Optic atrophy 1 (OPA1) is a mitochondrial inner membrane protein that has an important role in mitochondrial fusion and structural integrity. Dysfunctional OPA1 mutations cause atrophy of the optic ...nerve leading to blindness. Here, we show that OPA1 has an important role in the innate immune system. Using conditional knockout mice lacking Opa1 in neutrophils (Opa1
), we report that lack of OPA1 reduces the activity of mitochondrial electron transport complex I in neutrophils. This then causes a decline in adenosine-triphosphate (ATP) production through glycolysis due to lowered NAD
availability. Additionally, we show that OPA1-dependent ATP production in these cells is required for microtubule network assembly and for the formation of neutrophil extracellular traps. Finally, we show that Opa1
mice exhibit a reduced antibacterial defense capability against Pseudomonas aeruginosa.
Software Protection Using Dynamic PUFs Xiong, Wenjie; Schaller, Andre; Katzenbeisser, Stefan ...
IEEE transactions on information forensics and security,
2020, Letnik:
15
Journal Article
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Low-end computing devices are becoming increasingly ubiquitous, especially due to the widespread deployment of Internet-of-Things products. There is, however, much concern about sensitive data being ...processed on these low-end devices which have limited protection mechanisms in place. This paper proposes a Hardware-Entangled Software Protection (HESP) scheme that leverages hardware features to protect software code from malicious modification before or during run-time. It also enables implicit hardware authentication. Thus, the software will execute correctly only on an authorized device and if the timing of the software, e.g., control flow, was not changed through malicious modifications. The proposed ideas are based on the new concept of Dynamic Physically Unclonable Functions (PUFs). Dynamic PUFs have time-varying responses and can be used to tie the software execution to the timing of software and the physical properties of a hardware device. It is further combined with existing approaches for code self-checksumming, software obfuscation, and call graph and register value scrambling to create the HESP scheme. HESP is demonstrated on commodity, off-the-shelf computing devices, where a DRAM PUF is used as an instance of a Dynamic PUF. The protection scheme can be applied automatically to LLVM Intermediate Representation (IR) code through an AutoPatcher written in Python. For a sample program containing AES encryption and decryption routine, HESP introduces 48% execution time overhead and increases the binary file size by 32.5%, which is moderate compared to other schemes such as software obfuscation. It takes about 2.6 seconds on average for the tested programs to be patched and compiled through the modified compilation flow and scripts.
The aim of the study was to describe the clinical and genetic correlation of a c.469 G>A p.(Asp157Asn) heterozygous pathogenic variant in PRPH2 in two siblings of Italian origin.
Both patients ...underwent ophthalmic examination, electrophysiological testing, autofluorescence imaging, and optical coherence tomography (OCT). Screening for pathogenic variants of the obtained DNA from the family members was carried out.
The 52-year-old (♀, index patient) and 50-year-old (♂) siblings had BCVA (OD and OS) of 20/20 and 20/16 (♀) and 20/25 and 20/40 (♂), respectively, and suffered increased sensitivity to glare. Yellow irregular macular deposits, numerous small irregular hypo- and hyperreflective spots at the posterior pole, a patchy loss of photoreceptors, and retinal pigment epithelium (RPE) in the perifoveal region were seen. Electrophysiology showed dysfunction of rods and cones, with more affected cone dysfunction in the index patient, contrary to the generalised rod dysfunction in the brother of the index patient. The clinical, electrophysiological, and multimodal imaging findings of both siblings pointed towards Stargardt retinopathy with heterogenic presentation. The DNA analysis identified an autosomal dominant c.469 G>A p.(Asp157Asn) heterozygous pathogenic variant in PRPH2 associated with autosomal dominant cone-rod dystrophy and rod-cone dystrophy. PRPH2 codes for peripherin-2, a membrane protein that consists of 346 amino acids.
Our findings confirm a heterogeneity in clinical presentation associated with pathogenic variants in PRPH2. It may follow either an autosomal dominant or an autosomal recessive mode of inheritance and show a very heterogeneous clinical manifestation of retinal degeneration, e.g., autosomal dominant retinitis pigmentosa (♂ sibling; II-3) and autosomal dominant cone-rod dystrophy (index ♀ sibling; II-2), autosomal dominant macular dystrophy, and also autosomal recessive retinitis pigmentosa.
