A systematic review and meta-analyses of pregnancy and fetal outcomes in women with multiple sclerosis: a contribution from the IMI2 ConcePTION project.

Neurologists managing women with Multiple Sclerosis (MS) need information about the safety of disease modifying drugs (DMDs) during pregnancy. However, this knowledge is limited. The present study aims to summarize previous studies by performing a systematic review and meta-analyses. The terms "multiple sclerosis" combined with DMDs of interest and a broad profile for pregnancy terms were used to search Embase and Medline databases to identify relevant studies published from January 2000 to July 2019.1260 studies were identified and ten studies met our inclusion criteria. Pooled risk ratios (RR) of pregnancy and birth outcomes in pregnancies exposed to DMDs compared to those not exposed were calculated using a random effects model. For spontaneous abortion RR = 1.14, 95% CI 0.99-1.32, for preterm births RR = 0.93, 95% CI 0.72-1.21 and for major congenital malformations RR = 0.86, 95% CI 0.47-1.56. The most common major congenital malformations reported in MS patients exposed to MS drugs were atrial septal defect (ASD) (N = 4), polydactyly (N = 4) and club foot (N = 3), which are among the most prevalent birth defects observed in the general population. In conclusion, interferons, glatiramer acetate or natalizumab, do not appear to increase the risk for spontaneous abortions, pre-term birth or major congenital malformations. There were very few patients included that were exposed to fingolimod, azathioprine and rituximab; therefore, these results cannot be generalized across drugs. Future studies including internal comparators are needed to enable treating physicians and their patients to decide on the best treatment options

Scaling Up Magnetic Nanobead Synthesis with Improved Stability for Biomedical Applications

The growing interest in multifunctional nano-objects based on polymers and magnetic nanoparticles for biomedical applications motivated us to develop a scale-up protocol to increase the yield of polymeric magnetic nanobeads while aiming at keeping the structural features at optimal conditions. The protocol was applied to two different types of magnetic ferrite nanoparticles: the Mn-ferrite selected for their properties as contrast agents in magnetic resonance imaging and iron oxide nanostar shaped nanoparticles chosen for their heat performance in magnetic hyperthermia. At the same time, some experiments on surface functionalization of nanobeads with amino modified polyethyelene glycol (PEG) molecules have provided further insight into the formation mechanism of magnetic nanobeads and the need to cross-link the polymer shell to improve the stability of the beads, making them more suitable for further manipulation and use. The present work summarizes the most important parameters required to be controlled for the upscaling of nanobead synthesis in a bench protocol and proposes an alternative cross-linking strategy based on prefunctionalization of the polymer prior to the nanobead formation as a key parameter to improve the nanobead structural stability in solutions at different pHs and during surface functionalization

Valuing and Managing the Philippines’ Marine Resources toward a Prosperous Ocean-Based Blue Economy

The ocean-based “blue economy” is a significant part of the Philippine economy that has largely been taken for granted despite its enormous potential. It is of critical importance to a substantial segment of our population dependent on the seas and coastal resources for their livelihood and sustenance, appreciably enlarge the country’s wealth, and significantly contribute to its gross domestic product. This paper attempts to review the major issues concerning marine ecosystems in relation to the country’s pursuit of the blue economy. It discusses the economic and social activities in relation to the seas and coastal areas, and provides updated estimates of the real value of the country’s marine ecosystems’ goods and services. Based on primary and available secondary data, the marine ecosystems (excluding the continental shelf) can contribute a conservative monetary value of US$ 966.6 billion to the economy. In light of the risks and threats to the blue economy, the paper further discusses the country’s current national initiatives and involvement in regional collaborations toward ensuring its health and sustainable development. Given the Philippines’ vast largely untapped potential, a recommendation for the creation of a Department of Marine Resources, separate from the Department of Agriculture, seems in order

Computational mutagenesis reveals the role of active-site tyrosine in stabilising a boat conformation for the substrate:QM/MM molecular dynamics studies of wild-type and mutant xylanases

Molecular dynamics simulations have been performed for non-covalent complexes of phenyl b-xylobioside with the retaining endo-b-1,4-xylanase from B. circulans (BCX) and its Tyr69Phe mutant using a hybrid QM/MM methodology. A trajectory initiated for the wild-type enzyme–substrate complex with the proximal xylose ring bound at the –1 subsite (adjacent to the scissile glycosidic bond) in the 4C1 chair conformation shows spontaneous transformation to the 2,5B boat conformation, and potential of mean force calculations indicate that the boat is ~30 kJ mol-1 lower in free energy than the chair. Analogous simulations for the mutant lacking one oxygen atom confirm the key role of Tyr69 in stabilizing the boat in preference to the 4C1 chair conformation, with a relative free energy difference of about 20 kJ mol-1, by donating a hydrogen bond to the endocyclic oxygen of the proximal xylose ring. QM/MM MD simulations for phenyl b-xyloside in water, with and without a propionate/propionic acid pair to mimic the catalytic glutamate/glutamic acid pair of the enzyme, show the 4C1 chair to be stable, although a hydrogen bond between the OH group at C2 of xylose and the propionate moiety seems to provide some stabilization for the 2,5B conformatio

"Nanohybrids" based on pH-responsive hydrogels and inorganic nanoparticles for drug delivery and sensor applications.

