome due to mutations in RONIN (THAP11) and HCFC1, and show that this syndrome is both an inborn error of vitamin B12 metabolism and displays some features of ribosomopathy. [ABSTRACT FROM AUTHOR]

This study evaluates the strength behaviors and morphological characteristics of Lianyungang marine clay under the effect of porewater salinity. Soil at higher salinity was found to have increased internal friction angle and undrained shear strength. The difference in undrained shear strength enlarges as the confining pressure increases. Different stress paths were exhibited with soil at different salinities. Soil morphology analysis including scanning electron microscopy (SEM) and Image-Pro Plus (IPP) were employed to investigate the underlying mechanism of the enhanced strength behaviors of soft marine clay with increased salinity. Aggregated soil fabric was observed at higher salinity and contributed to enhanced strength. The results demonstrate that the aggregated soil structure is the primary mechanism responding to the enhanced strength behavior of marine clay under relatively high salinity (6%). Quantitative relationships were developed between the strength parameters and morphological characteristics of soil, i.e., area of particles, roundness of particles, area of pores, pore orientation, and fractal dimension of pore distribution, in the forms of empirical equations, and are expected to serve as the references for prediction in undrained behaviors of soft marine clays with known soil index. [ABSTRACT FROM AUTHOR]

Gene therapy for hemophilia using adeno-associated virus (AAV) derived vectors can reduce or eliminate patients' disease-related complications and improve their quality of life. Broad implementation globally will lead to societal gains and foster health equity. Several vector products each for factor IX (FIX) or factor VIII (FVIII) deficiency are in advanced clinical development. Safety data are reassuring. Efficacy data for up to 8 and 5 years, respectively, vary considerably among vector types and among individuals, but indicate significant reduction in bleeds and factor use. Products will soon be approved for marketing. This review highlights the relevant considerations for implementation of hemophilia gene therapy, specifically across a broad range of socioeconomic backgrounds globally, based on recent publications and our own experience. We address the current efficacy and safety data and relevant aspects of vector immunology. We then discuss pertinent implementation steps including pre-implementation and readiness assessments, considerations on cost, cost-effectiveness and payment models, approaches to education and informed consent, and the operational needs as well as the need for monitoring of health outcomes and implementation outcomes. To prevent a lag or complete lack of establishing access to this life-changing therapy option for all patients with hemophilia worldwide, adaptable pathways supported by collaborative and international efforts of all stakeholders are needed. [ABSTRACT FROM AUTHOR]

Despite the prevalence of peat in northern areas of Europe and elsewhere, there are comparatively few case histories of carefully monitored embankments constructed directly on peat. In addition the use of relatively advanced and commercially available numerical models for prediction of the settlement in peat has only infrequently been documented. Practising geotechnical engineers lack advice on the use of such models and in particular on the selection of the input parameters. This paper demonstrates that a combination of routine oedometer tests, careful use of published correlations and simulations of independent data can provide reliable input parameters. The work demonstrates a good match between field measurements and simulations, but shows that it is difficult to model all stages of loading accurately with one set of input parameters. The user may need to focus on what specific output is critical and a number of analyses may be needed to obtain accurate prediction for all cases. Although the focus of the model used was on creep prediction, the work demonstrates that other benefits of using a finite-element analysis over hand calculations – such as modelling layers, buoyancy, variation in parameters such as permeability with strain and time – are perhaps more important than creep. [ABSTRACT FROM AUTHOR]

Knowledge of soil thermal properties is necessary for the thermal evaluation and design in geotechnical engineering. In this study, the soil thermal properties of undisturbed lateritic clay with and without free iron oxides were measured during drying and wetting. Furthermore, mercury intrusion porosimetry and scanning electron microscopy tests were conducted on specimens to investigate how the free iron oxides affect the soil microstructure. Test results revealed that the thermal conductivity and diffusivity of the undisturbed lateritic clay with the free iron oxides removed (i.e., treated specimens) were higher than those with the free iron oxides (i.e., untreated specimens). The hysteresis effect on the soil thermal conductivity had reduced after removing the free iron oxides. Investigations showed that the microstructure of the treated specimens was denser, and the debris and granular units considerably increased compared with those of untreated specimens. The number and size of soil pores in the treated specimens was lower and smaller than those of untreated specimens. The difference in thermal conductivity and diffusivity between the treated and untreated specimens was mainly attributed to the different extent or quality of connections between neighbouring soil particles that affected the conductive heat transfer in specimens. After removing the free iron oxides, the connection and inclusion of the stable aggregates were destroyed; thus, the relatively large soil pores disappeared. The further dispersion of the soil particles forming the aggregates filled the relatively small pores in specimens, which increased the heat transfer path between neighbouring soil particles. [ABSTRACT FROM AUTHOR]

Cobalamin C disease is the most common inborn error of cobalamin metabolism, resulting from mutations in methylmalonic aciduria and homocystinuria type C protein (MMACHC) gene. There is associated elevation of homocysteine and methylmalonic acid and decreased synthesis of methionine. It is a multisystem disorder characterised by cognitive impairment, psychiatric manifestations, haematological manifestations and thromboembolic phenomena. Its variable clinical presentation and wide age distribution at presentation necessitates a high index of diagnostic suspicion. The diagnosis is suggested by amino acid chromatography and confirmed by sequencing analysis of the MMACHC gene. Parenteral hydroxycobalamin and betaine can bring significant clinical and biochemical improvement and is the recommended long-term therapy. [ABSTRACT FROM AUTHOR]