SF-1/NR5A1 is a transcriptional regulator of adrenal and gonadal development. NR5A1 disease-causing variants cause disorders of sex development (DSD) and adrenal failure, but most affected ...individuals show a broad DSD/reproductive phenotype only. Most NR5A1 variants show in vitro pathogenic effects, but not when tested in heterozygote state together with wild-type NR5A1 as usually seen in patients. Thus, the genotype-phenotype correlation for NR5A1 variants remains an unsolved question. We analyzed heterozygous 46,XY SF-1/NR5A1 patients by whole exome sequencing and used an algorithm for data analysis based on selected project-specific DSD- and SF-1-related genes. The variants detected were evaluated for their significance in literature, databases and checked in silico using webtools. We identified 19 potentially deleterious variants (one to seven per patient) in 18 genes in four 46,XY DSD subjects carrying heterozygous NR5A1 disease-causing variants. We constructed a scheme of all these hits within the landscape of currently known genes involved in male sex determination and differentiation. Our results suggest that the broad phenotype in these heterozygous NR5A1 46,XY DSD subjects may well be explained by an oligogenic mode of inheritance, in which multiple hits, individually non-deleterious, may contribute to a DSD phenotype unique to each heterozygous SF-1/NR5A1 individual.
Ornithine transcarbamylase (OTC) deficiency (OTCD) is an X-linked urea cycle disorder. In females - undergoing random X chromosomal inactivation (XCI) - disease severity depends on the XCI pattern. ...Hence, female OTCD subjects with favorable XCI display normal OTC expression and activity and are healthy carriers. Whereas females undergoing less favorable XCI may suffer from severe and fatal OTCD. In approximately 20% of patients with biochemical evidence of OTCD, no mutation can be identified hampering definitive diagnosis and adequate treatment.
Here, we describe a female patient with high suspicion of OTCD in whom molecular genetic work-up did not reveal pathogenic variants in the OTC gene. In her case, this was particularly challenging, since she was awaiting liver transplantation due to metabolic instability. In order to substantiate the suspected diagnosis of OTCD, we applied our previously reported in vitro OTCD liver disease model. Patient-derived skin fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) followed by differentiation into hepatocytes (hiPSC-Heps). Among five randomly selected hiPSC clones - differentiated into hiPSC-Heps - one clone expressed OTC protein, while the four remaining clones lacked OTC expression, supporting the patient's suspected diagnosis of OTCD.
To conclude, we demonstrate that hiPSC technology is a powerful diagnostic tool to substantiate the suspected diagnosis of OTCD in patients lacking genetic confirmation. Furthermore, selecting clones that exclusively express the wild-type OTC protein, could be used strategically as cellular therapy in future. Ultimately, this approach might be applicable to virtually any X-linked disease.
Induced pluripotent stem cell technology is a powerful diagnostic tool to substantiate the suspected diagnosis of OTCD in patients lacking genetic confirmation.
Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial ...magnesium channel TRPM6 (V ¹³⁹³I, K ¹⁵⁸⁴E) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6(V ¹³⁹³I) and TRPM6(K ¹⁵⁸⁴E), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T ¹³⁹¹) and TRPM6(S ¹⁵⁸³). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6(V ¹³⁹³I) and TRPM6(K ¹⁵⁸⁴E) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6(V ¹³⁹³I) and TRPM6(K ¹⁵⁸⁴E) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.
Eliminating Leakage in Reverse Fuzzy Extractors Schaller, Andre; Stanko, Taras; Skoric, Boris ...
IEEE transactions on information forensics and security,
2018-April, 2018-4-00, Letnik:
13, Številka:
4
Journal Article
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Odprti dostop
In recent years, physically unclonable functions (PUFs) have been proposed as a promising building block for key storage and device authentication. PUFs are physical systems, and as such, their ...responses are inherently noisy, precluding a straightforward derivation of cryptographic key material from raw PUF measurements. To overcome this drawback, fuzzy extractors are used to eliminate the noise and guarantee robust outputs. A special type is reverse fuzzy extractors, shifting the computational load of error correction toward a computationally powerful verifier. However, the reverse fuzzy extractor reveals error patterns to any eavesdropper, which may cause privacy issues (due to a systematic drift of the PUF responses, the error pattern is linkable to the identity) and even security problems (if the noise is data-dependent). In this paper, we quantify the issue of leakage due to asymmetry of noise, leveraging the binary asymmetric channel (BAC) model. We further propose to concatenate two BACs to form a symmetric channel, as a solution that is able to eliminate such noise. Finally, we propose a modified reverse fuzzy extractor that does not leak via the error patterns even in the case of systematic drift of the PUF responses.
