Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.

Retrospective Diagnosis of Ataxia-Telangiectasia in an Adolescent Patient With a Remote History of T-Cell Leukemia.

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar degeneration that is typically diagnosed in early childhood. A-T is associated with a predisposition to malignancies, particularly lymphoid tumors in childhood and early adulthood. An adolescent girl with minimal neurologic symptoms was diagnosed with A-T 8 years after completing therapy for T-cell acute lymphoblastic leukemia, following a diagnosis of ATM-mutated breast cancer in her mother. We highlight the importance of recognizing ATM mutations in T-cell acute lymphoblastic leukemia, appreciating the phenotypic heterogeneity of A-T, and defining optimal cancer screening in A-T patients.

Genotype-phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations.

BACKGROUND: Ataxia telangiectasia (A-T) is a neurodegenerative disorder. While patients with classic A-T generally die in their 20s, some patients with variant A-T, who have residual ataxia-telangiectasia mutated (ATM) kinase activity, have a milder phenotype. We noticed two commonly occurring ATM mutations that appeared to be associated with prolonged survival and decided to study patients carrying one of these mutations. METHODS: Data were retrospectively collected from the Dutch, Italian, German and French A-T cohorts. To supplement these data, we searched the literature for patients with identical genotypes. RESULTS: This study included 35 patients who were homozygous or compound heterozygous for the ATM c.3576G>A; p.(Ser1135_Lys1192del58) mutation and 24 patients who were compound heterozygous for the ATM c.8147T>C; p.(Val2716Ala) mutation. Compared with 51 patients with classic A-T from the Dutch cohort, patients with ATM c.3576G>A had a longer survival and were less likely to develop cancer, respiratory disease or immunodeficiency. This was also true for patients with ATM c.8147T>C, who additionally became wheelchair users later in life and had fewer telangiectasias. The oldest patient with A-T reported so far was a 78-year-old patient who was compound heterozygous for ATM c.8147T>C. ATM kinase activity was demonstrated in cells from all patients tested with the ATM c.8147T>C mutant protein and only at a low level in some patients with ATM c.3576G>A. CONCLUSION: Compared with classic A-T, the presence of ATM c.3576G>A results in a milder classic phenotype. Patients with ATM c.8147T>C have a variant phenotype with prolonged survival, which in exceptional cases may approach a near-normal lifespan.

Ataxia-telangiectasia: Immunodeficiency and survival.

Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first.

Catalytic Chan-Lam coupling using a 'tube-in-tube' reactor to deliver molecular oxygen as an oxidant.

A flow system to perform Chan-Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures. A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over extended reaction times.

First international workshop of the ATM and cancer risk group (4-5 December 2019).

The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary.

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

Delineating origins of stereocontrol in asymmetric Pd-catalyzed alpha-hydroxylation of 1,3-ketoesters.

Systematic studies of reaction conditions and subsequent optimization led to the identification of important parameters for stereoselectivity in the asymmetric alpha-hydroxylation reaction of 1,3-ketoesters. Enantioselectivities of up to 98% can be achieved for cyclic substrates and 88% for acyclic ketoesters. Subsequently, the combination of cyclic/acyclic ketoester, catalyst, and oxidant was found to have a profound effect on reaction rates and turnover-limiting steps. The stereochemistry of the reaction contradicts that observed for other similar electrophilic substitution reactions. This was rationalized by transition-state modeling, which revealed a number of cooperative weak interactions between oxidant, ligand, and counterion, together with C-H/pi interactions that cumulatively account for the unusual stereoselectivity.

Bacterial attachment on optical fibre surfaces.

