Validity of luminometry and bacteriological tests for diagnosing intramammary infection at dry-off in dairy cows.

The objective of this cross-sectional study was to estimate the validity of laboratory culture, Petrifilm and Tri-Plate on-farm culture systems, and luminometry to correctly identify IMI at dry-off in dairy cows, considering all tests as imperfect. From September 2020 until December 2021, we collected composite milk samples from cows before dry-off and divided them into 4 aliquots for the luminometry test, the Petrifilm (aerobic count), the Tri-Plate, and the laboratory culture. While we assessed multiple thresholds of relative light units (RLU) for the luminometry, we used thresholds of ≥100 cfu/mL for the laboratory culture, ≥ 50 cfu/mL for the Petrifilm, and ≥1 cfu for the Tri-Plate. We fitted Bayesian latent class analysis (LCA) models to estimate the sensitivity (Se) and specificity (Sp) for each test to identify IMI, with 95% credibility interval (BCI). Using different prevalence measures (0.30, 0.50, and 0.70), we calculated the predictive values (PV) and misclassification cost terms (MCT) at different false-negative to false-positive ratios (FN:FP). A total of 333 cows were enrolled in the study from one commercial Holstein herd. The validity of the luminometry was poor for all thresholds, with Se of 0.51 (95% BCI = 0.43-0.59) and Sp of 0.38 (95% BCI = 0.26-0.50) when using a threshold of ≥150 RLU. The laboratory culture had Se of 0.93 (95% BCI = 0.85-0.98) and Sp of 0.69 (95% BCI = 0.49-0.89), the Petrifilm had Se of 0.91 (95% BCI = 0.80-0.98) and Sp of 0.71 (95% BCI = 0.51-0.90), and the Tri-Plate had Se of 0.65 (95% BCI = 0.53-0.82) and Sp of 0.85 (95% BCI = 0.66-0.97). Bacteriological tests had good PVs, with comparable positive PV for all 3 tests, but lower negative PV for the Tri-Plate compared with the laboratory culture and the Petrifilm. For a prevalence of IMI of 0.30, all 3 tests had similar MCT, but for prevalence of 0.50 and 0.70, the Tri-Plate had higher MCT in scenarios where leaving a cow with IMI untreated is considered to have greater detrimental impacts than treating a healthy cow (i.e., FN:FP of 3:1). Our results showed that the bacteriological tests have adequate validity to diagnose IMI at dry-off, but the luminometry does not. We concluded that, while luminometry is not useful to identify IMI at dry-off, the Petrifilm and Tri-Plate tests performed similarly to the laboratory culture, depending on the prevalence and the importance of the FP and FN results.

A French single-center experience on allogeneic stem cell transplant cryopreservation during severe acute respiratory syndrome coronavirus 2 pandemic.