Defects of the mitochondrial respiratory chain complex II (succinate dehydrogenase (SDH) complex) are extremely rare. Of the four nuclear encoded proteins composing complex II, only mutations in the ...70 kDa flavoprotein (SDHA) and the recently identified complex II assembly factor (SDHAF1) have been found to be causative for mitochondrial respiratory chain diseases. Mutations in the other three subunits (SDHB, SDHC, SDHD) and the second assembly factor (SDHAF2) have so far only been associated with hereditary paragangliomas and phaeochromocytomas. Recessive germline mutations in SDHB have recently been associated with complex II deficiency and leukodystrophy in one patient.
We present the clinical and molecular investigations of the first patient with biochemical evidence of a severe isolated complex II deficiency due to compound heterozygous SDHD gene mutations. The patient presented with early progressive encephalomyopathy due to compound heterozygous p.E69 K and p.*164Lext*3 SDHD mutations. Native polyacrylamide gel electrophoresis and western blotting demonstrated an impaired complex II assembly. Complementation of a patient cell line additionally supported the pathogenicity of the novel identified mutations in SDHD.
This report describes the first case of isolated complex II deficiency due to recessive SDHD germline mutations. We therefore recommend screening for all SDH genes in isolated complex II deficiencies. It further emphasises the importance of appropriate genetic counselling to the family with regard to SDHD mutations and their role in tumorigenesis.
: We present a longitudinal clinical characterization of
-linked pattern dystrophy in an adult male patient.
: A patient affected by McArdle disease (glycogen storage disease type V) and homozygous ...for the nonsense variant
c.148C>T p.(Arg50*) underwent ophthalmic examinations over a 9-year-interval, including fundus photography, fundus autofluorescence, optical coherence tomography (OCT), OCT-angiography and electroretinography (ERG).
: At age 52, the patient was asymptomatic but yellow flecks were first observed in the macula of both eyes. This yellow flecks at the posterior pole progressed towards a pattern-like dystrophy over a 5-year-period. By fundus autofluorescence imaging the appearance of new hyperautofluorescent flecks and the extension of existing ones was observed over time. Concomitantly, a slow progression of the size of atrophic areas was seen at the posterior pole. Scotopic ERGs were within normal limits, but photopic Flicker responses were decreased, indicating reduced cone function.
: This additional case of
-linked pattern dystrophy further confirms retinopathy as a clinical phenotype associated with McArdle disease.
expression pattern suggests a disease mechanism involving impaired glycogen metabolism both in the retinal pigment epithelium and in cone photoreceptors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The ubiquity and pervasiveness of modern Internet of Things (IoT) devices opens up vast possibilities for novel applications, but simultaneously also allows spying on, and collecting data from, ...unsuspecting users to a previously unseen extent. This paper details a new attack form in this vein, in which the decay properties of widespread, off-the-shelf DRAM modules are exploited to accurately spy on the temperature in the vicinity of the DRAM-carrying device. Among others, this enables adversaries to remotely and purely digitally spy on personal behavior in users' private homes, or to collect security-critical data in server farms, cloud storage centers, or commercial production lines. We demonstrate that our attack can be performed by merely compromising the software of an IoT device and does not require hardware modifications or physical access at attack time. It can achieve temperature resolutions of up to <inline-formula> <tex-math notation="LaTeX">\mathbf {0.5^{\circ} }\text{C} </tex-math></inline-formula> over a range of <inline-formula> <tex-math notation="LaTeX">\mathbf {0^{\circ} }\text{C} </tex-math></inline-formula> to <inline-formula> <tex-math notation="LaTeX">\mathbf {70^{\circ} }\text{C} </tex-math></inline-formula> in practice. The presented attack works in devices that do not have a dedicated temperature sensor on board; as the DRAM modules already present in the device are abused to spy on the temperature. To complete the work, the paper discusses practical attack scenarios as well as possible countermeasures against the new temperature-spying attacks.
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