Optical fibres have received considerable attention as high-density sensor arrays suitable for both in vitro and in vivo measurements of biomolecules and biological processes in living organisms and/or nano-environments. The fibre surface was chemically modified by exposure to a selective etchant that preferentially erodes the fibre cores relative to the surrounding cladding material, thus producing a regular pattern of cylindrical wells of approximately 2.5 mum in diameter and 2.5 mum deep. The surface hydrophobicity of the etched and non-etched optical fibres was analysed using the sessile pico-drop method. The surface topography was characterised by atomic force microscopy (AFM), while the surface chemistry was probed by time-of-flight secondary ion mass spectrometry (ToF-SIMS). Six taxonomically different bacterial strains showed a consistent preference for attachment to the nano-scale smoother (R(q) = 273 nm), non-etched fibre surfaces (water contact angle, theta = 106 degrees +/- 4 degrees). In comparison, the surfaces of the etched optical fibres (water contact angle, theta = 96 degrees +/- 10 degrees) were not found to be amenable to bacterial attachment. Bacterial attachment on the non-etched optical fibre substrata varied among different strains.

Developing immune-regulatory materials using immobilized monosaccharides with immune-instructive properties.

New strategies for immune modulation have shown real promise in regenerative medicine as well as the fight against autoimmune diseases, allergies, and cancer. Dendritic cells (DCs) are gatekeepers of the immune system and their ability in shaping the adaptive immune responses makes DCs ideal targets for immune modulation. Carbohydrates are abundant in different biological systems and are known to modulate DC phenotype and function. However, how simple monosaccharides instruct DC function is less well understood. In this study, we used a combinatorial array of immobilized monosaccharides to investigate how they modulate DC phenotype and function and crucially the impact of such changes on downstream adaptive immune responses. Our data show that a selection of monosaccharides significantly suppress lipopolysaccharide-induced DC activation as evidenced by a reduction in CD40 expression, IL-12 production, and indoleamine 2,3-dioxygenase activity, while inducing a significant increase in IL-10 production. These changes are indicative of the induction of an anti-inflammatory or regulatory phenotype in DCs, which was further confirmed in DC-T cell co-cultures where DCs cultured on the 'regulatory' monosaccharide-coated surfaces were shown to induce naïve T cell polarization toward regulatory phenotype. Our data also highlighted a selection of monosaccharides that are able to promote mixed Treg and Th17 cell differentiation, a T cell phenotype expected to be highly immune suppressive. These data show the potential immunomodulatory effects of immobilized monosaccharides in priming DCs and skewing T cell differentiation toward an immune-regulatory phenotype. The ability to fine-tune immune responses using these simple carbohydrate combinations (e.g. as coatings for existing materials) can be utilized as novel tools for immune modulation with potential applications in regenerative medicine, implantable medical devices, and wound healing where reduction of inflammatory responses and maintaining immune homeostasis are desirable.

Which animals are at risk? Predicting species susceptibility to Covid-19.

In only a few months, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, leaving physicians, scientists, and public health officials racing to understand, treat, and contain this zoonotic disease. SARS-CoV-2 has made the leap from animals to humans, but little is known about variations in species susceptibility that could identify potential reservoir species, animal models, and the risk to pets, wildlife, and livestock. While there is evidence that certain species, such as cats, are susceptible, the vast majority of animal species, including those in close contact with humans, have unknown susceptibility. Hence, methods to predict their infection risk are urgently needed. SARS-CoV-2 spike protein binding to angiotensin converting enzyme 2 (ACE2) is critical for viral cell entry and infection. Here we identified key ACE2 residues that distinguish susceptible from resistant species using in-depth sequence and structural analyses of ACE2 and its binding to SARS-CoV-2. Our findings have important implications for identification of ACE2 and SARS-CoV-2 residues for therapeutic targeting and identification of animal species with increased susceptibility for infection on which to focus research and protection measures for environmental and public health.

Classic ataxia-telangiectasia: the phenotype of long-term survivors.