The FDA has predicted that at least 10-20 gene therapy products will be approved by 2025. The surge in the development of such therapies can be attributed to the advent of safe and effective gene delivery vectors such as adeno-associated virus (AAV). The enormous potential of AAV has been demonstrated by its use in over 100 clinical trials and the FDA’s approval of two AAV-based gene therapy products. Despite its demonstrated success in some clinical settings, AAV-based gene therapy is still plagued by issues related to host immunity, and recent studies have suggested that AAV vectors may actually integrate into the host cell genome, raising concerns over the potential for genotoxicity. To better understand these issues and develop means to overcome them, preclinical model systems that accurately recapitulate human physiology are needed. The objective of this review is to provide a brief overview of AAV gene therapy and its current hurdles, to discuss how 3D organoids, microphysiological systems, and body-on-a-chip platforms could serve as powerful models that could be adopted in the preclinical stage, and to provide some examples of the successful application of these models to answer critical questions regarding AAV biology and toxicity that could not have been answered using current animal models. Finally, technical considerations while adopting these models to study AAV gene therapy are also discussed. [ABSTRACT FROM AUTHOR]

To determine and evaluate the soil structure in situ conditions, a lot of research methods have been proposed. However, ascertaining the applicability of these methods to soils of entirely different "types of structure," which they can express and evaluate, is still a point of debate. With this in view, efforts have been made in this review to critically evaluate all the established and emerging soil structure research thinking, theories, and methods with respect to their merits and demerits. Then, a detailed analysis concerning published structured indexes and constitutive models based on these methods is done to evaluate the applicability. Also, this paper puts forward some suggestions and key points for their developments. Based on the analysis of literature, each existing research method can merely dictate one type of soil structure, and combination of multiple research methods may be an effective access to reveal the structure characteristics of soil comprehensively. Moreover, it will be the focus of soil structure research to quantitatively link the microstructure characteristics with the macro-structure characteristics. These results will be useful for geotechnical engineers and researchers who consider the soil structure in engineering survey and design. [ABSTRACT FROM AUTHOR]

Gap-graded granular soils are used as construction materials worldwide, and their hydraulic conductivity depends on their relative content of coarse and fine grains, initial conditions, and particle shape. In this study, a series of constant head hydraulic conductivity tests were performed on gap-graded granular soils with different initial relative densities, fine contents, and particle shapes. The test results show that the hydraulic conductivity decreases with an increase in fine fraction and then remains approximately constant beyond the "transitional fine content." The role of the structural effect on the hydraulic conductivity is different from that on the mechanical properties (such as stiffness and shear strength). This can be attributed to the degree of filling within inter-aggregate voids, disturbance of soil structure, and densified fine bridges between coarse aggregates. The equivalent void ratio concept was introduced into the Kozeny–Carman formula to capture the effect of fines (aggregates) on the "coarse-dominated" ("fine-dominated") structure, and a simple model is proposed to capture the change of hydraulic conductivity of gap-granular soils. The model incorporates a structural variable to capture the effect of fines on "coarse-dominated" structure and coarse aggregates on "fine-dominated" structure. The performance of the model was verified with experimental data from this study and previously reported data compiled from the literature. The results reveal that the proposed model is simple yet effective at capturing the hydraulic conductivity of gap-graded granular soils with a wide range of fine contents, initial conditions, and particle shapes. [ABSTRACT FROM AUTHOR]

