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Friedreich's ataxia is a rare disorder resulting from deficiency of frataxin, a mitochondrial protein implicated in the synthesis of iron-sulfur clusters. Preclinical studies in mice have shown that gene therapy is a promising approach to treat individuals with Friedreich's ataxia. However, a recent report provided evidence that AAVrh10-mediated overexpression of frataxin could lead to cardiotoxicity associated with mitochondrial dysfunction. While evaluating an AAV9-based frataxin gene therapy using a chicken β-actin promoter, we showed that toxic overexpression of frataxin could be reached in mouse liver and heart with doses between 1 × 1013 and 1 × 1014 vg/kg. In a mouse model of cardiac disease, these doses only corrected cardiac dysfunction partially and transiently and led to adverse findings associated with iron-sulfur cluster deficiency in liver. We demonstrated that toxicity required frataxin's primary function by using a frataxin construct bearing the N146K mutation, which impairs binding to the iron-sulfur cluster core complex. At the lowest tested dose, we observed moderate liver toxicity that was accompanied by progressive loss of transgene expression and liver regeneration. Together, our data provide insights into the toxicity of frataxin overexpression that should be considered in the development of a gene therapy approach for Friedreich's ataxia.

Abstract Background Optimization of vascular risk factor control is emerging as an alternative approach to improve cognitive outcomes in Alzheimer’s disease, although its efficacy is still under debate. We aimed to investigate the contribution of vascular risk factors on Alzheimer’s biomarkers and conversion rate to dementia in subjects with mild cognitive impairment (MCI) with low cerebral small vessel disease burden. Methods Two hundred ninety-five newly diagnosed MCI subjects were enrolled from March 2005 to May 2017 for a cross-sectional assessment of vascular risk factors and Alzheimer’s plasma and imaging biomarkers, followed by a cognitive outcome assessment 24 months after enrollment. The association between vascular risk factors and Alzheimer’s biomarkers were tested using multivariable linear regression models adjusted with age, gender, education, and APOE ε4 allele. The association between vascular risk factors and conversion to dementia was tested using multivariable logistic regression models adjusted with age, gender, education, and baseline Mini-Mental State Examination (MMSE) score. Results At baseline, higher low-density lipoprotein (LDL) cholesterol level was associated with more advanced plasma biomarkers, including Aβ42/Aβ40 ratio (P = 0.012) and tau level (P = 0.001). A history of hypertension was associated with more advanced white matter hyperintensity (P = 0.011), while statin therapy for dyslipidemia was associated with less advanced white matter hyperintensity (P = 0.002). At 24 months, individual vascular risk factor was not significantly associated with cognitive outcome. By contrast, statin therapy for dyslipidemia was associated with reduced conversion to dementia (adjusted OR = 0.191, 95% CI = 0.062~0.586, P = 0.004). Conclusions For MCI subjects, dyslipidemia may contribute to AD-related neurodegeneration while hypertension may contribute to vascular pathology. The association between statin therapy for dyslipidemia and reduced conversion to dementia supports further interventional study to evaluate the potential beneficial effect of statin in MCI subjects.

Background/Purpose: Researchers have recently proposed a preclinical stage of dementia of Alzheimer's type (DAT), referred to as subjective memory impairment (SMI), with the aim of developing methods for the early detection of DAT and subsequent intervention. It has been proposed that the objective memory functions of individuals with SMI are normal; however, arbitrary and semantic associations are both used to describe the processes of memory. No previous studies have investigated these processes among individuals with SMI. Methods: Cross-sectional analysis was used to compare the memory function of individuals with SMI, amnestic mild cognitive impairment (aMCI), or DAT. One hundred and eighty-three participants were recruited from the Memory Clinic of National Taiwan University Hospital and communities in northern Taiwan, including individuals with no memory complaints (HC, n = 30) and individuals with SMI (n = 61), aMCI-single domain (n = 24), aMCI-multiple domain (n = 33), or DAT (n = 35). The Word Sequence Learning Test (WSLT) was used to assess the formation of arbitrary associations and the Logical Memory subtest of the Wechsler Memory Scale-Third Edition was used to assess the formation of semantic associations. Results: Compared to the HC group, the SMI group performed poorly only on the WSLT, whereas the other groups performed poorly on both of the memory tasks. This study demonstrated that SMI individuals tend to perform poorly in the formation of arbitrary associations. Conclusion: Our findings suggest that tasks requiring arbitrary associations may provide greater sensitivity in the detection cognitive changes associated with preclinical DAT. Keywords: Alzheimer's disease, Mild cognitive impairment, Neuropsychology, Dementia

Lysosomal integral membrane protein-2 (LIMP-2) is a glucocerebrosidase receptor, which is linked to kidney failure and other diseases. Here the authors show that LIMP-2 is also a phospholipid receptor and present the lipid-bound structure of the LIMP-2 luminal domain dimer and discuss its lipid trafficking mechanism.

