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Positron emission tomography (PET) can provide information about tumor-associated macrophage (TAM) infiltration, as long as a suitable tracer is available. This study aimed to evaluate the radiolabeled peptide [ 18 F]AlF-NODA-MP-C6-CTHRSSVVC as a potential PET tracer for imaging of the CD163 receptor, which is expressed on M2-type tumor-associated macrophages. The conjugated peptide NODA-MP-C6-CTHRSSVVC was labeled with aluminum [ 18 F]fluoride. Tracer binding and its biodistribution were evaluated in an in vitro binding assay and in healthy BALB/c mice, respectively. In addition, different treatments with cyclophosphamide in tumor-bearing mice were used to assess whether the tracer could detect differences in CD163 expression caused by differential TAM infiltration. After 7 days of treatment, animals were injected with [ 18 F]AlF-NODA-MP-C6-CTHRSSVVC, and a 60-min dynamic PET scan was performed, followed by an ex vivo biodistribution study. [ 18 F]AlF-NODA-MP-C6-CTHRSSVVC was prepared in 23 ± 6 % radiochemical yield and showed approximately 50 % of specific receptor-mediated binding in an in vitro binding assay on human CD163-expressing tissue homogenates. No CD163-mediated binding of [ 18 F]AlF-NODA-MP-C6-CTHRSSVVC was detected by PET under normal physiological conditions in healthy BALB/c mice. On the other hand, CD163-positive xenograft tumors were clearly visualized with PET and a positive correlation was found between CD163 levels and the [ 18 F]AlF-NODA-MP-C6-CTHRSSVVC tumor-to-muscle ratio (TMR) obtained from the PET images (Pearson r = 0.76, p = 0.002). No significant differences in the CD163 protein level and in the tracer uptake between treatment groups were found in the tumors. Taken together, [ 18 F]AlF-NODA-MP-C6-CTHRSSVVC appears a promising candidate PET tracer for M2-type TAM, as it binds specifically to CD163 in vitro and its tumor uptake correlates well with CD163 expression in vivo., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest or relationships relevant to the contents of this manuscript to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In this Letter, we present a simple and versatile scheme for enhancing the nonclassical properties of light states using only linear optics and photodetectors. By combining a coherent state |α〉 and an arbitrary pure state of light |ϕ〉 (excluding coherent states) at two beam splitters, we show that the amplitude α of the coherent state can be tuned to filter out specific Fock components and generate states of light with increased nonclassical features. We provide two examples of input states and demonstrate the effectiveness of our scheme in enhancing the sub-Poissonian statistics or the quadrature squeezing of the output states.

Objective: In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the expanded cytosine adenine guanine (CAG) repeat in ATXN3 is the causal mutation, and its length is the main factor in determining the age at onset (AO) of clinical symptoms. However, the contribution of the expanded CAG repeat length to the rate of disease progression after onset has remained a matter of debate, even though an understanding of this factor is crucial for experimental data on disease modifiers and their translation to clinical trials and their design., Methods: Eighty-two Dutch patients with SCA3/MJD were evaluated annually for 15 years using the International Cooperative Ataxia Rating Scale (ICARS). Using linear growth curve models, ICARS progression rates were calculated and tested for their relation to the length of the CAG repeat expansion and to the residual age at onset (RAO): The difference between the observed AO and the AO predicted on the basis of the CAG repeat length., Results: On average, ICARS scores increased 2.57 points/year of disease. The length of the CAG repeat was positively correlated with a more rapid ICARS progression, explaining 30% of the differences between patients. Combining both the length of the CAG repeat and RAO as comodifiers explained up to 47% of the interpatient variation in ICARS progression., Interpretation: Our data imply that the length of the expanded CAG repeat in ATXN3 is a major determinant of clinical decline, which suggests that CAG-dependent molecular mechanisms similar to those responsible for disease onset also contribute to the rate of disease progression in SCA3/MJD. ANN NEUROL 2021;89:66-73., (© 2020 American Neurological Association.)