Background: cblC deficiency is the most common type of methylmalonic aciduria in China. Late-onset patients present with various non-specific symptoms and are usually misdiagnosed. The purpose of this study is to investigate the clinical features of patients with late-onset cblC deficiency and explore diagnosis and management strategies around puberty.Results: This study included 56 patients (35 males and 21 females) with late-onset cblC deficiency who were admitted to our clinic between 2002 and September 2021. The diagnosis was confirmed by metabolic and genetic tests. The clinical and biochemical features, disease triggers, outcome, and associated genetic variants were examined. The onset age ranged from 10 to 20 years (median age, 12 years). Fifteen patients (26.8%) presented with symptoms after infection or sports training. Further, 46 patients (82.1%) had neuropsychiatric diseases; 11 patients (19.6%), cardiovascular diseases; and 6 patients (10.7%), pulmonary hypertension. Renal damage was observed in 6 cases (10.7%). Genetic analysis revealed 21 variants of the MMACHC gene in the 56 patients. The top five common variants detected in 112 alleles were c.482G > A (36.6%), c.609G > A (16.1%), c.658_660delAAG (9.8%), c.80A > G (8.0%), and c.567dupT (6.3%). Thirty-nine patients carried the c.482G > A variant. Among 13 patients who exhibited spastic paraplegia as the main manifestation, 11 patients carried c.482G > A variants. Six patients who presented with psychotic disorders and spastic paraplegia had compound heterozygotic c.482G > A and other variants. All the patients showed improvement after metabolic treatment with cobalamin, L-carnitine, and betaine, and 30 school-aged patients returned to school. Two female patients got married and had healthy babies.Conclusions: Patients with late-onset cblC deficiency present with a wide variety of neuropsychiatric symptoms and other presentations, including multiple organ damage. As a result, cb1C deficiency can easily be misdiagnosed as other conditions. Metabolic and genetic studies are important for accurate diagnosis, and metabolic treatment with cobalamin, L-carnitine, and betaine appears to be beneficial. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, the first being Alzheimer's disease. Patients with PD have a loss of dopaminergic neurons in the substantia nigra of the basal ganglia, which controls voluntary movements, causing a motor impairment as a result of dopaminergic signaling impairment. Studies have shown that mutations in several genes, such as SNCA, PARK2, PINK1, DJ-1, ATP13A2, and LRRK2, and the exposure to neurotoxic agents can potentially increase the chances of PD development. The nematode Caenorhabditis elegans (C. elegans) plays an important role in studying the risk factors, such as genetic factors, aging, exposure to chemicals, disease progression, and drug treatments for PD. C. elegans has a conserved neurotransmission system during evolution; it produces dopamine, through the eight dopaminergic neurons; it can be used to study the effect of neurotoxins and also has strains that express human α-synuclein. Furthermore, the human PD-related genes, LRK-1, PINK-1, PDR-1, DJR-1.1, and CATP-6, are present and functional in this model. Therefore, this review focuses on highlighting and discussing the use of C. elegans an in vivo model in PD-related studies. Here, we identified that nematodes exposed to the neurotoxins, such as 6-OHDA, MPTP, paraquat, and rotenone, had a progressive loss of dopaminergic neurons, dopamine deficits, and decreased survival rate. Several studies have reported that expression of human LRRK2 (G2019S) caused neurodegeneration and pink-1, pdr-1, and djr-1.1 deletion caused several effects PD-related in C. elegans, including mitochondrial dysfunctions. Of note, the deletion of catp-6 in nematodes caused behavioral dysfunction, mitochondrial damage, and reduced survival. In addition, nematodes expressing α-synuclein had neurodegeneration and dopamine-dependent deficits. Therefore, C. elegans can be considered an accurate animal model of PD that can be used to elucidate to assess the underlying mechanisms implicated in PD to find novel therapeutic targets., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Gene Therapy Medicinal Products consist of a recombinant nucleic acid intended for the modulation or manipulation of a genetic sequence. A single administration of a novel gene therapy has the potential to be curative, with a durable long-term benefit to patients. Adeno-associated viral vectors have become the viral vector of choice for in vivo delivery of therapeutic transgenes as they are mildly immunogenic, can effectively transduce a variety of human tissues and cells, and have low levels of genomic integration. Central to the effective translation of data generated in discovery studies to the clinic is the selection of appropriate animal species for pivotal non-clinical studies. This review aims to support the selection of appropriate animal models for non-clinical studies to advance the development of novel adeno-associated virus gene therapies., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Current specific treatments for mucopolysaccharidoses (MPSs) include enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). Both treatments are hampered by several limitations, including lack of efficacy on brain and skeletal manifestations, need for lifelong injections, and high costs. Therefore, more effective treatments are needed. Gene therapy in MPSs is aimed at obtaining high levels of the therapeutic enzyme in multiple tissues either by engrafted gene-modified hematopoietic stem progenitor cells (ex vivo) or by direct infusion of a viral vector expressing the therapeutic gene (in vivo). This review focuses on the most recent clinical progress in gene therapies for MPSs. The various gene therapy approaches with their strengths and limitations are discussed., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Liver cancer is increasing due to the rise in metabolic dysfunction-associated steatohepatitis (MASH). High-mobility group box-1 (HMGB1) is involved in the pathogenesis of chronic liver disease, but its role in MASH-associated liver cancer is unknown. We hypothesized that an increase in hepatocyte-derived HMGB1 in a mouse model of inactivation of PTEN that causes MASH could promote MASH-induced tumorigenesis., Methods: We analyzed publicly available transcriptomics datasets, and to explore the effect of overexpressing HMGB1 in cancer progression, we injected 1.5-month-old Pten∆Hep mice with adeno-associated virus serotype-8 (AAV8) vectors to overexpress HMGB1-EGFP or EGFP, and sacrificed them at 3, 9 and 11 months of age., Results: We found that HMGB1 mRNA increases in human MASH and MASH-induced hepatocellular carcinoma (MASH-HCC) compared to healthy livers. Male and female Pten∆Hep mice overexpressing HMGB1 showed accelerated liver tumor development at 9 and 11 months, respectively, with increased tumor size and volume, compared to control Pten∆Hep mice. Moreover, Pten∆Hep mice overexpressing HMGB1, had increased incidence of mixed HCC-intrahepatic cholangiocarcinoma (iCCA). All iCCAs were positive for nuclear YAP and SOX9. Male Pten∆Hep mice overexpressing HMGB1 showed increased cell proliferation and F4/80+ cells at 3 and 9 months., Conclusion: Overexpression of HMGB1 in hepatocytes accelerates liver tumorigenesis in Pten∆Hep mice, enhancing cell proliferation and F4/80+ cells to drive MASH-induced liver cancer., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

In this review, we describe the multidisciplinary, multidimensional care required to optimize outcomes for pediatric transplant recipients with rare genetic kidney diseases. Transplant success, recipient survival, and improvement in quality of life depend on collaboration between patients, families, and a team of specialists with medical, as well as nonmedical expertise. A multidisciplinary transplant team composed of experts from medicine, surgery, nursing, nutrition, social services, transplant coordination, psychology, and pharmacology, is now standard in most transplant centers and is critical to the success of a transplant. In addition to these professionals, other specialists, such as cardiologists, urologists, geneticists, metabolic disease specialists, occupational therapists, case management, child life, chaplain, and palliative care services, have a crucial role to play in the preparation, surgery, and follow-up care, especially when a pediatric patient has a rare genetic disorder leading to renal involvement, and the need for transplantation. In order to describe this multidisciplinary care, we divide the genetic renal diseases into five subgroups-metabolic and tubular disorders, glomerular diseases, congenital anomalies of the kidney and urinary tract, ciliopathies including cystic diseases, and miscellaneous renal conditions; and describe for each, the need for care beyond that provided by the standard transplant team members., (© 2023 Wiley Periodicals LLC.)

