Molecular studies on Burton's tyrosine kinase

X-Linked agammaglobulinaemia (XLA) is a humoral immunodeficiency resulting from a block in the B cell maturation pathway at the pre-B cell stage. Affected males have normal numbers of pre-B cells in the bone marrow but virtually no mature B cells in the peripheral circulation and are unable to produce immunoglobulin of all isotypes. The gene defective in XLA has been identified as a non-receptor tyrosine kinase and named Btk (Bruton's tyrosine kinase). Btk is a modular protein related to but distinct from the Src family of tyrosine kinases. However, the precise pathways in which Btk is involved and its exact role in lymphocyte maturation remain unclear This thesis describes a programme of work ranging from the identification of the genetic defects in Btk through to studies attempting to define the role of Btk in intracellular signalling by the use of gene transfer technology. Mutation analysis of Btk cDNA from individuals with XLA using single stranded conformational polymorphism (SSCP) analysis and direct sequencing resulted in the identification of 5 mutations. In three unrelated individuals the same mutation was identified suggesting the presence of a mutational hotspot in Btk. Subsequent studies investigated the expression and activity of Btk protein in primary cells from XLA patients in order to correlate the clinical phenotype with the genetic defect. However, it was shown that regardless of the mutation or clinical phenotype, there was complete lack of Btk expression and activity. These assays were also used to confirm the diagnosis of XLA in certain individuals in whom XLA was suspected but not confirmed by genetic analysis. Gene transfer technology was used to create in vitro models with which study the function of the Btk protein. Retroviral vectors encoding a copy of wild type and kinase mutant Btk were generated and used to express Btk in a fibroblast line to study the binding of Btk to candidate signalling proteins. Retroviral transfer of Btk into an EBV transformed B cell line from an XLA patient with a null phenotype was also performed in order to study reconstitution of B cell function

A concept for a novel polymer extruder part 2: rotational barrel segment

This paper presents a novel concept of an extrusion machine for polymer plastics, polymer-matrix materials, and food processing applications. The design of the extruder includes a rotational barrel segment to enable kinematic activation in the process of plasticizing the material and improvement in the homogenization level. The tests included a FEM-based numerical analysis of the rotational barrel segment design. The numerical calculations comprised a fully coupled thermal-stress analysis, used to solve a non-linear geometric and physical problem. The numerical calculation results proved that the designed structural parts of the rotational barrel segment had sufficient strength and that the design of the rotational barrel segment was suitable in terms of the required temperature distribution within the structural parts. The numerical calculation tool used in the analysis was ABAQUS , commercially available software

A concept for a novel polymer extruder part 1: active grooved feed section

This paper presents a novel concept for an extruder to be used with plastics and polymer composites, especially in the food industry. The design solutions include a grooved feed section with adjustable geometric parameters, which makes it possible for dynamic adjustment of the depth, inclination angle and number of grooves used for granulate transport during continuous operation of the machine. The proposed grooved feed section concept facilitates optimum performance, and is adjustable to suit the general parameters of production. The scope of our study also included the numerical strength and thermal analysis of the designed grooved feed section, conducted using the finite element method. Numerical calculation involved a coupled temperaturedisplacement analysis which constituted a geometrically and physically non-linear problem. The results corroborated the achievement of satisfactory strength for the structural elements of the grooved feed section in the extruder and demonstrated the suitability of the adopted solution in terms of temperature distribution in the parts of the machine, as well as the correct concept of the rcial program

Special symposium: In vitro plant recalcitrance loss of plant organogenic totipotency in the course of In vitro neoplastic progression

Summary: The aptitude for organogenesis from normal hormone-dependent cultures very commonly decreases as the tissues are serially subcultured. The reasons for the loss of regenerative ability may vary under different circumstances: genetic variation in the cell population, epigenetic changes, disappearance of an organogenesis-promoting substance, etc. The same reasons may be evoked for the progressive and eventually irreversible loss of organogenic totipotency in the course of neoplastic progressions from hormone-independent tumors and hyperhydric teratomas to cancers. As in animal cells, plant cells at the end of a neoplastic progression have probably undergone several independent genetic accidents with cumulative effects. They indeed are characterized by atypical biochemical cycles from which they are apparently unable to escape. The metabolic changes are probably not the primary defects that cause cancer, rather they may allow the cells to survive. How these changes, namely an oxidative stress, affect organogenesis is not known. The literature focuses on somatic mutations and epigenetic changes that cause aberrant regulation of cell cycle genes and their machiner

Electrochemical push-pull probe: from scanning electrochemical microscopy (SECM) to multimodal altering of cell microenvironment

To understand biological processes at the cellular level, a general approach is to alter the cells’ environment and to study their chemical responses. Herein, we present the implementation of an electrochemical push-pull probe, which combines a microfluidic system with a microelectrode, as a tool for locally altering the microenvironment of few adherent living cells by working in two different perturbation modes, namely electrochemical (i.e. electrochemical generation of a chemical effector compound) and microfluidic (i.e. infusion of a chemical effector compound from the pushing microchannel, while aspirating it through the pulling channel thereby focusing the flow between the channels). The effect of several parameters such as flow rate, working distance and probe inclination angle on the affected area of adherently growing cells was investigated both theoretically and experimentally. As a proof of concept, localized fluorescent labeling and pH changes were purposely introduced to validate the probe as a tool for studying adherent cancer cells through the control over the chemical composition of the extracellular space with high spatiotemporal resolution. A very good agreement between experimental and simulated results showed for instance, that the electrochemical perturbation mode enables to affect precisely only few living cells localized in a high-density cell culture

Gold(I) as an Artificial Cyclase: Short Stereodivergent Syntheses of (−)-Epiglobulol and (−)-4β,7α- and (−)-4α,7α-Aromadendranediols

Three natural aromadendrane sesquiterpenes, (−)‐epiglobulol, (−)‐4β,7α‐aromadendranediol, and (−)‐4α,7α‐aromadendranediol, have been synthesized in only seven steps in 12, 15, and 17 % overall yields, respectively, from (E,E)‐farnesol by a stereodivergent gold(I)‐catalyzed cascade reaction which forms the tricyclic aromadendrane core in a single step. These are the shortest total syntheses of these natural compounds

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Margarita de Sossa, Sixteenth-Century Puebla de los Ángeles, New Spain (Mexico)

Margarita de Sossa’s freedom journey was defiant and entrepreneurial. In her early twenties, still enslaved in Portugal, she took possession of her body; after refusing to endure her owner’s sexual demands, he sold her, and she was transported to Mexico. There, she purchased her freedom with money earned as a healer and then conducted an enviable business as an innkeeper. Sossa’s biography provides striking insights into how she conceptualized freedom in terms that included – but was not limited to – legal manumission. Her transatlantic biography offers a rare insight into the life of a free black woman (and former slave) in late sixteenth-century Puebla, who sought to establish various degrees of freedom for herself. Whether she was refusing to acquiesce to an abusive owner, embracing entrepreneurship, marrying, purchasing her own slave property, or later using the courts to petition for divorce. Sossa continued to advocate on her own behalf. Her biography shows that obtaining legal manumission was not always equivalent to independence and autonomy, particularly if married to an abusive husband, or if financial successes inspired the envy of neighbors

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages