Development of a topical bacteriophage gel targeting Cutibacterium acnes for acne prone skin and results of a phase 1 cosmetic randomized clinical trial.

Background: Topical antibiotics are frequently used to treat acne vulgaris. Their prolonged use, often for longer durations than recommended, has led to antibiotic resistance in Cutibacterium acnes (C. acnes), a bacterium implicated in acne pathophysiology. Bacteriophage (phage), which specifically target C. acnes by a different mechanism of action and do not harm potentially beneficial bacteria, may offer an alternative approach for improvement of the appearance of acne prone skin. Objectives: To identify and characterize C. acnes targeting phage, carry out a comprehensive preclinical safety evaluation of phages selected for further development and examine their safety, tolerability and ability to target facial C. acnes when applied topically in a cosmetic clinical study including participants with mild-to-moderate acne. Methods: Phages were isolated by conventional microbiological methods also used to examine their breadth of host range on different C. acnes strains and specificity to this bacterial species. Safety assessment of three selected phages was carried out by complete genomic analysis to assure the absence of undesired sequences and by ex vivo models employed to evaluate the safety, irritability and potential systemic bioavailability of phage applied topically. A randomized, controlled clinical study assessed safety, tolerability and efficacy in targeting facial C. acnes. Results: Wide host range phages that also target antibiotic resistant C. acnes were identified. Their genomes were shown to be free of undesired genes. The three-phage cocktail, BX001, was not irritant to human skin or ocular tissues in ex vivo models and did not permeate through human epidermis. In a cosmetic clinical study, topically applied BX001 was safe and well tolerated and reduced the facial burden of C. acnes. Conclusions: Combined in silico and ex vivo approaches successfully predicted the observed safety and efficacy of C. acnes targeting phage when these were topically administered in a well-controlled cosmetic clinical study.

Thiol functionalised silica microsphere loaded polymeric hydrogel: Development of a novel hybrid sorbent for removal of lead and cadmium.

Current study presents a facile synthesis method for thiol functionalised silica microsphere loaded polymeric hydrogel. Silica microspheres were synthesised as core shell particles by sol-gel method followed by hydrolysis and condensation reaction to form the silica core. The silica was functionalised with thiol and the functionalised silica microsphere was subsequently impregnated into polymeric alginate matrix to form thiol functionalised silica microspheres loaded alginate hydrogel beads (SH-SiO2MS-Ca-Alg). The developed components and final products were characterised by BET, FTIR, DLS, SEM-EDS. The developed SH-SiO2MS-Ca-Alg hydrogel beads were used for efficient removal of Pb and Cd [72-97 % for Pb; 60-85 % for Cd at concentration range of 0.1-100 µg mL-1 and optimum pH 5-7] from aquatic medium. The sorption capacities evaluated for Pb and Cd from Langmuir isotherm were 127.99 and 70.68 mgg-1 respectively. Uptake kinetics, isotherm, thermodynamics, intraparticle diffusion studies were carried out for both Pb (II) and Cd (II). Mechanism of Pb (II) and Cd (II) removal by SH-SiO2MS-Ca-Alg hydrogel hybrid beads was proposed with the help of zeta potentials of SH-SiO2MS at different pH along with fraction diagram of Pb and Cd.

Design of the collection optics for the Core Plasma Thomson Scattering (CPTS) in ITER.

In the ITER Core Plasma Thomson Scattering, the scattered light collection optics system is installed both inside and outside the diagnostic port under vacuum. The length of the optical path (∼6 m) and the need to shield the neutron and γ radiation increased the complexity of the system with the inclusion of multiple dog-legs, forcing the use of many elements with optical power. Multiple rounds of design have been required in order to satisfy iteratively the system requirements in terms of resolution, aberration, and shielding. The adoption of quasi-free-form reflective surfaces for several mirrors eventually allowed the correct compromise between all conflicting requirements.

Sub-Femto-g Free Fall for Space-Based Gravitational Wave Observatories: LISA Pathfinder Results.

We report the first results of the LISA Pathfinder in-flight experiment. The results demonstrate that two free-falling reference test masses, such as those needed for a space-based gravitational wave observatory like LISA, can be put in free fall with a relative acceleration noise with a square root of the power spectral density of 5.2±0.1 fm s^{-2}/sqrt[Hz], or (0.54±0.01)×10^{-15} g/sqrt[Hz], with g the standard gravity, for frequencies between 0.7 and 20 mHz. This value is lower than the LISA Pathfinder requirement by more than a factor 5 and within a factor 1.25 of the requirement for the LISA mission, and is compatible with Brownian noise from viscous damping due to the residual gas surrounding the test masses. Above 60 mHz the acceleration noise is dominated by interferometer displacement readout noise at a level of (34.8±0.3) fm/sqrt[Hz], about 2 orders of magnitude better than requirements. At f≤0.5 mHz we observe a low-frequency tail that stays below 12 fm s^{-2}/sqrt[Hz] down to 0.1 mHz. This performance would allow for a space-based gravitational wave observatory with a sensitivity close to what was originally foreseen for LISA.