BACKGROUND AIMS: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative treatment for chemo-resistant hematological malignancies. Because of transport restriction imposed by the coronavirus disease 2019 pandemic, regulatory bodies and societies recommended graft cryopreservation before recipient conditioning. However, the freezing and thawing processes, including washing steps, might impair CD34+ cell recovery and viability, thereby impacting the recipient engraftment. Over 1 year (between March 2020 and May 2021), we aimed to analyze the results of frozen/thawed peripheral blood stem cell allografts in terms of stem cell quality and clinical outcomes. METHODS: Transplant quality was evaluated by comparing total nucleated cells (TNCs), CD34+ cells and colony-forming unit-granulocyte/macrophage (CFU-GM)/kg numbers as well as TNC and CD34+ cell viabilities before and after thawing. Intrinsic biological parameters such as granulocyte, platelet and CD34+ cell concentrations were analyzed, as they might be responsible for a quality loss. The impact of the CD34+ cell richness of the graft on TNC and CD34 yields was evaluated by designing three groups of transplants based on their CD34 /kg value at collection: >8 × 10 6/kg, between 6 and 8 × 106/kg and <6 × 106/kg. The consequences of cryopreservation were compared in the fresh and thawed group by evaluating the main transplant outcomes. RESULTS: Over 1 year, 76 recipients were included in the study; 57 patients received a thawed and 19 patients a fresh allo-SCT. None received allo-SCT from a severe acute respiratory syndrome coronavirus 2-positive donor. The freezing of 57 transplants led to the storage of 309 bags, for a mean storage time (between freezing and thawing) of 14 days. For the fresh transplant group, only 41 bags were stored for potential future donor lymphocyte infusions. Regarding the graft characteristics at collection, median number of cryopreserved TNC and CD34+ cells/kg were greater than those for fresh infusions. After thawing, median yields were 74.0%, 69.0% and 48.0% for TNC, CD34+ cells and CFU-GM, respectively. The median TNC dose/kg obtained after thawing was 5.8 × 108, with a median viability of 76%. The median CD34+ cells/kg was 5 × 106, with a median viability of 87%. In the fresh transplant group, the median TNC/kg was 5.9 × 108/kg, and the median CD34+ cells/kg and CFU-GM/kg were 6 × 106/kg and 276.5 × 104/kg, respectively. Sixty-one percent of the thawed transplants were out of specifications regarding the CD34+ cells/ kg requested cell dose (6 × 106/kg) and 85% of them would have had this dose if their hematopoietic stem cell transplant had been infused fresh. Regarding fresh grafts, 15.8% contained less than 6 × 106 CD34+ cells /kg and came from peripheral blood stem cells that did not reach 6 × 106 CD34+ cells /kg at collection. Regarding the factor that impaired CD34 and TNC yield after thawing, no significant impact of the granulocyte count, the platelet count or the CD34+ cells concentration/µL was observed. However, grafts containing more than 8 × 10 6/kg at collection showed a significantly lower TNC and CD34 yield. CONCLUSIONS: Transplant outcomes (engraftment, graft-versus-host disease, infections, relapse or death) were not significantly different between the two groups.

Adipocyte size, adipose tissue fibrosis, macrophage infiltration and disease risk are different in younger and older individuals with childhood versus adulthood onset obesity.

BACKGROUND: The timing of obesity onset and age have been shown to affect the risk of obesity-related comorbidities, although the impact of each of these factors on markers of adipose tissue function remains unclear. OBJECTIVE: The aim of this study was to determine whether differences in regional adipose tissue characteristics vary with age and age of obesity onset, and whether these differences are associated with the markers of cardiometabolic health. METHODS: Adipose tissue samples were obtained from 80 female bariatric surgery candidates who were classified by age of obesity onset and age into 4 groups: (1) younger adults (<40 y) with childhood-onset obesity (<18 y) (Child-Young); (2) younger adults with adulthood-onset obesity (>18 y) (Adult-Young); (3) older adults (>55 y) with childhood-onset obesity (Child-Old); and (4) older adults with adulthood-onset obesity (Adult-Old). Adipocyte diameter, adipose tissue fibrosis, and macrophage infiltration were determined in subcutaneous (SAT) and visceral adipose tissue (VAT). Clinical parameters were obtained from participants' medical records. RESULTS: Visceral adipocyte size in the Child-Young group was the smallest of all the groups. Age affected visceral infiltration of M1-like cells with greater percent of M1-like cells in the Adult-Old and Child-Old groups. Though not significant, a stepwise increase in M2-like macrophages in VAT was observed with Adult-Young having the smallest followed by Adult-Old, Child-Young, and Child-Old having the greatest percent of M2-like macrophages. Pericellular fibrosis accumulation in SAT and VAT varied with both age and onset, particularly in the Child-Old group, which had the lowest fibrosis levels. Markers of cardiometabolic health (fasting glucose, glycated hemoglobin, total, HDL- and LDL-cholesterol and triglyceride concentrations) were positively and well-associated with adipose tissue characteristics of the Child-Old group but not of the Adult-Young group. CONCLUSION: Older adults with childhood-onset obesity, who had the greatest duration of obesity exposure, were particularly vulnerable to the cardiometabolic effects associated with perturbations in adipose tissue characteristics. These results suggest that age and age of obesity onset may have independent and cumulative effects on obesity pathology.

Crystal-to-Crystal Transition of Ultrasoft Colloids under Shear.

Ultrasoft colloids typically do not spontaneously crystallize, but rather vitrify, at high concentrations. Combining in situ rheo-small-angle-neutron-scattering experiments and numerical simulations we show that shear facilitates crystallization of colloidal star polymers in the vicinity of their glass transition. With increasing shear rate well beyond rheological yielding, a transition is found from an initial bcc-dominated structure to an fcc-dominated one. This crystal-to-crystal transition is not accompanied by intermediate melting but occurs via a sudden reorganization of the crystal structure. Our results provide a new avenue to tailor colloidal crystallization and the crystal-to-crystal transition at the molecular level by coupling softness and shear.

