Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling.

AIMS/HYPOTHESIS: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic founder effect, and to study the mechanism of loss of function of the mutant receptor. METHODS: Biochemical profiling and DNA haplotype analysis of affected patients were performed. Insulin receptor expression in lymphoblastoid cells from a homozygous p.Ile119Met INSR patient, and in cells heterologously expressing the mutant receptor, was examined. Insulin binding, insulin-stimulated receptor autophosphorylation, and cooperativity and pH dependency of insulin dissociation were also assessed. RESULTS: All patients had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the INSR mutant to be no larger than 28 kb. An increased insulin proreceptor to β subunit ratio was seen in patient-derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited decreased insulin dissociation rates with preserved cooperativity, a difference accentuated at low pH. CONCLUSIONS/INTERPRETATION: The p.Ile119Met INSR appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant patients with ancestry from this region. Despite collectively compelling genetic, clinical and biochemical evidence for its pathogenicity, loss of function in conventional in vitro assays is subtle, suggesting mildly impaired receptor recycling only

Genetic Exchange of Multidrug Efflux Pumps among Two Enterobacterial Species with Distinctive Ecological Niches

AcrAB-TolC is the major multidrug efflux system in Enterobacteriaceae recognizing structurally unrelated molecules including antibiotics, dyes, and detergents. Additionally, in Escherichia coli it mediates resistance to bile salts. In the plant pathogen Erwinia amylovora AcrAB-TolC is required for virulence and phytoalexin resistance. Exchange analysis of AcrAB-TolC was conducted by complementing mutants of both species defective in acrB or tolC with alleles from either species. The acrB and tolC mutants exhibited increased susceptibility profiles for 24 different antibiotics. All mutants were complemented with acrAB or tolC, respectively, regardless of the taxonomic origin of the alleles. Importantly, complementation of E. amylovora mutants with respective E. coli genes restored virulence on apple plants. It was concluded that AcrAB and TolC of both species could interact and that these interactions did not yield in altered functions despite the divergent ecological niches, to which E. coli and E. amylovora have adopted

Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)

OBJECTIVE: To identify genetic causes of COACH syndrome BACKGROUND: COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). METHODS: In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. RESUlTS: 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). CONCLUSIONS: Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L

Toll-Like Receptor Agonists Synergize with CD40L to Induce Either Proliferation or Plasma Cell Differentiation of Mouse B Cells

In a classical dogma, pathogens are sensed (via recognition of Pathogen Associated Molecular Patterns (PAMPs)) by innate immune cells that in turn activate adaptive immune cells. However, recent data showed that TLRs (Toll Like Receptors), the most characterized class of Pattern Recognition Receptors, are also expressed by adaptive immune B cells. B cells play an important role in protective immunity essentially by differentiating into antibody-secreting cells (ASC). This differentiation requires at least two signals: the recognition of an antigen by the B cell specific receptor (BCR) and a T cell co-stimulatory signal provided mainly by CD154/CD40L acting on CD40. In order to better understand interactions of innate and adaptive B cell stimulatory signals, we evaluated the outcome of combinations of TLRs, BCR and/or CD40 stimulation. For this purpose, mouse spleen B cells were activated with synthetic TLR agonists, recombinant mouse CD40L and agonist anti-BCR antibodies. As expected, TLR agonists induced mouse B cell proliferation and activation or differentiation into ASC. Interestingly, addition of CD40 signal to TLR agonists stimulated either B cell proliferation and activation (TLR3, TLR4, and TLR9) or differentiation into ASC (TLR1/2, TLR2/6, TLR4 and TLR7). Addition of a BCR signal to CD40L and either TLR3 or TLR9 agonists did not induce differentiation into ASC, which could be interpreted as an entrance into the memory pathway. In conclusion, our results suggest that PAMPs synergize with signals from adaptive immunity to regulate B lymphocyte fate during humoral immune response

A global action agenda for turning the tide on fatty liver disease

Background and Aims: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. Approach and Results: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of “agree” responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% “agree”). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. Conclusions: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.publishedVersio

Direct effects of organic pollutants on the growth and gene expression of the Baltic Sea model bacterium Rheinheimera sp. BAL341

Organic pollutants (OPs) are critically toxic, bioaccumulative and globally widespread. Moreover, several OPs negatively influence aquatic wildlife. Although bacteria are major drivers of the ocean carbon cycle and the turnover of vital elements, there is limited knowledge of OP effects on heterotrophic bacterioplankton. We therefore investigated growth and gene expression responses of the Baltic Sea model bacterium Rheinheimera sp. BAL341 to environmentally relevant concentrations of distinct classes of OPs in 2-h incubation experiments. During exponential growth, exposure to a mix of polycyclic aromatic hydrocarbons, alkanes and organophosphate esters (denoted MIX) resulted in a significant decrease (between 9% and 18%) in bacterial abundance and production compared with controls. In contrast, combined exposure to perfluorooctanesulfonic acids and perfluorooctanoic acids (denoted PFAS) had no significant effect on growth. Nevertheless, MIX and PFAS exposures both induced significant shifts in gene expression profiles compared with controls in exponential growth. This involved several functional metabolism categories (e.g. stress response and fatty acids metabolism), some of which were pollutant-specific (e.g. phosphate acquisition and alkane-1 monooxygenase genes). In stationary phase, only two genes in the MIX treatment were significantly differentially expressed. The substantial direct influence of OPs on metabolism during bacterial growth suggests that widespread OPs could severely alter biogeochemical processes governed by bacterioplankton. © 2019 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.Funding text #1 Received 8 April, 2019; revised 15 May, 2019; accepted 15 May, 2019. *For correspondence. E-mail [email protected]; Tel. +46725949448 Microbial Biotechnology (2019) 12(5), 892–906 doi:10.1111/1751-7915.13441 Funding Information. This research was supported by the BONUS BLUEPRINT project, which has received funding from BONUS, the joint Baltic Sea research and development programme (Art 185), and the Swedish research council FORMAS. Funding was also provided through the Swedish governmental strong research programme EcoChange (FORMAS). Work by ECG and MVC was supported by a Fundación BBVA award to MVC (14_CMA_020) and by the Spanish MEIC through the project ISOMICS (CTM2015-65691-R). Funding text #2 We thank Josef Lautin for excellent technical assistance in the laboratory and Prof. Jordi Dachs for advice on organic pollutants. The authors would like to acknowledge the support from Science for Life Laboratory, the National Genomics Infrastructure, NGI, and Uppmax for providing assistance in massive parallel sequencing and computational infrastructure. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Funding text #3 Science (UPPMAX) under project b2011200. The research was supported by the BONUS BLUEPRINT project, which has received funding from BONUS, the joint Baltic Sea research and development programme (Art 185), and the Swedish research council FORMAS. Funding was also provided through the Swedish governmental strong research programme EcoChange (FORMAS). Work by ECG and MVC was supported by a Fundación BBVA award to MVC (14_CMA_020) and by the Spanish MEIC through the project ISOMICS (CTM2015-65691-R).Peer reviewe