Approaching Free Fall on Two Degrees of Freedom: Simultaneous Measurement of Residual Force and Torque on a Double Torsion Pendulum.

A torsion pendulum with 2 soft degrees of freedom (DOFs), realized by off-axis cascading two torsion fibers, has been built and operated. This instrument helps characterize the geodesic motion of a test mass for LISA Pathfinder or any other free-fall space mission, providing information on cross talk and other effects that cannot be detected when monitoring a single DOF. We show that it is possible to simultaneously measure both the residual force and the residual torque acting on a quasifree test mass. As an example of the investigations that a double pendulum allows, we report the measurement of the force-to-torque cross talk, i.e., the amount of actuation signal, produced by applying a force on the suspended test mass, that leaks into the rotational DOF, detected by measuring the corresponding (unwanted) torque.

Chevron beam dump for ITER edge Thomson scattering system.

This paper contains the design of the beam dump for the ITER edge Thomson scattering system and mainly concerns its lifetime under the harsh thermal and electromagnetic loads as well as tight space allocation. The lifetime was estimated from the multi-pulse laser-induced damage threshold. In order to extend its lifetime, the structure of the beam dump was optimized. A number of bent sheets aligned parallel in the beam dump form a shape called a chevron which enables it to avoid the concentration of the incident laser pulse energy. The chevron beam dump is expected to withstand thermal loads due to nuclear heating, radiation from the plasma, and numerous incident laser pulses throughout the entire ITER project with a reasonable margin for the peak factor of the beam profile. Structural analysis was also carried out in case of electromagnetic loads during a disruption. Moreover, detailed issues for more accurate assessments of the beam dump's lifetime are clarified. Variation of the bi-directional reflection distribution function (BRDF) due to erosion by or contamination of neutral particles derived from the plasma is one of the most critical issues that needs to be resolved. In this paper, the BRDF was assumed, and the total amount of stray light and the absorbed laser energy profile on the beam dump were evaluated.

Increasing the bandwidth of resonant gravitational antennas: the case of explorer.

Resonant gravitational wave detectors with an observation bandwidth of tens of hertz are a reality: the antenna Explorer, operated at CERN by the ROG Collaboration, has been upgraded with a new readout. In this new configuration, it exhibits an unprecedented useful bandwidth: in over 55 Hz about its center operating frequency of 919 Hz the spectral sensitivity is better than 10(-20) Hz(-1/2). We describe the detector and its sensitivity and discuss the foreseeable upgrades to even larger bandwidths.

Cloning and characterization of the human activity-dependent neuroprotective protein.

We have recently cloned the mouse activity-dependent neuroprotective protein (ADNP). Here, we disclose the cloning of human ADNP (hADNP) from a fetal brain cDNA library. Comparative sequence analysis of these two ADNP orthologs indicated 90% identity at the mRNA level. Several single nucleotide polymorphic sites were noticed. The deduced protein structure contained nine zinc fingers, a proline-rich region, a nuclear bipartite localization signal, and a homeobox domain profile, suggesting a transcription factor function. Further comparative analysis identified an ADNP paralog (33% identity and 46% similarity), indicating that these genes belong to a novel protein family with a nine-zinc finger motif followed by a homeobox domain. The hADNP gene structure spans approximately 40 kilobases and includes five exons and four introns with alternative splicing of an untranslated second exon. The hADNP gene was mapped to chromosome 20q12-13.2, a region associated with aggressive tumor growth, frequently amplified in many neoplasias, including breast, bladder, ovarian, pancreatic, and colon cancers. hADNP mRNA is abundantly expressed in distinct normal tissues, and high expression levels were encountered in malignant cells. Down-regulation of ADNP by antisense oligodeoxynucleotides up-regulated the tumor suppressor p53 and reduced the viability of intestinal cancer cells by 90%. Thus, ADNP is implicated in maintaining cell survival, perhaps through modulation of p53.

First search for gravitational wave bursts with a network of detectors

We report the initial results from a search for bursts of gravitational radiation by a network of five cryogenic resonant detectors during 1997 and 1998. This is the first significant search with more than two detectors observing simultaneously. No gravitational wave burst was detected. The false alarm rate was lower than 1 per 10(4) yr when three or more detectors were operating simultaneously. The typical threshold was H approximately 4x10(-21) Hz-1 on the Fourier component at approximately 10(3) Hz of the gravitational wave strain amplitude. New upper limits for amplitude and rate of gravitational wave bursts have been set.