OBJECTIVE: Patients with classic ataxia-telangiectasia (A-T) generally die in the second or third decade of life. Clinical descriptions of A-T tend to focus on the symptoms at presentation. However, during the course of the disease, other symptoms and complications emerge. As long-term survivors with classic A-T develop a complex multisystem disorder with a largely unknown extent and severity, we aimed to comprehensively assess their full clinical picture. METHODS: Data from Dutch patients with classic A-T above the age of 30 years were retrospectively collected. In addition, we searched the literature for descriptions of classic A-T patients who survived beyond the age of 30 years. RESULTS: In the Dutch cohort, seven classic A-T patients survived beyond 30 years of age. Fourteen additional patients were retrieved by the literature search. Common problems in older patients with classic A-T were linked to ageing. Most patients had pulmonary, endocrine, cardiovascular, and gastro-intestinal problems. All patients had a tetraparesis with contractures. This led to immobilization and frequent hospital admissions. Most patients expressed the wish to no longer undergo intensive medical treatments, and waived follow-up programs. CONCLUSIONS: Paucity of descriptions in the literature, and withdrawal from medical care complicate the acquisition of follow-up data on the natural history of long-term survivors. Irrespective of these limitations, we have obtained impression of the many problems that these patients face when surviving beyond 30 years of age. Awareness of these problems is needed to guide follow-up, counselling, and (palliative) care; decisions about life-prolonging treatments should be well considered.

Palladium-catalysed enantioselective alpha-hydroxylation of beta-ketoesters.

Highly enantioselective alpha-hydroxylation of cyclic and acyclic 1,3-ketoesters can be achieved with up to 98% ee using a dicationic palladium(ii) catalyst and dimethyldioxirane as oxidant.

Progressive Ataxia with Elevated Alpha-Fetoprotein: Diagnostic Issues and Review of the Literature.

Background: Ataxias represent a challenging group of disorders due to significant clinical overlap. Here, we present a patient with early-onset progressive ataxia, polyneuropathy and discuss how elevation of alpha fetoprotein (AFP) narrows the differential diagnosis. Case report: Ataxia, polyneuropathy, and mild elevation of AFP are features compatible with ataxia with oculomotor apraxia type 2 (AOA2) but also with ataxia with oculomotor apraxia type 4 (AOA4). A genetic analysis demonstrated biallelic mutations in senataxin (SETX), confirming the diagnosis of AOA2. Discussion: Mild elevation of AFP is found in patients with AOA2 and AOA4, and higher levels are commonly seen in ataxia-telangiectasia. AFP is a useful diagnostic tool but not a biomarker for disease progression in AOA2.

Trajectories of motor abnormalities in milder phenotypes of ataxia telangiectasia.

OBJECTIVE: To describe and classify the neurologic trajectories in patients with mild neurologic forms of ataxia telangiectasia (A-T) from the Dutch A-T cohort, combined with patients reported in the literature. METHODS: Clinical, genetic, and laboratory data of 14 patients with mild neurologic phenotypes of A-T from the Dutch cohort were analyzed and combined with corresponding data from the literature. A mild neurologic phenotype was defined by a later onset, nonataxia presenting or dominant feature, or slower progression compared to the classic A-T phenotype. Neurologic trajectories were classified based on age at onset, presenting feature, and follow-up data. RESULTS: One hundred five patients were included in the study. Neurologic trajectories were categorized into 6 groups: patients with childhood-onset extrapyramidal (EP) features with cerebellar symptoms developing later (group 1; 18 patients), childhood-onset cerebellar symptoms, with EP features developing later (group 2; 35 patients), childhood- to adolescence-onset dystonia, without cerebellar symptoms (group 3; 23 patients), childhood- to adolescence-onset isolated cerebellar symptoms (group 4; 22 patients), childhood- to adult-onset prominent muscle weakness (group 5; 2 patients), and patients with adult-onset EP features, with anterior horn cell disease arising subsequently (group 6; 5 patients). CONCLUSIONS: This systematic study of the different motor abnormalities and their course over time in patients with mild phenotypes of A-T, enabled us to recognize 6 essentially different phenotypic patterns. Awareness of these different trajectories of motor abnormalities in milder forms of A-T will contribute to a reduction of diagnostic delay in this severe multisystem disorder.

Regulation of cell cycle progression by Swe1p and Hog1p following hypertonic stress.