Rapid advancements in automated genomic technologies have uncovered many unique findings about the turtle genome and its associated features including olfactory gene expansions and duplications of toll-like receptors. However, despite the advent of large-scale sequencing, assembly, and annotation, about 40–50% of genes in eukaryotic genomes are left without functional annotation, severely limiting our knowledge of the biological information of genes. Additionally, these automated processes are prone to errors since draft genomes consist of several disconnected scaffolds whose order is unknown; erroneous draft assemblies may also be contaminated with foreign sequences and propagate to cause errors in annotation. Many of these automated annotations are thus incomplete and inaccurate, highlighting the need for functional annotation to link gene sequences to biological identity. In this study, we have functionally annotated two genes of the red-bellied short-neck turtle (Emydura subglobosa), a member of the relatively understudied pleurodire lineage of turtles. We improved upon initial ab initio gene predictions through homology-based evidence and generated refined consensus gene models. Through functional, localization, and structural analyses of the predicted proteins, we discovered conserved putative genes encoding mitochondrial proteins that play a role in C21-steroid hormone biosynthetic processes and fatty acid catabolism—both of which are distantly related by the tricarboxylic acid (TCA) cycle and share similar metabolic pathways. Overall, these findings further our knowledge about the genetic features underlying turtle physiology, morphology, and longevity, which have important implications for the treatment of human diseases and evolutionary studies. [ABSTRACT FROM AUTHOR]

Quantifying the magnitude of an earthquake is very important for long-term and medium-term earthquake prediction, post-earthquake emergency rescue and seismic hazard assessment. Paleo-seismology is the investigation of past earthquakes in the geological record, in particular their location, timing and size. Uncertainties remain in the paleo-earthquake magnitudes determined by traditional surface rupture parameters, especially because most seismic events do not result in surface ruptures or are of less than 0.3 m (M = ~ 6–6.8). To address the problem of magnitude evaluation of earthquakes that did not reveal major dislocations, this paper deals with the methods used to determine the seismic shaking intensity based on the types and forms of soft-sediment deformation structures, including maximum liquefaction distance, thickness of disturbed layer, empirical formulae, and thickness of rapidly deposited sand layer. Then we discuss and analyze these methods in terms of their theoretical basis, advantages and disadvantages, accuracy, applicability and problems. We chose two case studies: first, a typical seismics-related deposit (liquefied layer and disrupted layer) represented by a seismite in the late-Pleistocene Lake Lisan section near Masada in the Dead Sea Basin; and second, the liquefied diapir triggered by an earthquake in the late-Quaternary lacustrine sediments at Luobozhai in the upper reaches of the Minjiang River, East Tibet. The five methods listed above are employed to determine earthquake magnitudes associated with the seismics-related deposit and liquefied diapir, yielding magnitudes of 5.5–6.5 and 6.0–7.0, respectively. The combination of the five methods, provided a new and relatively convenient method for determining seismic shaking, especially in lacustrine sediments. This study can serve as a valid reference for comparing methods of calculating the magnitude of a paleo-earthquake based on surface rupture parameters, and provides a better understanding of the long-term seismic activity and risk in tectonically active regions. [ABSTRACT FROM AUTHOR]

Dual-porosity structures of fine-grained soils can noticeably affect their ability to retain water. This work jointly employs axis translation technique, filter paper method, and vapor equilibrium technique to study the soil–water retention curve (SWRC) over a wide suction range of Nanyang expansive soil characterized by double porosity. Mercury intrusion porosimetry tests are carried out to investigate the correlations between the aforementioned water-retention response and underlying pore structure characteristics. The test data show that dual-porosity distribution leads to bimodal SWRC. The change in void ratio mainly affects the median size of the inter-aggregate pores and consequently the portion of SWRC at low suction range. Based on these experimental observations, this work presents an SWRC equation for fine-grained soils with dual-porosity structures. Attracting water through capillary and adsorptive processes is explicitly distinguished. The capillary water is described by a relation that includes the characteristics of both inter- and intra-aggregate pore size distributions as parameters for representing bimodal characteristics. The adsorbed water is modeled by a relation that considers capillary condensation within intra-aggregate pores and allows for the decoupling between adsorptive water-retention mechanism and void ratio change. The latter feature is the foundation for the model to include the void ratio effect on SWRC in a way consistent with how it affects the pore structures of soils. By simulating test data in this work and in the literature, the proposed model is shown to be capable of representing the water-retention behavior of fine-grained soils with dual-porosity structures under different void ratios. To include the aforementioned key factors that influence the SWRC of fine-grained soils, seven parameters are required in the proposed model. This feature can reduce the practical applicability of the model. Future directions to enhance this aspect are discussed. [ABSTRACT FROM AUTHOR]

In this paper, we compare the performance of two data-driven algorithms to deal with an automatic classification problem in geomorphology: Direct Sampling (DS) and Random Forest (RF). The main goal is to provide a semi-automated procedure for the geomorphological mapping of alpine environments, using a manually mapped zone as training dataset and predictor variables to infer the classification of a target zone. The applicability of DS to geomorphological classification was never investigated before. Instead, RF based classification has already been applied in few studies, but only with a limited number of geomorphological classes. The outcomes of both approaches are validated by comparing the eight detected classes with a geomorphological map elaborated on the field and considered as ground truth. Both DS and RF give satisfactory results and provide similar performances in term of accuracy and Cohen's Kappa values. The map obtained with RF presents a noisier spatial distribution of classes than when using DS, because DS takes into account the spatial dependence of the different classes. Results suggest that DS and RF are both suitable techniques for the semi-automated geomorphological mapping in alpine environments at regional scale, opening the way for further improvements. [ABSTRACT FROM AUTHOR]