Allyl-PEG capped inorganic NPs, including magnetic iron oxide (IONPs), fluorescent CdSe/ZnS quantum dots (QDs), and metallic gold (AuNPs of 5 and 10 nm) both individually and in combination, were covalently attached to pH-responsive poly(2-vinylpyridine-co-divinylbenzene) nanogels via a facile and robust one-step surfactant-free emulsion polymerization procedure. Control of the NPs associated to the nanogels was achieved by the late injection of the NPs to the polymerization solution at a stage when just polymeric radicals were present. Remarkably, by varying the total amount of NPs injected, the swelling behavior could be affected. Furthermore, the magnetic response as well as the optical features of the nanogels containing either IONPs or QDs could be modified. In addition, a radical quenching in case of gold nanoparticles was observed, thus affecting the final nanogel geometry

Controlled Release of Doxorubicin Loaded within Magnetic Thermo-responsive Nanocarriers under Magnetic and Thermal Actuation in a Microfluidic Channel

We report a procedure to grow thermo-responsive polymer shells at the surface of magnetic nanocarriers made of multiple iron oxide superparamagnetic nanoparticles embedded in poly(maleic anhydride-alt-1-ocatadecene) polymer nanobeads. Depending on the comonomers and on their relative composition, tunable phase transition temperatures in the range between 26 and 47 °C under physiological conditions could be achieved. Using a suitable microfluidic platform combining magnetic nanostructures and channels mimicking capillaries of the circulatory system, we demonstrate that thermo-responsive nanobeads are suitable for localized drug delivery with combined thermal and magnetic activation. Below the critical temperature nanobeads are stable in suspension, retain their cargo, and cannot be easily trapped by magnetic fields. Increasing the temperature above the critical temperature causes the aggregation of nanobeads, forming clusters with a magnetic moment high enough to permit their capture by suitable magnetic g..

Loop Interactions during Catalysis by Dihydrofolate Reductase fromMoritella profunda

Dihydrofolate reductase (DHFR) is often used as a model system to study the relation between protein dynamics and catalysis. We have studied a number of variants of the cold-adapted DHFR from Moritella profunda (MpDHFR), in which the catalytically important M20 and FG loops have been altered, and present a comparison with the corresponding variants of the wellstudied DHFR from Escherichia coli (EcDHFR). Mutations in the M20 loop do not affect the actual chemical step of transfer of hydride from reduced nicotinamide adenine dinucleotide phosphate to the substrate 7,8-dihydrofolate in the catalytic cycle in either enzyme; they affect the steady state turnover rate in EcDHFR but not in MpDHFR. Mutations in the FG loop also have different effects on catalysis by the two DHFRs. Despite the two enzymes most likely sharing a common catalytic cycle at pH 7, motions of these loops, known to be important for progression through the catalytic cycle in EcDHFR, appear not to play a significant role in MpDHFR

Genetic Evidence for Involvement of Neuronally Expressed S1P1 Receptor in Nociceptor Sensitization and Inflammatory Pain

Sphingosine-1-phosphate (S1P) is a key regulator of immune response. Immune cells, epithelia and blood cells generate high levels of S1P in inflamed tissue. However, it is not known if S1P acts on the endings of nociceptive neurons, thereby contributing to the generation of inflammatory pain. We found that the S1P1 receptor for S1P is expressed in subpopulations of sensory neurons including nociceptors. Both S1P and agonists at the S1P1 receptor induced hypersensitivity to noxious thermal stimulation in vitro and in vivo. S1P-induced hypersensitivity was strongly attenuated in mice lacking TRPV1 channels. S1P and inflammation-induced hypersensitivity was significantly reduced in mice with a conditional nociceptor-specific deletion of the S1P1 receptor. Our data show that neuronally expressed S1P1 receptors play a significant role in regulating nociceptor function and that S1P/S1P1 signaling may be a key player in the onset of thermal hypersensitivity and hyperalgesia associated with inflammation

Search for a vector-like quark T′ → tH via the diphoton decay mode of the Higgs boson in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for the electroweak production of a vector-like quark T′, decaying to a top quark and a Higgs boson is presented. The search is based on a sample of proton-proton collision events recorded at the LHC at = 13 TeV, corresponding to an integrated luminosity of 138 fb−1. This is the first T′ search that exploits the Higgs boson decay to a pair of photons. For narrow isospin singlet T′ states with masses up to 1.1 TeV, the excellent diphoton invariant mass resolution of 1–2% results in an increased sensitivity compared to previous searches based on the same production mechanism. The electroweak production of a T′ quark with mass up to 960 GeV is excluded at 95% confidence level, assuming a coupling strength κT = 0.25 and a relative decay width Γ/MT′ < 5%

Measurement of the Higgs boson inclusive and differential fiducial production cross sections in the diphoton decay channel with pp collisions at s \sqrt{s} = 13 TeV

The measurements of the inclusive and differential fiducial cross sections of the Higgs boson decaying to a pair of photons are presented. The analysis is performed using proton-proton collisions data recorded with the CMS detector at the LHC at a centre-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 137 fb$^{−1}$. The inclusive fiducial cross section is measured to be $σ_{fid}$=73.4$^{+5.4}_{−5.3}$(stat)$^{+2.4}_{−2.2}$(syst) fb, in agreement with the standard model expectation of 75.4 ± 4.1 fb. The measurements are also performed in fiducial regions targeting different production modes and as function of several observables describing the diphoton system, the number of additional jets present in the event, and other kinematic observables. Two double differential measurements are performed. No significant deviations from the standard model expectations are observed