Expanding the Genetic Spectrum of ANOS1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism

STUDY QUESTION: What is the prevalence and functional consequence of ANOS1 (KAL1) mutations in a group of men with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Three of forty-two (7.1%) patients presented ANOS1 mutations, including a novel splice site mutation leading to exon skipping and a novel contiguous gene deletion associated with ichthyosis. WHAT IS KNOWN ALREADY: CHH is characterized by lack of pubertal development and infertility, due to deficient production, secretion or action of GnRH, and can be associated with anosmia/hyposmia (Kallmann syndrome, KS) or with a normal sense of smell (normosmic CHH). Mutations in the anosmin-1 (ANOS1) gene are responsible for the X-linked recessive form of KS. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 42 unrelated men with CHH (20 with KS and 22 with normosmic CHH). PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were screened for mutations in the ANOS1 gene by DNA sequencing. Identified mutations were further investigated by RT-PCR analysis and multiplex ligation-dependent probe amplification (MLPA) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Hemizygous mutations were identified in three (7.1%) KS cases: a novel splice acceptor site mutation (c.542-1G>C), leading to skipping of exon 5 in the ANOS1 transcript in a patient with self-reported normosmia (but hyposmic upon testing); a recurrent nonsense mutation (c.571C>T, p.Arg191*); and a novel 4.8 Mb deletion involving ANOS1 and eight other genes (VCX3B, VCX2, PNPLA4, VCX, STS, HDHD1, VCX3A and NLGN4X) in KS associated with ichthyosis. LIMITATIONS, REASONS FOR CAUTION: Objective olfactory testing was not performed in all cases of self-reported normosmia and this may have underestimated the olfactory deficits. WIDER IMPLICATIONS OF THE FINDINGS: This study further expands the spectrum of known genetic defects associated with CHH and suggests that patients with self-reported normal olfactory function should not be excluded from ANOS1 genetic testing. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Portuguese Foundation for Science and Technology. The authors have no conflicts of interest.info:eu-repo/semantics/publishedVersio

Expanding the Genetic Spectrum of ANOS1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism

STUDY QUESTION: What is the prevalence and functional consequence of ANOS1 (KAL1) mutations in a group of men with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Three of forty-two (7.1%) patients presented ANOS1 mutations, including a novel splice site mutation leading to exon skipping and a novel contiguous gene deletion associated with ichthyosis. WHAT IS KNOWN ALREADY: CHH is characterized by lack of pubertal development and infertility, due to deficient production, secretion or action of GnRH, and can be associated with anosmia/hyposmia (Kallmann syndrome, KS) or with a normal sense of smell (normosmic CHH). Mutations in the anosmin-1 (ANOS1) gene are responsible for the X-linked recessive form of KS. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 42 unrelated men with CHH (20 with KS and 22 with normosmic CHH). PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were screened for mutations in the ANOS1 gene by DNA sequencing. Identified mutations were further investigated by RT-PCR analysis and multiplex ligation-dependent probe amplification (MLPA) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Hemizygous mutations were identified in three (7.1%) KS cases: a novel splice acceptor site mutation (c.542-1G>C), leading to skipping of exon 5 in the ANOS1 transcript in a patient with self-reported normosmia (but hyposmic upon testing); a recurrent nonsense mutation (c.571C>T, p.Arg191*); and a novel 4.8 Mb deletion involving ANOS1 and eight other genes (VCX3B, VCX2, PNPLA4, VCX, STS, HDHD1, VCX3A and NLGN4X) in KS associated with ichthyosis. LIMITATIONS, REASONS FOR CAUTION: Objective olfactory testing was not performed in all cases of self-reported normosmia and this may have underestimated the olfactory deficits. WIDER IMPLICATIONS OF THE FINDINGS: This study further expands the spectrum of known genetic defects associated with CHH and suggests that patients with self-reported normal olfactory function should not be excluded from ANOS1 genetic testing. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Portuguese Foundation for Science and Technology. The authors have no conflicts of interest.info:eu-repo/semantics/publishedVersio

Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform

OBJECTIVE: To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Cross-sectional study. SETTING: Multicentric. PATIENT(S): Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis. RESULT(S): Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient. CONCLUSION(S): Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoform

Thickness dependence of spin wave excitations in an artificial square spin ice-like geometry

We present a comparative study of the spin wave properties in two magnetic films patterned into an artificial square spin ice-like geometry. The array elements are rectangular islands with the same lateral dimensions but with different thicknesses: 10 nm and 30 nm. Using Brillouin light scattering, the frequencies of spin wave excitations were measured as a function of the magnetic field going from positive to negative saturation. We find substantial changes with thickness to spin wave mode frequencies and the number of detected modes. Frequencies of spin waves localized at element edges are observed to evolve non-monotonically with magnetic fields and soften at critical fields. These critical fields enable us to extract information of the magnetization reversal of individual islands within the array. Finally, we discuss the effects of separation between islands and examine the possibilities for dynamic coupling through the overlap of collective edge modes

Review of technology‐supported multimodal solutions for people with dementia

Funding Information: This research was partially funded by FAITH project (H2020?SC1?DTH?2019?875358), CARELINK project (AAL?CALL?2016?049), and Funda??o para a Ci?ncia e Tecnologia through the program UIDB/00066/2020 (CTS?Center of Technology and Systems).Acknowledgments: The authors acknowledge the European Commission for its support and partial funding; the partners of the research project FAITH project (H2020?SC1?DTH?2019?875358); and CARELINK, AAL?CALL?2016?049 funded by AAL JP and co?funded by the European Commission and National Funding Authorities of Ireland, Belgium, Portugal, and Switzerland. Partial support also comes from Funda??o para a Ci?ncia e Tecnologia through the program UIDB/00066/2020 (CTS?Center of Technology and Systems). Funding Information: Acknowledgments: The authors acknowledge the European Commission for its support and partial funding; the partners of the research project FAITH project (H2020‐SC1‐DTH‐2019‐875358); and CARELINK, AAL‐CALL‐2016‐049 funded by AAL JP and co‐funded by the European Commission and National Funding Authorities of Ireland, Belgium, Portugal, and Switzerland. Partial support also comes from Fundação para a Ciência e Tecnologia through the program UIDB/00066/2020 (CTS—Center of Technology and Systems). Funding Information: Funding: This research was partially funded by FAITH project (H2020‐SC1‐DTH‐2019‐875358), CARELINK project (AAL‐CALL‐2016‐049), and Fundação para a Ciência e Tecnologia through the program UIDB/00066/2020 (CTS—Center of Technology and Systems). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.The number of people living with dementia in the world is rising at an unprecedented rate, and no country will be spared. Furthermore, neither decisive treatment nor effective medicines have yet become effective. One potential alternative to this emerging challenge is utilizing supportive technologies and services that not only assist people with dementia to do their daily activities safely and independently, but also reduce the overwhelming pressure on their caregivers. Thus, for this study, a systematic literature review is conducted in an attempt to gain an overview of the latest findings in this field of study and to address some commercially available supportive technologies and services that have potential application for people living with dementia. To this end, 30 potential supportive technologies and 15 active supportive services are identified from the literature and related websites. The technologies and services are classified into different classes and subclasses (according to their functionalities, capabilities, and features) aiming to facilitate their understanding and evaluation. The results of this work are aimed as a base for designing, integrating, developing, adapting, and customizing potential multimodal solutions for the specific needs of vulnerable people of our societies, such as those who suffer from different degrees of dementia.publishersversionpublishe

Genetic divergence among African and American cotton (Gossypium hirsutum L. race latifolium H.) cultivars and inbred lines through random amplification of polymorphic DNA (RAPD) markers.