Relativistic Electron Streaming Instabilities Modulate Proton Beams Accelerated in Laser-Plasma Interactions.

We report experimental evidence that multi-MeV protons accelerated in relativistic laser-plasma interactions are modulated by strong filamentary electromagnetic fields. Modulations are observed when a preplasma is developed on the rear side of a µm-scale solid-density hydrogen target. Under such conditions, electromagnetic fields are amplified by the relativistic electron Weibel instability and are maximized at the critical density region of the target. The analysis of the spatial profile of the protons indicates the generation of B>10 MG and E>0.1 MV/µm fields with a µm-scale wavelength. These results are in good agreement with three-dimensional particle-in-cell simulations and analytical estimates, which further confirm that this process is dominant for different target materials provided that a preplasma is formed on the rear side with scale length ≳0.13λ_{0}sqrt[a_{0}]. These findings impose important constraints on the preplasma levels required for high-quality proton acceleration for multipurpose applications.

[Religious and cultural aspects of organ transplantation]. / Aspects religieux et culturels liés à la transplantation d'organes.

The number of transplantations is mainly limited by the shortage of organs, thereby leading to potentially lethal delays for patients registered on waiting lists. Among the causes of refusals of organ donation, religious reasons are often advocated. In order to make the point, we organized a debate between representatives of secularism ( " laïcité ") and of the most represented religions in Belgium, i.e. catholic, Islamic and Judaic. Even though the representation of death was variable, organ donation is authorized and even encouraged by the fundamental texts. Refusals of organ donation result more often from personal interpretations by local preachers. Therefore, the gathering of political and religious authorities in order to promote organ donation is desirable instead of sowing doubt for pseudo-religious reasons.

En médecine de transplantation, la pénurie d'organes représente le principal obstacle et cause de retard aux greffes vitales pour les receveurs inscrits sur liste d'attente. Parmi les causes de refus de don d'organes, des raisons d'ordre religieux sont souvent invoquées. Afin de faire le point sur cette problématique, nous avons organisé un débat rassemblant des représentants de la laïcité et des religions monothéistes les plus représentées en Belgique : catholicisme, islam, judaïsme. Il est apparu que, si la représentation de la mort varie selon les courants, le don d'organes est en fait autorisé, voire encouragé par les textes fondateurs des trois religions. Les refus sont plutôt le fait d'une interprétation personnelle par des prédicateurs. Dès lors, il serait judicieux de rassembler les forces politiques et spirituelles afin de promouvoir le don d'organes plutôt que de semer le doute à son sujet sous des prétextes pseudo-religieux.

Intense THz Pulses with large ponderomotive potential generated from large aperture photoconductive antennas.

We report the generation of free space terahertz (THz) pulses with energy up to 8.3 ± 0.2 µJ from an encapsulated interdigitated ZnSe Large Aperture Photo-Conductive Antenna (LAPCA). An aperture of 12.2 cm2 is illuminated using a 400 nm pump laser with multi-mJ energies at 10 Hz repetition rate. The calculated THz peak electric field is 331 ± 4 kV/cm with a spectrum characterized by a median frequency of 0.28 THz. Given its relatively low frequency, this THz field will accelerate charged particles efficiently having very large ponderomotive energy of 15 ± 1 eV for electrons in vacuum. The scaling of the emission is studied with respect to the dimensions of the antenna, and it is observed that the capacitance of the LAPCA leads to a severe decrease in and distortion of the biasing voltage pulse, fundamentally limiting the maximum applied bias field and consequently the maximum energy of the radiated THz pulses. In order to demonstrate the advantages of this source in the strong field regime, an open-aperture Z-scan experiment was performed on n-doped InGaAs, which showed significant absorption bleaching.

Evaluation of Adhesion Forces for the Manipulation of Micro-Objects in Submerged Environment through Deposition of pH Responsive Polyelectrolyte Layers.