CAG-repeat expansions in at least eight different genes cause neurodegeneration. The length of the extended polyglutamine stretches in the corresponding proteins is proportionally related to their aggregation propensity. Although these proteins are ubiquitously expressed, they predominantly cause toxicity to neurons. To understand this neuronal hypersensitivity, we generated induced pluripotent stem cell (iPSC) lines of spinocerebellar ataxia type 3 and Huntington's disease patients. iPSC generation and neuronal differentiation are unaffected by polyglutamine proteins and show no spontaneous aggregate formation. However, upon glutamate treatment, aggregates form in neurons but not in patient-derived neural progenitors. During differentiation, the chaperone network is drastically rewired, including loss of expression of the anti-amyloidogenic chaperone DNAJB6. Upregulation of DNAJB6 in neurons antagonizes glutamate-induced aggregation, while knockdown of DNAJB6 in progenitors results in spontaneous polyglutamine aggregation. Loss of DNAJB6 expression upon differentiation is confirmed in vivo, explaining why stem cells are intrinsically protected against amyloidogenesis and protein aggregates are dominantly present in neurons., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The original version of this article unfortunately contained some mistakes in Table 2. The additional row (just above SCA2) with the following information "SCA1, 1(1), 1, 50, 74, 24, 46 and 0/1" should be inserted.

Relative frequency of hereditary ataxias remains unknown in many regions of Latin America. We described the relative frequency in spinocerebellar ataxias (SCA) due to (CAG)n and to (ATTCT)n expansions, as well as Friedreich ataxia (FRDA), among cases series of ataxic individuals from Peru. Among ataxic index cases from 104 families (38 of them with and 66 without autosomal dominant pattern of inheritance), we identified 22 SCA10, 8 SCA2, 3 SCA6, 2 SCA3, 2 SCA7, 1 SCA1, and 9 FRDA cases (or families). SCA10 was by far the most frequent one. Findings in SCA10 and FRDA families were of note. Affected genitors were not detected in 7 out of 22 SCA10 nuclear families; then overall maximal penetrance of SCA10 was estimated as 85%; in multiplex families, penetrance was 94%. Two out of nine FRDA cases carried only one allele with a GAA expansion. SCA10 was the most frequent hereditary ataxia in Peru. Our data suggested that ATTCT expansions at ATXN10 might not be fully penetrant and/or instability between generations might frequently cross the limits between non-penetrant and penetrant lengths. A unique distribution of inherited ataxias in Peru requires specific screening panels, considering SCA10 as first line of local diagnosis guidelines.

Spinocerebellar ataxia type 3, or Machado-Joseph disease (SCA3/MJD), is caused by an expansion of CAG repeats, which is inversely correlated to age at onset (AO) of symptoms. However, on average, just 55.2% of variation in AO can be explained by expansion length. Additional modulators, such as polymorphic CAG tract in ATXN2 gene, can raise to 63.0% of the variation in AO. A sequence variation (rs3512) in FAN1 gene has previously been shown to be associated with late AO in Huntington's disease and polyglutaminopathies associated to ataxia. In the present study, genotype frequency of rs3512 was demonstrated in a cohort of SCA3/MJD patients from South Brazil, and these data were correlated to AO. The disease started 2.44 years earlier in subjects with the G/G genotype when compared to those subjects carrying the same CAGexp length at the ATXN3 gene and other genotypes (C/G and C/C) at rs3512. Placing together data on rs3512 genotype with data on CAG tract in ATXN2, AO of patients with G/G genotype was 2.58 years earlier, and a delay of 4.25 years was observed in patients that carry a short ATXN2 allele. Data presented here add further insights on the contribution of other factors in AO of SCA3/MJD beyond the causal mutation. Thus, well-known modifiers can help to unveil new ones and, as a whole, to better elucidate the mechanisms behind disease onset.