Geothermal environments are characterized by dynamic redox and temperature fluctuations inherited from the exposure of deeply-sourced, hot, reducing fluids to low-temperature, oxidizing ambient environments. To investigate whether microbial assemblages shifted in response to the changes of a redox state within acidic hot ponds, we collected three paired water and sediment samples from the Tatun Volcano Group, assessed metabolic roles of community members, and correlated their functional capabilities with geochemical factors along depth. Molecular analyses revealed that Sulfolobus spp., Acidianus spp. and Vulcanisaeta spp. capable of respiring elemental sulfur under oxic and/or low-oxygen conditions were the major archaeal members in planktonic communities. In contrast, obligate anaerobic Caldisphaera spp. dominated over others in bottom-dwelling communities. Bacteria were only detected in one locality wherein the majority was affiliated with microaerophilic Hydrogenobaculum spp. Cluster analyses indicated that archaeal communities associated with sediments tended to cluster together and branch off those with water. In addition, the quantities of dissolved oxygen within the water column were substantially less than those in equilibrium with atmospheric oxygen, indicating a net oxygen consumption most likely catalyzed by microbial processes. These lines of evidence suggest that the segregation of planktonic from bottom-dwelling archaeal assemblages could be accounted for by the oxygen affinities inherited in individual archaeal members. Community assemblages in geothermal ecosystems would be often underrepresented without cautious sampling of both water and sediments.

The Taiwan Chelungpu Drilling Project (TCDP) has provided an unprecedented opportunity to reveal a terrestrial subsurface microbial ecosystem that has possibly experienced continuous disturbance by the arccontinental collision since 5 Ma. The drilling penetrated Pliocene-Pleistocene sedimentary rocks to a depth of 2000 meters below the land surface (mbls) and encountered two major fault zones. Sixteen samples retrieved from the drilled cores at depths between 464 to 1451 mbls were examined to characterize microbial community structures through cultivation-based approaches. Cultivation experiments were performed with various media at temperatures ranging from 30 to 50¢XC. The results indicate that fermenters and heterotrophic sulfate reducers, using complex organic carbon, were ubiquitously present in most samples. Acetate-utilizing and H2 ¡Vutilizing sulfate reducers were restricted to shallower intervals along the depth profile. Iron reducers and methanogens were only cultivated in a few shallow samples. Twelve pure strains including 8 fermenters, 3 iron reducers and 1 sulfate reducer originally enriched at 30 or 40¢XC were isolated and identified with 16S rDNA sequence analyses. They were phylogenetically affiliated with Firmicutes, Bacteriodes, Actinobacteria, and Proteobacteria in various degrees of similarity. The presence of metabolism was not correlated with lithology, depth, temperature and the appearance of fracture throughout the core. The ubiquitous appearance of fermentation and organotrophic sulfate reduction suggests that organic carbon sources were readily accessible in this deep terrestrial subsurface environment. These results infer that the foreland sedimentary strata disturbed by tectonic activities over a geological time scale might support a heterotrophy-dominated deep terrestrial subsurface microbial ecosystem.

The Taiwan Chelungpu Drilling Project (TCDP) has provided an unprecedented opportunity to reveal a terrestrial subsurface microbial ecosystem that has possibly experienced continuous disturbance by the arccontinental collision since 5 Ma. The drilling penetrated Pliocene-Pleistocene sedimentary rocks to a depth of 2000 meters below the land surface (mbls) and encountered two major fault zones. Sixteen samples retrieved from the drilled cores at depths between 464 to 1451 mbls were examined to characterize microbial community structures through cultivation-based approaches. Cultivation experiments were performed with various media at temperatures ranging from 30 to _ The results indicate that fermenters and heterotrophic sulfate reducers, using complex organic carbon, were ubiquitously present in most samples. Acetate-utilizing and H2 _ sulfate reducers were restricted to shallower intervals along the depth profile. Iron reducers and methanogens were only cultivated in a few shallow samples. Twelve pure strains including 8 fermenters, 3 iron reducers and 1 sulfate reducer originally enriched at 30 or _ were isolated and identified with 16S rDNA sequence analyses. They were phylogenetically affiliated with Firmicutes, Bacteriodes, Actinobacteria, and Proteobacteria in various degrees of similarity. The presence of metabolism was not correlated with lithology, depth, temperature and the appearance of fracture throughout the core. The ubiquitous appearance of fermentation and organotrophic sulfate reduction suggests that organic carbon sources were readily accessible in this deep terrestrial subsurface environment. These results infer that the foreland sedimentary strata disturbed by tectonic activities over a geological time scale might support a heterotrophy-dominated deep terrestrial subsurface microbial ecosystem.