Homologous recombination (HR)-based gene therapy using adeno-associated viruses (AAV-HR) without nucleases has several advantages over classic gene therapy, especially the potential for permanent transgene expression. However, the low efficiency of AAV-HR remains a major limitation. Here, we tested a series of small-molecule compounds and found that ribonucleotide reductase (RNR) inhibitors substantially enhance AAV-HR efficiency in mouse and human liver cell lines approximately threefold. Short-term administration of the RNR inhibitor fludarabine increased the in vivo efficiency of both non-nuclease- and CRISPR/Cas9-mediated AAV-HR two- to sevenfold in the murine liver, without causing overt toxicity. Fludarabine administration induced transient DNA damage signaling in both proliferating and quiescent hepatocytes. Notably, the majority of AAV-HR events occurred in non-proliferating hepatocytes in both fludarabine-treated and control mice, suggesting that the induction of transient DNA repair signaling in non-dividing hepatocytes was responsible for enhancing AAV-HR efficiency in mice. These results suggest that use of a clinically approved RNR inhibitor can potentiate AAV-HR-based genome-editing therapeutics.Fludarabine-induced DNA damage pathways enhance the in vivo efficiency of homologous recombination-based gene editing. [ABSTRACT FROM AUTHOR]

To evaluate the current evidence on dating interventions, their theoretical underpinnings and effectiveness for adult neuro-atypical populations. A literature search was completed using CINAHL, Communication Source, PsycARTICLES, PsycINFO, SocINDEX, MEDLINE, Embase, AMED and EMB Reviews (all), for English-language, peer-reviewed studies into interventions for relationships or dating among adults with acquired brain injuries (ABI), learning disabilities or autistic spectrum disorder (ASD). Demographic data and intervention details were extracted for all included studies. Standard checklists were used for methodological quality and intervention description. Narrative synthesis for studies rating above poor quality. A total of 11 studies (13 articles) were eligible, ABI (n = 6), learning disability (n = 4), ASD (n = 1). These comprised five comparison or control group studies, two pre-post studies and four case studies. The methodological quality was varied, but intervention descriptions were generally poor. While all studies reported positive outcomes, firm conclusions on their effectiveness are difficult due to the high number of before-after analyses and variation in content and outcome measures used. More high-quality studies are needed to assess the effectiveness of interventions. Also, greater consensus is needed on the key behaviors for dating and relationships and the measures to assess these. Intimate relationships are important to quality of life, but challenging for many people in neuro-atypical populations. There are a small number of researched interventions to support dating or marital relationships among adults with ABI, ASD or learning disabilities. Rehabilitation professionals should ask about dating and relationships and support people if this area is identified as important. Rehabilitation professionals should consider different interventions for dating skills and marital relationships. [ABSTRACT FROM AUTHOR]

Maple syrup urine disease (MSUD) is a rare recessively inherited metabolic disorder causing accumulation of branched chain amino acids leading to neonatal death, if untreated. Treatment for MSUD represents an unmet need because the current treatment with life-long low-protein diet is challenging to maintain, and despite treatment the risk of acute decompensations and neuropsychiatric symptoms remains. Here, based on significant liver contribution to the catabolism of the branched chain amino acid leucine, we develop a liver-directed adeno-associated virus (AAV8) gene therapy for MSUD. We establish and characterize the Bckdha (branched chain keto acid dehydrogenase a)−/− mouse that exhibits a lethal neonatal phenotype mimicking human MSUD. Animals were treated at P0 with intravenous human BCKDHA AAV8 vectors under the control of either a ubiquitous or a liver-specific promoter. BCKDHA gene transfer rescued the lethal phenotype. While the use of a ubiquitous promoter fully and sustainably rescued the disease (long-term survival, normal phenotype and correction of biochemical abnormalities), liver-specific expression of BCKDHA led to partial, though sustained rescue. Here we show efficacy of gene therapy for MSUD demonstrating its potential for clinical translation. Maple syrup urine disease (MSUD) is a rare inborn error of metabolism, which is currently treated with life-long low-protein diet that can be challenging to maintain. Here the authors develop an AAV8-directed gene therapy providing sustainable disease rescue in a mouse model of MSUD. [ABSTRACT FROM AUTHOR]

Overseas, relict deep-seated coastal landslides have attracted significant analysis because of potential hazards caused by sea level rise and climate change. Despite the rapid growth in the Auckland region, regional coastal landslide hazards are poorly understood. We investigated the geomorphology and material properties of Ohuka coastal landslide on the southwestern coastline of the Auckland region, to better understand the failure mechanism. The site is formed on weak Neogene sediments of varying lithological properties, with very low angles of dip, exposed on both the seaward (west) and landward (east) flanks of Ohuka Hill. Displacement appears to have been rotational, along a low-angled basal shear surface, the Koheroa Clay Seam. The surface geomorphology consists of discontinuous uphill-facing scarplets indictive of rotational slump blocks, along the basal shear surface. However, the preservation of slump block surface topography is hindered due to the lack of a thick, strong caprock, and high annual rainfall (1400 mm), and erosion. The proposed failure mechanism and general geometry is consistent with correlations between graben width and depth to failure plane reported from bedding-controlled coastal landslides formed on low dip angles in southern England. This provides important context, given the paucity of New Zealand bedding-controlled coastal landslide case studies. [ABSTRACT FROM AUTHOR]