The pathophysiology of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and many others converge at alpha-synuclein (α-Syn) aggregation. Although it is still not entirely clear what precise biophysical processes act as triggers, cumulative evidence points towards a crucial role for protein quality control (PQC) systems in modulating α-Syn aggregation and toxicity. These encompass distinct cellular strategies that tightly balance protein production, stability, and degradation, ultimately regulating α-Syn levels. Here, we review the main aspects of α-Syn biology, focusing on the cellular PQC components that are at the heart of recognizing and disposing toxic, aggregate-prone α-Syn assemblies: molecular chaperones and the ubiquitin-proteasome system and autophagy-lysosome pathway, respectively. A deeper understanding of these basic protein homeostasis mechanisms might contribute to the development of new therapeutic strategies envisioning the prevention and/or enhanced degradation of α-Syn aggregates.

Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine disease that progressively affects the cerebellum, brainstem, and retina. SCA7 is quite rare, and insights into biomarkers and pre-clinical phases are still missing. We aimed to describe neurologic and ophthalmological findings observed in symptomatic and pre-symptomatic SCA7 subjects. Several neurologic scales, visual acuity, visual fields obtained by computer perimetry, and macular thickness in optical coherence tomography (mOCT) were measured in symptomatic carriers and at risk relatives. Molecular analysis of the ATXN7 was done blindly in individuals at risk. Thirteen symptomatic carriers, 3 pre-symptomatic subjects, and 5 related controls were enrolled. Symptomatic carriers presented scores significantly different from those of controls in most neurologic and ophthalmological scores. Gradual changes from controls to pre-symptomatic and then to symptomatic carriers were seen in mean (SD) of visual fields - 1.34 (1.15), - 2.81 (1.66). and - 9.56 (7.26); mOCT - 1.11 (2.6), - 3.48 (3.54), and - 7.73 (2.56) Z scores; and "Spinocerebellar Ataxia Functional Index (SCAFI)" - 1.16 (0.28), 0.65 (0.56), and - 0.61 (0.44), respectively. Visual fields and SCAFI were significantly correlated with time to disease onset (pre-symptomatic)/disease duration (symptomatic carriers). Visual fields, mOCT, and SCAFI stood out as candidates for state biomarkers for SCA7 since pre-symptomatic stages of disease.

The original version of this article unfortunately contained a mistake. The spelling of the surname of one co-author from the publication entitled "Selective Forces Related to Spinocerebellar Ataxia Type 2" that was recently published in the journal "The Cerebelum" was incorrect.

Spinocerebellar ataxia type 2 (SCA2) is caused by an unstable expanded CAG repeat tract (CAGexp) at ATXN2. Although prone to selective forces such as anticipation, SCA2 frequency seems to be stable in populations. Our aim was to estimate reproductive success, segregation patterns, and role of anticipation in SCA2. Adult subjects from families with molecular diagnosis provided data about all his/her relatives. Affected and unaffected sibs older than 65.7 years of age were used to estimate reproductive success and segregation patterns. Twenty-one SCA2 families were studied, including 1017 individuals (164 affected) who were born from 1840 to 2012. The median number of children of the non-carriers and carriers, among 99 subjects included in the reproductive success analysis, were 2 and 3 (p < 0.025), respectively. Therefore, the reproductive success of carriers was 1.5. There were 137 non-carriers (59.6%) and 93 carriers (40.4%) (p = 0.04), among subjects included in the segregation analysis. Age at onset across generations pointed to anticipation as a frequent phenomenon. We raised evidence in favor of increased reproductive success related to the carrier state at ATXN2, and segregation distortion favoring normal alleles. Since majority of normal alleles analyzed carried 22 repeats, we propose that this distortion segregation can be related to the high frequency of this allele in human chromosomes.