Cotton (Gossypium spp.) is an important cash crop and the second largest source of textile fiber and edible oil throughout the world. This study was conducted to investigate the genetic divergence through random amplified polymorphism (RAPD) molecular markers among the introduced African and American cultivars and inbred lines of cotton (Gossypium hirsutum L. raça latifolium H.) in Mozambique. We used 24 RAPD primers that amplified a total of 166 bands, identifying 90.96% ofpolymorphism. The intra and inter group genetic variability quantification evidenced significant variability of 16.30% between the African and American groups. The highest genetic similarity was observed among the African commercial cotton cultivars, whereas American cultivars and inbred lines were considered the most dissimilar ones. The arithmetic complement of Jaccard, obtained with 151 RAPD molecular markers showed that African cultivars Albar BC853 and STAM 42 were the most similar, while the most dissimilar combinations were TAMCOT Sphinx and ISA 205 followed by TAMCOT Sphinx vs ALBAR BC853 and TAMCOT Sphinx vs REMU 40 combinations.Keywords: Molecular variance analysis, decamer primers, dissimilarity, Gossypium hirsutum, molecular markers

Optical conversion of pure spin currents in hybrid molecular devices

Carbon-based molecules offer unparalleled potential for THz and optical devices controlled by pure spin currents: a low-dissipation flow of electronic spins with no net charge displacement. However, the research so far has been focused on the electrical conversion of the spin imbalance, where molecular materials are used to mimic their crystalline counterparts. Here, we use spin currents to access the molecular dynamics and optical properties of a fullerene layer. The spin mixing conductance across Py/C60 interfaces is increased by 10% (5 × 1018 m−2) under optical irradiation. Measurements show up to a 30% higher light absorbance and a factor of 2 larger photoemission during spin pumping. We also observe a 0.15 THz slowdown and a narrowing of the vibrational peaks. The effects are attributed to changes in the non-radiative damping and energy transfer. This opens new research paths in hybrid magneto-molecular optoelectronics, and the optical detection of spin physics in these materials

Validation of Dunbar's number in Twitter conversations

Modern society's increasing dependency on online tools for both work and recreation opens up unique opportunities for the study of social interactions. A large survey of online exchanges or conversations on Twitter, collected across six months involving 1.7 million individuals is presented here. We test the theoretical cognitive limit on the number of stable social relationships known as Dunbar's number. We find that users can entertain a maximum of 100-200 stable relationships in support for Dunbar's prediction. The "economy of attention" is limited in the online world by cognitive and biological constraints as predicted by Dunbar's theory. Inspired by this empirical evidence we propose a simple dynamical mechanism, based on finite priority queuing and time resources, that reproduces the observed social behavior.Comment: 8 pages, 6 figure

Spectrum and Frequency of GJB2 Mutations in a Cohort of 264 Portuguese Nonsyndromic Sensorineural Hearing Loss Patients

OBJECTIVE: To assess the spectrum and prevalence of mutations in the GJB2 gene in Portuguese nonsyndromic sensorineural hearing loss (NSSHL) patients. DESIGN: Sequencing of the coding region, basal promoter, exon 1, and donor splice site of the GJB2 gene; screening for the presence of the two common GJB6 deletions. STUDY SAMPLE: A cohort of 264 Portuguese NSSHL patients. RESULTS: At least one out of 21 different GJB2 variants was identified in 80 (30.2%) of the 264 patients analysed. Two mutant alleles were found in 53 (20%) of these probands, of which 83% (44/53) harboured at least one c.35delG allele. Twenty-seven (10.2%) of the probands harboured only one mutant allele. Subsequent analysis revealed that the GJB6 deletion del(GJB6-D13S1854) was present in at least 7.4% (2/27) of the patients carrying only one mutant GJB2 allele. Overall, one in five (55/264) of the patients were diagnosed as having DFNB1-related NSSHL, of which the vast majority (53/55) harboured only GJB2 mutations. CONCLUSIONS: This study provides clear demonstration that mutations in the GJB2 gene are an important cause of NSSHL in Portugal, thus representing a valuable indicator as regards therapeutical and rehabilitation options, as well as genetic counseling of these patients and their families