Purpose: Deterioration of soil physical properties, especially poor soil structure, is the foremost cause for the low productivity of saline-alkali soils. The application of frost heaving in the soil has the potential to alter the physical properties of soils and subsequently affect the hydraulic characteristics of saline-alkali soils. However, insufficient research regarding their microscopic characteristics can be found among the existing studies. Methods: This paper investigates the influences of the frost heave on the microstructure and porosity of coastal saline-alkali soils in terms of the temperature and water contents. The microstructure and overall porosity of soils were analyzed before and after being frozen by using polarizing microscope. Results: Results indicated that frost heave significantly improved the microstructure and porosity of soils. The pores of the coastal saline-alkali soils mainly consist of small pores and micropores with weak water and salt transport capacity, and the average soil porosity is only 23.41%. Under the frozen-heaving effect, the pores of saline-alkali soils with diameters larger than 20 μm increase significantly, and the average soil porosity reaches 34.06%, which is 45.49% higher than that before freezing. Water content and temperature are the primary factors affecting micro-characteristics of soil under frost heave, and more significant influence came from the water content. Conclusion: The results show that the frost heave can considerably improve the structural characteristics of the saline-alkali soil. [ABSTRACT FROM AUTHOR]

This paper presents an experimental investigation on the effects of soil structure and anisotropy on the undrained shear behavior of natural clays. A series of laboratory K0-consolidated undrained (CK0U) and isotropically consolidated undrained (CIU) triaxial tests were conducted on both undisturbed and reconstituted clay specimens. Test results showed that the undrained shear strength for both undisturbed and reconstituted specimens obtained from the CK0U test is higher than the CIU test at a given effective global stress (p′). Comparison of the difference in undrained strength showed that the effect of soil structure on undrained shear strength will gradually lose with the increasing consolidation stress while the effect of soil anisotropy will gradually increase with the increase of the consolidation stress. The effect of soil structure and anisotropy on soil cohesion is negligible. The soil structure and anisotropy mainly affect the total friction angle of specimens yet the influence on the effective friction angle is slight. Undrained shear strength of natural undisturbed clay samples consolidated isotropically or anisotropically can be well predicted using the piecewise function proposed in the present study. [ABSTRACT FROM AUTHOR]

The undrained shear strength of the sensitive clays is an important parameter for the design of the foundation of the civil engineering structures. In this study, novel hybrid machine learning approaches, namely ANFIS-CA and ANFIS-PSO, are developed to predict the undrained shear strength of the sensitive clays. These approaches are based on adaptive neuro-fuzzy inference system (ANFIS) and two metaheuristic optimizations techniques including cultural algorithm (CA) and particle swarm optimization (PSO). Unlike other empirical methods that relied on accurate determination of the pre-consolidation pressure, the proposed approaches are based on five reliable input parameters: depth, effective vertical stress, natural water content, liquid limit, and plastic limit. For this purpose, data of 216 sensitive clay samples obtained from different parts of Southern Finland were used for validating and training models. Standard statistical measures were used to evaluate performance of the models. The results show that the proposed hybrid ANFIS-PSO model obtained reasonably good accuracy (correlation coefficient: R = 0.715), in comparison with ANFIS-CA model (R = 0.6) in predicting the undrained shear strength of the sensitive clays. Therefore, the ANFIS-PSO model is very promising to predict the undrained shear strength of the sensitive clays with limited input parameters. [ABSTRACT FROM AUTHOR]

Studies on rainfall-induced landslides are essential for protecting the lives and property in hilly regions. Augmented numerical investigation considering geotechnical, geological, and environmental parameters of the slope for the past landslides and potential slip surfaces helps in identifying appropriate triggering mechanisms and preventive measures. In this work, numerical modelling was carried out for predicting the time of landslide occurrence of a shallow landslide based on the laboratory estimated soil water characteristic curve (SWCC) data, net rainfall infiltration, runoff, and geological characteristics of the study area. The accurate estimation of the SWCC was vital in the back-analysis of a landslide as SWCC directly governs the hydraulic and shear strength characteristics of the unsaturated slope. Instantaneously measured SWCC by the sensors severely overestimated the suction values for a given water content for the studied soil at different compaction densities. The back-analyzed rainfall-induced slope stability analysis of the case study showed that the estimated factor of safety variation with time by using the conventional SWCC estimation was inconsistent with the observed time of failure. A laboratory method was proposed to evaluate “equilibrium SWCC” data to account for the hydraulic equilibrium between the suction sensor and the field soil. The equilibrium SWCC data accurately predicted the time of landslide occurrence and slip surface. Further, the present study also highlighted the significance of the field density and net rainfall infiltration, considering climatic data, on forensic investigations through sensitivity analysis. [ABSTRACT FROM AUTHOR]

The roof collapse of deep cavities has been investigated only under fully dry or saturated conditions. However, natural soils are largely unsaturated, and consequently, their mechanical behavior is significantly different owing to the presence of matric suction. In this study, a novel analytical solution for the roof collapse of deep cavities in unsaturated soils is developed based on the upper bound theorem and the nonlinear Mohr–Coulomb criterion, and the width of a cavity with an arbitrary shape at collapse is derived. Subsequently, a parametric study is conducted to investigate the effects of water retention properties, effective cohesion, friction angle, supporting pressure, and nonlinear coefficient on the safety factors of rectangular deep cavities. It is found that matric suction and soil type have significant influences on the stability of deep cavities. There is a peak for the safety factors of deep cavities as the matric suction increases when the water‐holding capacity of the soil is low. This novel analytical solution provides a new insight into the stability of deep cavities in unsaturated soils. [ABSTRACT FROM AUTHOR]