Objectives: To perform a systematic review and meta-analysis of genetic risk factors for age at onset (AO) in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD)., Methods: Two authors independently reviewed reports on the mathematical relationship between CAG length at the expanded ATXN3 allele (CAGexp), and other genetic variants if available, and AO. Publications from January 1994 to September 2017 in English, Portuguese or Spanish and indexed in MEDLINE (PubMed), LILACS or EMBASE were considered. Inclusion criteria were reports with >20 SCA3/MJD carriers with molecular diagnosis performed by capillary electrophoresis. Non-overlapping cohorts were determined on contact with corresponding authors. A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42017073071)., Results: Eleven studies were eligible for meta-analysis, comprising 10 individual-participant (n=2099 subjects) and two aggregated data cohorts. On average, CAGexp explained 55.2% (95% CI 50.8 to 59.0; p<0.001) of AO variability. Population-specific factors accounted for 8.3% of AO variance. Cohorts clustered into distinct geographic groups, evidencing significantly earlier AO in non-Portuguese Europeans than in Portuguese/South Brazilians with similar CAGexp lengths. Presence of intermediate ATXN2 alleles (27-33 CAG repeats) significantly correlated with earlier AO. Familial factors accounted for ~10% of AO variability. CAGexp, origin, family effects and CAG length at ATXN2 together explained 73.5% of AO variance., Conclusions: Current evidence supports genetic modulation of AO in SCA3/MJD by CAGexp, ATXN2 and family-specific and population-specific factors. Future studies should take these into account in the search for new genetic modifiers of AO, which could be of therapeutic relevance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the length of CAG repeat expansions in ATXN3 shows an inverse correlation with age at onset (AO). Recently, a formula for predicting AO based on CAG expansion was developed for European carriers. We tested this formula in SCA3/MJD carriers from distinct origins and developed population-specific models to predict AO., Methods: This was a parametric survival modelling study., Results: The European formula (EF) was tested in 739 independent SCA3/MJD carriers from South Brazil, Taiwan and the Portuguese Azorean islands, and it largely underestimated AO in South Brazilian and Taiwanese test cohorts. This finding challenged the universal use of the EF, leading us to develop and validate population-specific models for AO prediction. Using validation cohorts, we showed that Brazilian and Taiwanese formulas largely outperformed the EF in a population-specific manner. Inversely, the EF was more accurate at predicting AO among Portuguese Azorean patients. Hence, specific prediction models were required for each SCA3/MJD ethnic group., Conclusions: Our data strongly support the existence of as yet unknown factors that modulate AO in SCA3/MJD in a population-dependent manner, independent of CAG expansion length. The generated models are made available to the scientific community as they can be useful for future studies on SCA3/MJD carriers from distinct geographical origins., (© 2018 EAN.)

Background: Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration. We aimed to describe the progression rate of ataxia, by the Scale for the Assessment and Rating of Ataxia (SARA), as well as the progression rate of the overall neurological picture, by the Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), and not only during the study duration but also in a disease duration model. Comparisons between these models might allow us to explore whether progression is linear during the disease duration in SCA2; and to look for potential modifiers., Results: Eighty-eight evaluations were prospectively done on 49 symptomatic subjects; on average (SD), study duration and disease duration models covered 13 (2.16) months and 14 (6.66) years of individuals' life, respectively. SARA progressed 1.75 (CI 95%: 0.92-2.57) versus 0.79 (95% CI 0.45 to 1.14) points/year in the study duration and disease duration models. NESSCA progressed 1.45 (CI 95%: 0.74-2.16) versus 0.41 (95% CI 0.24 to 0.59) points/year in the same models. In order to explain these discrepancies, the progression rates of the study duration model were plotted against disease duration. Then an acceleration was detected after 10 years of disease duration: SARA scores progressed 0.35 before and 2.45 points/year after this deadline (p = 0.013). Age at onset, mutation severity, and presence of amyotrophy, parkinsonism, dystonic manifestations and cognitive decline at baseline did not influence the rate of disease progression., Conclusions: NESSCA and SARA progression rates were not constant during disease duration in SCA2: early phases of disease were associated with slower progressions. Modelling of future clinical trials on SCA2 should take this phenomenon into account, since disease duration might impact on inclusion criteria, sample size, and study duration. Our database is available online and accessible to future studies aimed to compare the present data with other cohorts.