Cosmic rays observed by the resonant gravitational wave detector NAUTILUS

The passage of cosmic rays has been observed to excite mechanical vibrations in the resonant gravitational wave detector NAUTILUS operating at temperature of 100 mK. A very significant correlation (more than 10 standard deviations) is found.

Experimental intrauterine growth retardation alters renal development.

Vascular placental insufficiency is considered a common pathogenic factor in human intrauterine growth retardation (IUGR), resulting in small-for-gestational-age, asymmetric newborns. IUGR neonates experience higher morbidity and mortality rates, as well as a possible contribution towards late sequelae, such as hypertension, and cardiovascular disease in adulthood. To simulate vascular placental insufficiency, an experimental rabbit IUGR model was used. Intrauterine growth retardation was achieved by ligation of 25-30% uteroplacental vessels of half of the fetuses during the last third of gestation. Ischemic fetuses were significantly small, asymmetric, and had a disproportionately small body with a relatively large head. The kidneys from all groups were analyzed for relative estimated glomeruli number (REGN) using an unbiased blind design. The glomeruli number was significantly reduced in the asymmetric IUGR rabbit fetuses, probably due to decreased renal vascular supply. Our results support the concept that the reduced number of glomeruli may contribute to impaired renal function, thus predisposing to neonatal renal dysfunction and late sequelae, such as adult hypertension. This study emphasizes the clinical importance of early IUGR diagnosis and prevention.

A novel VIP responsive gene. Activity dependent neuroprotective protein.

Activity dependent neuroprotective protein (ADNP, 828 amino acids, pI 5.99) is a glial-derived protein that contains a femtomolar active neuroprotective peptide, NAPVSIPQ (NAP). VIP induces a two- to threefold increase in ADNP mRNA in astrocytes, suggesting that ADNP is a VIP-responsive gene. ADNP is widely distributed in the mouse hippocampus, cerebellum, and cerebral cortex. VIP has been shown to possess neuroprotective activity that may be exerted through the activation of glial proteins. We suggest that ADNP may be part of the VIP protection pathway through the femtomolar-acting NAP and through putative interaction with other macromolecules.

A femtomolar-acting neuroprotective peptide induces increased levels of heat shock protein 60 in rat cortical neurons: a potential neuroprotective mechanism.

Activity-dependent neurotrophic factor (ADNF) was recently isolated from conditioned media of astrocytes stimulated with vasoactive intestinal peptide (VIP). ADNF provided neuroprotection at femtomolar concentration against a wide variety of toxic insults. A nine amino acid peptide (ADNF-9) captured with even greater potency the neuroprotective activity exhibited by the parent protein. Utilizing Northern and Western blot analyses, it was now shown that ADNF-9 increased the expression of heat shock protein 60 (hsp60) in rat cerebral cortical cultures. In contrast, treatment with the Alzheimer's toxin, the beta-amyloid peptide, reduced the amount of intracellular hsp60. Treatment with ADNF-9 prevented the reduction in hsp60 produced by the beta-amyloid peptide. The protection against the beta-amyloid peptide-associated cell death provided by ADNF-9 may be mediated in part by intracellular increases in hsp60.

Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide.

The vulnerability of neurons and the irreversibility of loss make discoveries of neuroprotective compounds fundamentally important. Here, the complete coding sequence of a novel protein (828 amino acids, pI 5.99), derived from mouse neuroglial cells, is revealed. The sequence contained (1) a neuroprotective peptide, NAPVSIPQ, sharing structural and immunological homologies with the previously reported, activity-dependent neurotrophic factor; (2) a glutaredoxin active site; and (3) a zinc binding domain. Gene expression was enriched in the mouse hippocampus and cerebellum and augmented in the presence of the neuropeptide vasoactive intestinal peptide, in cerebral cortical astrocytes. In mixed neuron-astrocyte cultures, NAPVSIPQ provided neuroprotection at subfemtomolar concentrations against toxicity associated with tetrodotoxin (electrical blockade), the beta-amyloid peptide (the Alzheimer's disease neurotoxin), N-methyl-D-aspartate (excitotoxicity), and the human immunodeficiency virus envelope protein. Daily NAPVSIPQ injections to newborn apolipoprotein E-deficient mice accelerated the acquisition of developmental reflexes and prevented short-term memory deficits. Comparative studies suggested that NAPVSIPQ was more efficacious than other neuroprotective peptides in the apolipoprotein E-deficiency model. A potential basis for rational drug design against neurodegeneration is suggested with NAPVSIPQ as a lead compound. The relative enrichment of the novel mRNA transcripts in the brain and the increases found in the presence of vasoactive intestinal peptide, an established neuroprotective substance, imply a role for the cloned protein in neuronal function.