Taking both pile end stress diffusion effect and pile‐soil interface softening effect into account, a new nonlinear method for the vertical settlement of pile is proposed in this paper. In detail, a new model, namely stress bubble fictitious soil pile model, is proposed to simulate the support from the pile bottom soil. The nonlinear soil softening model is introduced to establish the relationship between unit pile shaft friction and pile‐soil relative displacement. Then, a nonlinear calculation method for load‐settlement analysis in multilayered soil is developed with the integration of these two models. The validity and accuracy of the proposed method are verified through the comparisons against experimental and existing simplified methods. At last, a detailed parametric study is conducted to assess the influence of the parameters related to the proposed model and pile‐soil system on the load‐displacement behavior of single pile. The promotion of this method could hugely boost the prediction of the single pile settlement for the preliminary design of pile foundation in layered soil. [ABSTRACT FROM AUTHOR]

Most childhood neuromuscular disorders are caused by mutations causing abnormal expression or regulation of single genes or genetic pathways. The potential for gene therapy, gene editing and genetic therapies to ameliorate the course of these conditions is extraordinarily exciting, but there are significant challenges associated with their use, particularly with respect to safety, efficacy, cost and equity. Engagement with these novel technologies mandates careful assessment of the benefits and burdens of treatment for the patient, their family and their society. The examples provided by spinal muscular atrophy and Duchenne muscular dystrophy illustrate the potential value and challenges of gene and genetic therapies for paediatric neurological conditions. The cost and complexity of administration of these agents is a challenge for all countries. Jurisdictional variations in availability of newborn screening, genetic diagnostics, drug approval and reimbursement pathways, treatment and rehabilitation will affect equity of access, nationally and internationally. These challenges will best be addressed by collaboration by governments, pharma, clinicians and patient groups to establish frameworks for safe and cost-effective use of these exciting new therapies. [ABSTRACT FROM AUTHOR]

Challenges to the widespread application of gene therapy with adeno-associated viral (AAV) vectors include dominant conditions due to gain-of-function mutations which require allele-specific knockout, as well as long-term transgene expression from proliferating tissues, which is hampered by AAV DNA episomal status. To overcome these challenges, we used CRISPR/Cas9-mediated homology-independent targeted integration (HITI) in retina and liver as paradigmatic target tissues. We show that AAV-HITI targets photoreceptors of both mouse and pig retina, and this results in significant improvements to retinal morphology and function in mice with autosomal dominant retinitis pigmentosa. In addition, we show that neonatal systemic AAV-HITI delivery achieves stable liver transgene expression and phenotypic improvement in a mouse model of a severe lysosomal storage disease. We also show that HITI applications predominantly result in on-target editing. These results lay the groundwork for the application of AAV-HITI for the treatment of diseases affecting various organs.Limits of AAV-mediated gene therapy include targeting dominant mutations and inducing long-term transgene expression. Here, the authors show that AAV-HITI results in efficient allele-independent integration of a donor DNA in both retina and liver providing therapeutic benefit in mouse models of either a genetic form of blindness or a lysosomal storage disease, respectively. [ABSTRACT FROM AUTHOR]

The number of great magnitude tailings dam collapses has made society increasingly aware of the need to better understand the risk associated with tailings dams' collapse. Also, the analysis and studies of prior disasters should define the risk profiles and lead to the adoption of more adequate and successful policies and measures to reduce hazards. For this, we evaluated the material post-failure behavior, the construction methods, the failure causes and the geographical distribution of tailings dams' failures worldwide. The post-failure behavior was evaluated by the occurrence or absence of flow sliding recorded after the collapse. The historical risks were analyzed by the F–N curve. It was thus possible to better understand these structures' safety historically, as well as to analyze their relationship with the material's behavior. The statistics indicate the correlation between flow behavior and the event consequences. A correlation was also observed deriving from upstream failures, certain materials, some causes of failure and flow sliding. The F–N charts analysis remarks that the unsafety of tailings dams is due to upstream dams since other construction methods present risks under acceptable ranges. [ABSTRACT FROM AUTHOR]

The fundamental objective of earthquake engineering is to protect lives and livelihoods through the reduction of seismic risk. Directly or indirectly, this generally requires quantification of the risk, for which quantification of the seismic hazard is required as a basic input. Over the last several decades, the practice of seismic hazard analysis has evolved enormously, firstly with the introduction of a rational framework for handling the apparent randomness in earthquake processes, which also enabled risk assessments to consider both the severity and likelihood of earthquake effects. The next major evolutionary step was the identification of epistemic uncertainties related to incomplete knowledge, and the formulation of frameworks for both their quantification and their incorporation into hazard assessments. Despite these advances in the practice of seismic hazard analysis, it is not uncommon for the acceptance of seismic hazard estimates to be hindered by invalid comparisons, resistance to new information that challenges prevailing views, and attachment to previous estimates of the hazard. The challenge of achieving impartial acceptance of seismic hazard and risk estimates becomes even more acute in the case of earthquakes attributed to human activities. A more rational evaluation of seismic hazard and risk due to induced earthquakes may be facilitated by adopting, with appropriate adaptations, the advances in risk quantification and risk mitigation developed for natural seismicity. While such practices may provide an impartial starting point for decision making regarding risk mitigation measures, the most promising avenue to achieve broad societal acceptance of the risks associated with induced earthquakes is through effective regulation, which needs to be transparent, independent, and informed by risk considerations based on both sound seismological science and reliable earthquake engineering. [ABSTRACT FROM AUTHOR]