Exposure of yeast cells to an increase in external osmolarity induces a temporary growth arrest. Recovery from this stress is mediated by the accumulation of intracellular glycerol and the transcription of several stress response genes. Increased external osmolarity causes a transient accumulation of 1N and 2N cells and a concomitant depletion of S phase cells. Hypertonic stress triggers a cell cycle delay in G2 phase cells that appears distinct from the morphogenesis checkpoint, which operates in early S phase cells. Hypertonic stress causes a decrease in CLB2 mRNA, phosphorylation of Cdc28p, and inhibition of Clb2p-Cdc28p kinase activity, whereas Clb2 protein levels are unaffected. Like the morphogenesis checkpoint, the osmotic stress-induced G2 delay is dependent upon the kinase Swe1p, but is not tightly correlated with inhibition of Clb2p-Cdc28p kinase activity. Thus, deletion of SWE1 does not prevent the hypertonic stress-induced inhibition of Clb2p-Cdc28p kinase activity. Mutation of the Swe1p phosphorylation site on Cdc28p (Y19) does not fully eliminate the Swe1p-dependent cell cycle delay, suggesting that Swe1p may have functions independent of Cdc28p phosphorylation. Conversely, deletion of the mitogen-activated protein kinase HOG1 does prevent Clb2p-Cdc28p inhibition by hypertonic stress, but does not block Cdc28p phosphorylation or alleviate the cell cycle delay. However, Hog1p does contribute to proper nuclear segregation after hypertonic stress in cells that lack Swe1p. These results suggest a hypertonic stress-induced cell cycle delay in G2 phase that is mediated in a novel way by Swe1p in cooperation with Hog1p.

Sea-level projections representing the deeply uncertain contribution of the West Antarctic ice sheet.

There is a growing awareness that uncertainties surrounding future sea-level projections may be much larger than typically perceived. Recently published projections appear widely divergent and highly sensitive to non-trivial model choices. Moreover, the West Antarctic ice sheet (WAIS) may be much less stable than previous believed, enabling a rapid disintegration. Here, we present a set of probabilistic sea-level projections that approximates the deeply uncertain WAIS contributions. The projections aim to inform robust decisions by clarifying the sensitivity to non-trivial or controversial assumptions. We show that the deeply uncertain WAIS contribution can dominate other uncertainties within decades. These deep uncertainties call for the development of robust adaptive strategies. These decision-making needs, in turn, require mission-oriented basic science, for example about potential signposts and the maximum rate of WAIS-induced sea-level changes.

Engineering serendipity: High-throughput discovery of materials that resist bacterial attachment.

Controlling the colonisation of materials by microorganisms is important in a wide range of industries and clinical settings. To date, the underlying mechanisms that govern the interactions of bacteria with material surfaces remain poorly understood, limiting the ab initio design and engineering of biomaterials to control bacterial attachment. Combinatorial approaches involving high-throughput screening have emerged as key tools for identifying materials to control bacterial attachment. The hundreds of different materials assessed using these methods can be carried out with the aid of computational modelling. This approach can develop an understanding of the rules used to predict bacterial attachment to surfaces of non-toxic synthetic materials. Here we outline our view on the state of this field and the challenges and opportunities in this area for the coming years. STATEMENT OF SIGNIFICANCE: This opinion article on high throughput screening methods reflects one aspect of how the field of biomaterials research has developed and progressed. The piece takes the reader through key developments in biomaterials discovery, particularly focusing on need to reduce bacterial colonisation of surfaces. Such bacterial resistant surfaces are increasingly required in this age of antibiotic resistance. The influence and origin of high-throughput methods are discussed with insights into the future of biomaterials development where computational methods may drive materials development into new fertile areas of discovery. New biomaterials will exhibit responsiveness to adapt to the biological environment and promote better integration and reduced rejection or infection.

Theophylline in stable chronic airflow obstruction. A reappraisal.

Theophylline is commonly recommended for patients who have stable chronic airflow obstruction (CAO). Recent evidence confirms that serum theophylline concentrations between 10 and 20 mg/L may increase forced expiratory volume in 1 s (FEV1) and forced vital capacity in these patients. Exercise tolerance, however, and the classic respiratory symptoms of wheezing, breathlessness, cough, and sense of well-being do not improve. A reappraisal of the role of this medication in patients with stable CAO is therefore necessary; we recommend not prescribing this medication for all patients. Instead, the response of FEV1 after isoproterenol inhalation (0.15 mg) should be monitored. This simple test has good efficacy for predicting the response to oral theophylline therapy and could diminish the cost and unnecessary side effects of theophylline while benefiting those who will respond.