New Approaches to Exciting Exergame-Experiences for People with Motor Function Impairments

Eckert, M.; Gómez-Martinho, I.; Meneses, J.; Martínez, J.-F.; Sensors 2017, 17, 354. doi:10.3390/s17020354             
OPEN ACCESS

The work presented here suggests new ways to tackle exergames for physical rehabilitation and to improve the players’ immersion and involvement. The primary (but not exclusive) purpose is to increase the motivation of children and adolescents with severe physical impairments, for doing their required exercises while playing. The proposed gaming environment is based on the Kinect sensor and the Blender Game Engine. A middleware has been implemented that efficiently transmits the data from the sensor to the game. Inside the game, different newly proposed mechanisms have been developed to distinguish pure exercise-gestures from other movements used to control the game (e.g., opening a menu). The main contribution is the amplification of weak movements, which allows the physically impaired to have similar gaming experiences as the average population. To test the feasibility of the proposed methods, four mini-games were implemented and tested by a group of 11 volunteers with different disabilities, most of them bound to a wheelchair. Their performance has also been compared to that of a healthy control group. Results are generally positive and motivating, although there is much to do to improve the functionalities. There is a major demand for applications that help to include disabled people in society and to improve their life conditions. This work will contribute towards providing them with more fun during exercise.

ISCU(M108I) and ISCU(D39V) differ from wild type ISCU in their failure to form cysteine desulfurase complexes containing both frataxin and ferredoxin

Kai Cai, Ronnie O. Frederick, Marco Tonelli, and John L. Markley; Biochemistry, Just Accepted Manuscript DOI: 10.1021/acs.biochem.7b01234

Whereas iron-sulfur (Fe-S) cluster assembly on the wild-type scaffold protein ISCU, as catalyzed by the human cysteine desulfurase complex (SDA), exhibits a requirement for frataxin (FXN), assembly on variant ISCU(M108I) has been shown to bypass the FXN requirement. Wild-type ISCU populates two interconverting conformational states: one structured and one dynamically disordered. We show here that ISCU(M108I) populates only the structured state as does another variant ISCU(D39V). We have compared the properties ISCU, ISCU(M108I), and ISCU(D39V), with and without FXN, in both the cysteine desulfurase step of Fe-S cluster assembly and in the overall Fe-S cluster assembly reaction. In the cysteine desulfurase step with DTT as the reductant, FXN was found to stimulate cluster assembly with both the wild-type and structured variants, although the effect was less prominent with ISCU(D39V) than with wild-type or ISCU(M108I). In overall Fe-S cluster assembly, frataxin was found to stimulate cluster assembly with both the wild-type and structured variants when the reductant was DTT; however, with the physiological reductant, reduced ferredoxin 2 (rdFDX2), frataxin stimulated the reaction with wild-type ISCU but not with the fully-structured variants. Through NMR titration experiments, we discovered that, wild-type ISCU, frataxin, and rdFDX2 all bind to SDA. However, when ISCU was replaced by the fully-structured variant ISCU(M108I), the addition of rdFDX2 to the SDA-ISCU(M108I)-FXN complex led to the release of FXN. Thus, the displacement of FXN by rdFDX2 explains the failure of FXN to stimulate Fe-S cluster assembly on ISCU(M108I).

Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy

Lucia Montenegro, Rita Turnaturi, Carmela Parenti and Lorella Pasquinucci; Nanomaterials 2018, 8(2), 87; doi:10.3390/nano8020087

The key role of antioxidants in treating and preventing many systemic and topical diseases is well recognized. One of the most potent antioxidants available for pharmaceutical and cosmetic use is Idebenone (IDE), a synthetic analogue of Coenzyme Q10. Unfortunately, IDE’s unfavorable physicochemical properties such as poor water solubility and high lipophilicity impair its bioavailability after oral and topical administration and prevent its parenteral use. In recent decades, many strategies have been proposed to improve IDE effectiveness in the treatment of neurodegenerative diseases and skin disorders. After a brief description of IDE potential therapeutic applications and its pharmacokinetic and pharmacodynamic profile, this review will focus on the different approaches investigated to overcome IDE drawbacks, such as IDE incorporation into different types of delivery systems (liposomes, cyclodextrins, microemulsions, self-micro-emulsifying drug delivery systems, lipid-based nanoparticles, polymeric nanoparticles) and IDE chemical modification. The results of these studies will be illustrated with emphasis on the most innovative strategies and their future perspectives.

Jotrol IND Application Submission for MPS and Friedrich's Ataxia Imminent

Mathew Shanley, Rare Disease Report. FEBRUARY 05, 2018

Jupiter Orphan Therapeutics, Inc. (JOT) announced this morning that it intends to submit an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for Jotrol in mucopolysaccharidosis type 1 (MPS I), among other indications, within the next few weeks.
"We will initiate the IND in MPS I and plan to cross-reference PK and safety data in follow-on indications. We are well prepared to gear up for a study in Friedreich's Ataxia (FA) and will thereafter determine if Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) or Leber's Hereditary Optic Neuropathy (LHON) will be the 3rd indication we approach. An IND submission for FA is planned for quarter 2 of 2018, and for MELAS and/or LHON no later than quarter 4," stated JOT Chief Security Officer Dr. Marshall Hayward in a press release.
JOT has used an isomer of the resveratrol to develop a pharmaceutical grade compound that can be properly tested in clinical trials, and successful pre-clinical data have shown that it can increase levels of frataxin.