Rainfall-induced landslides are among the most fatal and destructive geological hazards in the mountainous regions where active faulting is a major geological process. So far, many studies have been conducted on the various factors that influence or trigger rainfall-induced landslides; however, lesser attention has been paid to the proximity of rainfall-induced landslides to major faults. First time, this paper is going to discuss the concepts of fault damage zone and fault zone processes that interact and influence the occurrence of rainfall-induced landslides. This is done by introducing the concept of fault damage zone and its architecture and then presenting several examples from high mountains of Alborz and Zagros in which fault zones interact proactively with mass movement processes. Fault zone processes control the rainfall-induced landslides by three ways: (1) increasing fracture density near major faults that produces more debris and reduces rock strength, (2) weak minerals growing in fault zones in which clay minerals grow and (3) topographic features produced by active faulting. Presented examples show how active faulting can influence localization of rainfall-induced landslides. Intensely weathered rocks in the fault zone are a major source of sediment flux combined with the water to form mudflows. Additionally, fault mechanism and movement direction of fault blocks influence on internal geometry and attitude of minor structures is fault zone that controls properties of rock materials in the fault zone and therefore influence on slope strength. The interaction and connectivity among tectonic faults, river systems and erosion is a complex feature that should be considered in modeling landslides in the mountainous regions. [ABSTRACT FROM AUTHOR]

Background: To compare MMA-related gene mutations in MMA children and the population in Qingdao, discuss the blood propionyl carnitine (C3), free carnitine (C0) methionine (MET), the mutual ratio and division difference in normal group, carrier group, and MMA group to analyze the relationship between some hotspot mutations and biochemical indicators. Methods: In total 3,700 newborns testing negative in tandem mass spectrometry (MS/MS) were selected at random and submitted for testing 8 pathogenic sites in MMACHC and 10 in MMUT. The gene mutations in 84 cases with detected mutation genes and 42 diagnosed children were compared. The levels and concentration distribution of C3, C0, MET, C3/C2, C3/C0, C3/MET in the blood samples of three groups were analyzed as well as the difference of biochemical indicators in newborns with hotspot mutations (c.609A>G, c.482G>A, and c.658-660delAAG). Results: All 8 pathogenic mutations in MMACHC in the population were detected and were basically consistent with the mutation types and frequency order in MMA group. The first three were c.609G>A, c.482G>A, and c.658_660delAAG. There were more types of mutation sites detected in MMA group than carrier group. Five out of 10 MMUT gene mutations were detected in the population, and 9 MMUT gene mutation sites were detected in MMA group. The findings in the two groups and the preset sites were not completely consistent. C3, C0, C3/C2, C3/C0, C3/MET in MMA group were higher than carrier and normal groups, and the difference was statistically significant; the MET in MMA group was lower than carrier and normal groups, and the difference was statistically significant. Based on the three sets of data distribution graphs, C3, C3/C2, C3/C0, and C3/MET were well distinguished. There were differences in the average C3 and C0 levels between carrier and normal groups, but with an obvious cross distribution in the graphs, and no difference in other indicators. In contrast to non-carrier group, C0, C3, C3/C0, C3/C2, and C3/MET concentration levels were higher in 609A>G mutation group, while MET level was lower, with statistical significance; in c.482G>A mutation group, C3, C3/C0, C3/C2, and C3/MET concentration levels were lower than non-carrier group, while MET level was higher, with statistical significance; in c.658-660delAAG mutation group, C0, C3, C3/C0, C3/C2, MET, and C3/MET concentration levels were not statistically different in contrast to other groups. Conclusions: The top three mutations in MMA children in Qingdao area are c.609A>G, c.482G>A, c.658-660del AAG mutations in MMAHC; C3, C3/C2, C3/C0 can be used as specific prompt indicators for MMA screening; C3, C3/C2, C3/C0, C3/MET can be used as specific prompt indicators for combined MMA screening; abnormalities in biochemical indicators in hotspot mutation group intuitively explains c.609A>G mutation and early-onset MMA. c.482G>A mutation links with late-onset MMA. [ABSTRACT FROM AUTHOR]

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Landslides are the main secondary effects of earthquakes in mountainous areas. The spatial distribution of these landslides is controlled by the local seismic ground motion and the local slope stability. While gravitational instabilities in arid and semi-arid environments are understudied, we document the landslides triggered by the Sarpol Zahab earthquake (November 12, 2017, Mw7.3, Iran/Iraq border), the largest event ever recorded in the semi-arid Zagros Mountains. An original earthquake-induced landslide inventory was derived, encompassing landslides of various sizes and velocities (from rapid disrupted rockfalls to slow-moving coherent landslides). This inventory confirms the low level of triggered landslides in semi-arid environments. It also displays clear differences in the spatial and volumetric distributions of earthquake-induced landslides, having 386 rockfalls of limited size triggered around the epicenter, and 9 giant (areas of ca. 106 m2) active and ancient deep-seated landslides coseismically accelerated at locations up to 180 km from the epicenter. This unusual distant triggering is discussed and interpreted as an interaction between the earthquake source properties and the local geological conditions, emphasizing the key role of seismic ground motion variability at short spatial scales in triggering landslides. Finally, the study documents the kinematics of slow-moving ancient landslides accelerated by earthquakes, and opens up new perspectives for studying landslide triggering over short (~ 1–10 years) and long-time (~ 1000–10,000 years) periods. [ABSTRACT FROM AUTHOR]

Since 2016, 3 innovative therapies for spinal muscular atrophy (SMA) have changed the face of the disease. Although these therapies often result in remarkable improvements in infants and children, benefits in adults are modest and treatment is not curative. Concerns have been raised about the enormous costs of these medications, the ultimate burden to taxpayers, and the costs to society of withholding treatments and sacrificing or disadvantaging some individuals. Physicians are best positioned to serve our patients by carefully considering the costs, benefits, implications for quality of life (QOL), and the interplay of these factors within the framework of core ethical principles that guide clinical care. ANN NEUROL 2022;91:305–316 [ABSTRACT FROM AUTHOR]