Expanded polyglutamine (polyQ) stretches in at least nine unrelated proteins lead to inherited neuronal dysfunction and degeneration. The expansion size in all diseases correlates with age at onset (AO) of disease and with polyQ protein aggregation, indicating that the expanded polyQ stretch is the main driving force for the disease onset. Interestingly, there is marked interpatient variability in expansion thresholds for a given disease. Between different polyQ diseases the repeat length vs. AO also indicates the existence of modulatory effects on aggregation of the upstream and downstream amino acid sequences flanking the Q expansion. This can be either due to intrinsic modulation of aggregation by the flanking regions, or due to differential interaction with other proteins, such as the components of the cellular protein quality control network. Indeed, several lines of evidence suggest that molecular chaperones have impact on the handling of different polyQ proteins. Here, we review factors differentially influencing polyQ aggregation: the Q-stretch itself, modulatory flanking sequences, interaction partners, cleavage of polyQ-containing proteins, and post-translational modifications, with a special focus on the role of molecular chaperones. By discussing typical examples of how these factors influence aggregation, we provide more insight on the variability of AO between different diseases as well as within the same polyQ disorder, on the molecular level.

Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta-CAGexp from parent-offspring pairs, and delta-CAGexp between siblings were obtained. One hundred and fifty-nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta-CAGexp among 115 direct parent-offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta-CAGexp between 269 siblings correlated with their delta-of-age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Expanded CAG repeats lead to debilitating neurodegenerative disorders characterized by aggregation of proteins with expanded polyglutamine (polyQ) tracts. The mechanism of aggregation involves primary and secondary nucleation steps. We show how a noncanonical member of the DNAJ-chaperone family, DNAJB6, inhibits the conversion of soluble polyQ peptides into amyloid fibrils, in particular by suppressing primary nucleation. This inhibition is mediated by a serine/threonine-rich region that provides an array of surface-exposed hydroxyl groups that bind to polyQ peptides and may disrupt the formation of the H bonds essential for the stability of amyloid fibrils. Early prevention of polyQ aggregation by DNAJB6 occurs also in cells and leads to delayed neurite retraction even before aggregates are visible. In a mouse model, brain-specific coexpression of DNAJB6 delays polyQ aggregation, relieves symptoms, and prolongs lifespan, pointing to DNAJB6 as a potential target for disease therapy and tool for unraveling early events in the onset of polyQ diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Onset of Machado-Joseph disease (SCA3/MJD) before adolescence has been rarely reported. This study aims to describe a cohort of SCA3/MJD with onset before 12 years of age, comparing their disease progression with the progression observed in patients with usual disease onset. We identified all cases from our cohort whose onset was before adolescence. After consent, patients were examined with clinical scales Scale for the Assessment and Rating of Ataxia (SARA) and Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). Gender, age, age at onset, disease duration, CAG expanded repeats, transmitting parent, and anticipation of cases with infantile and adult onset were studied. Progression of NESSCA and SARA scores was estimated through a mixed model, and was compared with a historical group with onset after adolescence. Between 2000 and 2014, 461 symptomatic individuals from our region were diagnosed as SCA3/MJD. Onset of eight cases (2.2%), all heterozygotes, was before adolescence: seven were females (p = 0.054). CAG expanded repeats--75 ± 3 versus 84 ± 4--and anticipations--7 ± 9.7 versus 14.4 ± 7.2 years--were different between early childhood and adult onset groups (p < 0.03). The median survival of early childhood onset group was 23 years of age. The annual progression of SARA--2.3 and 0.6 points/year (p = 0.001)--and NESSCA--2.04 and 0.88 points/year (p = 0.043)--was faster in childhood than in adult onset group. Onset of SCA3/MJD before adolescence was related to larger expanded CAG repeats in heterozygosis; females seemed to be at higher risk. Disease progression was faster than in SCA3/MJD starting after 12 years.

Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5'UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity.

In some cases Neu-Laxova syndrome (NLS) is linked to serine deficiency due to mutations in the phosphoglycerate dehydrogenase (PHGDH) gene. We describe the prenatal and postnatal findings in a fetus with one of the most severe NLS phenotypes described so far, caused by a homozygous nonsense mutation of PHGDH. Serial ultrasound (US) and pre- and postnatal magnetic resonance imaging (MRI) evaluations were performed. Prenatally, serial US evaluations suggested symmetric growth restriction, microcephaly, hypoplasia of the cerebellar vermis, micrognathia, hydrops, shortened limbs, arthrogryposis, and talipes equinovarus. The prenatal MRI confirmed these findings prompting a diagnosis of NLS. After birth, radiological imaging did not detect any gross bone abnormalities. DNA was extracted from fetal and parental peripheral blood, all coding exons of PHGDH were PCR-amplified and subjected to Sanger sequencing. Sequencing of PHGDH identified a homozygous premature stop codon mutation (c.1297C>T; p.Gln433*) in fetal DNA, both parents (first-cousins) being heterozygotes. Based on previous associations of mutations in this gene with a milder NLS phenotype, as well as cases of serine deficiency, these observations lend further support to a genotype-phenotype correlation between the degree of PHGDH inactivation and disease severity., (© 2015 Wiley Periodicals, Inc.)

Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.

The Firmicutes bacteria participate extensively in virulence and pathological processes. Enterococcus faecalis is a commensal microorganism; however, it is also a pathogenic bacterium mainly associated with nosocomial infections in immunocompromised patients. Iron-sulfur [Fe-S] clusters are inorganic prosthetic groups involved in diverse biological processes, whose in vivo formation requires several specific protein machineries. Escherichia coli is one of the most frequently studied microorganisms regarding [Fe-S] cluster biogenesis and encodes the iron-sulfur cluster and sulfur assimilation systems. In Firmicutes species, a unique operon composed of the sufCDSUB genes is responsible for [Fe-S] cluster biogenesis. The aim of this study was to investigate the potential of the E. faecalis sufCDSUB system in the [Fe-S] cluster assembly using oxidative stress and iron depletion as adverse growth conditions. Quantitative real-time polymerase chain reaction demonstrated, for the first time, that Gram-positive bacteria possess an OxyR component responsive to oxidative stress conditions, as fully described for E. coli models. Likewise, strong expression of the sufCDSUB genes was observed in low concentrations of hydrogen peroxide, indicating that the lowest concentration of oxygen free radicals inside cells, known to be highly damaging to [Fe-S] clusters, is sufficient to trigger the transcriptional machinery for prompt replacement of [Fe-S] clusters.

Iron-sulfur clusters (ISC) ([Fe-S]) are evolutionarily ancient and ubiquitous inorganic prosthetic groups present in almost all living organisms, whose biosynthetic assembly is dependent on complex protein machineries. [Fe-S] clusters are involved in biologically important processes, ranging from electron transfer catalysis to transcriptional regulatory roles. Three different systems involved in [Fe-S] cluster assembly have already been characterized in Proteobacteria, namely, the nitrogen fixation system, the ISC system and the sulfur assimilation system. Although they are well described in various microorganisms, these machineries are poorly characterized in members of the Firmicutes phylum, to which several groups of pathogenic bacteria belong. Recently, several research groups have made efforts to elucidate the biogenesis of [Fe-S] clusters at the molecular level in Firmicutes, and many important characteristics have been described. Considering the pivotal role of [Fe-S] clusters in a number of biological processes, the review presented here focuses on the description of the biosynthetic machineries for [Fe-S] cluster biogenesis in prokaryotes, followed by a discussion on recent results observed for Firmicutes [Fe-S] cluster assembly.