To study the genotype - phenotype correlation of Friedreich’s Ataxia (FRDA) patients in Indian population

I. Ahmad, A. Kumar Srivastava, M. Faruq, V. Padma Srivastava M., Parkinsonism & Related Disorders, Volume 46, Supplement 2, January 2018, Page e7, ISSN 1353-8020, doi:10.1016/j.parkreldis.2017.11.023.

This is the largest genotype and phenotype series on FRDA in Indian population. This study showed GAA1 size affects the cerebellar atrophy, muscles twisting and tremor.

Paediatric genomics: diagnosing rare disease in children

Caroline F. Wright, David R. FitzPatrick & Helen V. Firth, Nature Reviews Genetics, Published online:05 February 2018, doi:10.1038/nrg.2017.116

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition. However, making a molecular diagnosis with current technologies and knowledge is often still a challenge. Paediatric genomics is an immature but rapidly evolving field that tackles this issue by incorporating next-generation sequencing technologies, especially whole-exome sequencing and whole-genome sequencing, into research and clinical workflows. This complex multidisciplinary approach, coupled with the increasing availability of population genetic variation data, has already resulted in an increased discovery rate of causative genes and in improved diagnosis of rare paediatric disease. Importantly, for affected families, a better understanding of the genetic basis of rare disease translates to more accurate prognosis, management, surveillance and genetic advice; stimulates research into new therapies; andenables provision of better support.

Ethical, legal and social implications of paediatric genomics:
Paediatric genomics has many of the same ethical, legal and social issues that clinical genetics has been dealing with for decades, such as reproductive autonomy, informed consent for research, misattributed parentage and implications for family members. Issues which are more complicated for paediatric testing: the reduced capacity of the child to consent to testing and/or research means that parents and clinicians have an increased role in deciding what may be in the best interests of the child. Most of the novel ethical issues in the era of genomics relate to the storage, interpretation and access of data.


Data storage: it is not clear who should have access to that data and when they should be allowed access to it. Should access be limited to clinicians involved in the direct care of the family or opened to researchers in industry and/or academia?
Confidentiality versus data access: Parents are often asked to make decisions about their child’s data that may have irreversible repercussions. Should these decisions be revisited when the child approaches and passes the age of majority?
Duty of care: For clinicians, the issue of data access is linked to the question of whether their duty of care is limited to finding a diagnosis for the child’s immediate problems or whether it extends beyond the scope of the initial investigation. The duty of care could also extend to looking for incidental predispositions to adult-onset conditions or to adverse drug reactions either in the child or their parents. In general, investigating children for adult-onset conditions for which there is no early treatment is not recommended.

Tandem repeats mediating genetic plasticity in health and disease

Anthony J. Hannan, Nature Reviews Genetics, Published online: 05 February 2018, doi:10.1038/nrg.2017.115

Accumulating evidence suggests that many classes of DNA repeats exhibit attributes that distinguish them from other genetic variants, including the fact that they are more liable to mutation; this enables them to mediate genetic plasticity. The expansion of tandem repeats, particularly of short tandem repeats, can cause a range of disorders (including Huntington disease, various ataxias, motor neuron disease, frontotemporal dementia, fragile X syndrome and other neurological disorders), and emerging data suggest that tandem repeat polymorphisms (TRPs) can also regulate gene expression in healthy individuals. TRPs in human genomes may also contribute to the missing heritability of polygenic disorders. A better understanding of tandem repeats and their associated repeatome, as well as their capacity for genetic plasticity via both germline and somatic mutations, is needed to transform our understanding of the role of TRPs in health and disease.

Serum uric acid in Friedreich Ataxia

Tommaso Schirinzi, Gessica Vasco, Ginevra Zanni, Sara Petrillo, Fiorella Piemonte, Enrico Castelli, Enrico Silvio Bertini, Clinical Biochemistry, Available online 2 February 2018, ISSN 0009-9120, doi:10.1016/j.clinbiochem.2018.01.022.

Serum UA levels resulted significantly higher in FRDA than CTL, independently from age, gender and BMI. At the cut-off value of 4.45 mg/dl, serum UA discriminates FRDA from CTL with >70% of sensitivity and >60% of specificity. No correlations emerged with clinical data. Contrarily to other neurodegenerative diseases, in FRDA, we observed an independent increase of serum UA content. Taking in account previous experimental findings, we speculate that such a finding may result from biochemical impairment induced by the genetic defect, acting as a sort of compensatory antioxidant defense although proper dedicated studies are mandatory. This preliminary report focuses UA as a potential biomarker for FRDA and encourages further studies on novel therapeutic strategies.

Differential gene expression analysis reveals pathway based functional association of dysregulated genes in Friedreich’s ataxia

H.N. Singh, V. Swarup, A.K. Srivastava, Parkinsonism & Related Disorders, Volume 46, Supplement 2, January 2018, Page e34, ISSN 1353-8020,  doi:10.1016/j.parkreldis.2017.11.112.

A total of 3594 different gene-sets were identified and analyzed in the expression analysis. Out of 3594 gene-sets, 2009 were up-regulated in
the control phenotype and 1585 genes were up-regulated in FRDA conditions.

Sequence-specific DNA Binding Pyrrole–Imidazole Polyamides and Their Applications

Yusuke Kawamoto, Toshikazu Bando, Hiroshi Sugiyama, Bioorganic & Medicinal Chemistry, Available online 1 February 2018, ISSN 0968-0896, doi:10.1016/j.bmc.2018.01.026.

Pyrrole–imidazole polyamides (Py–Im polyamides) are cell-permeable compounds that bind to the minor groove of double-stranded DNA in a sequence-specific manner without causing denaturation of the DNA. These compounds can be used to control gene expression and to stain specific sequences in cells. Here, we review the history, structural variations, and functional investigations of Py–Im polyamides.