Optimization of surface treatment for reversible adhesion of micro-objects in liquid environment for the need in microassembly processes is presented. A spherical borosilicate probe and planar oxidized silicon wafer substrates were modified by deposition of pH sensitive polyelectrolyte films through layer-by-layer technique. Branched polyethylenimine (b-PEI) and poly(sodium styrenesulfonate) (PSS) were deposited in alternating manner on surfaces, and the influence of polyelectrolyte concentration, pH of deposition, and number of layers on the adhesion were successively examined. The multilayer buildup was followed by optical reflectometry (OR) and dissipative quartz crystal microbalance (QCM-D). The adhesion forces were monitored in aqueous environment at variable pH values by colloidal probe AFM microscopy. The thermodynamic work of adhesion was derived from the pull-off forces by using the Johnson-Kendall-Roberts (JKR) model and compared to the work of adhesion determined from contact angle measurements. It was found out that they correlate well, however, the values accessed from JKR model were underestimated, which was attributed mainly to the effect of surface roughness. Obtained results have demonstrated that it is possible to achieve repeatable reversible adhesion with the change of pH of submerged environment by appropriately tailoring the surface properties and therefore the prevailing surface forces.

FOLFIRINOX for locally advanced pancreatic adenocarcinoma: results of an AGEO multicenter prospective observational cohort.

BACKGROUND: First-line treatment with FOLFIRINOX significantly increases overall survival (OS) in patients with metastatic pancreatic adenocarcinoma (PA) compared with gemcitabine. The aim of this observational cohort was to evaluate the tolerability and efficacy of this regimen in unresectable locally advanced PA (LAPA). PATIENTS AND METHODS: From February 2010 to February 2012, all consecutive patients from 11 French centers treated by FOLFIRINOX for a histologically proven LAPA were prospectively enrolled. Unresectability was defined independently by each center's multidisciplinary staff at diagnosis. Absence of metastatic disease was confirmed by chest-abdomen-pelvis computed tomography scan. FOLFIRINOX was delivered every 2 weeks as previously reported until progressive disease, major toxicity, or consolidation treatment by radiotherapy and/or surgery. RESULTS: Seventy-seven patients were enrolled. They received a median number of five cycles (1-30). Grade 3-4 toxicities were neutropenia (11 %), nausea (9 %), diarrhea (6 %), fatigue (6 %), and anemia (1 %). Grade 2-3 sensory neuropathy occurred in 25 % of patients. No toxic death was reported and only 6 % of patients had to stop treatment because of toxicity. Disease control rate was 84 with 28 % of objective response (Response Evaluation Criteria in Solid Tumors). Seventy-five percent of patients received a consolidation therapy: 70 % had radiotherapy and 36 % underwent a surgical resection, with a curative intent. Within the whole cohort, 1-year OS rate was 77 % (95 % CI 65-86) and 1-year progression-free survival rate was 59 % (95 % CI 46-70). CONCLUSION: First-line FOLFIRINOX for LAPA seems to be effective and have a manageable toxicity profile. These promising results will have to be confirmed in a phase III randomized trial.

Equation of state of liquid mercury to 520 K and 7 GPa from acoustic velocity measurements.

Ultrafast acoustics measurements on liquid mercury have been performed at high pressure and temperature in a diamond anvil cell using picosecond acoustic interferometry. We extract the density of mercury from adiabatic sound velocities using a numerical iterative procedure. We also report the pressure and temperature dependence of the thermal expansion, isothermal and adiabatic compressibility, bulk modulus, and pressure derivative of the latter up to 7 GPa and 520 K. We finally show that the sound velocity follows a scaling law as a function of density in the overall measured metallic state.

Charge equilibrium of a laser-generated carbon-ion beam in warm dense matter.

Using ion carbon beams generated by high intensity short pulse lasers we perform measurements of single shot mean charge equilibration in cold or isochorically heated solid density aluminum matter. We demonstrate that plasma effects in such matter heated up to 1 eV do not significantly impact the equilibration of carbon ions with energies 0.045-0.5 MeV/nucleon. Furthermore, these measurements allow for a first evaluation of semiempirical formulas or ab initio models that are being used to predict the mean of the equilibrium charge state distribution for light ions passing through warm dense matter.

Response shift effects on measuring post-operative quality of life among breast cancer patients: a multicenter cohort study.

PURPOSE: To characterize response shift effects in patients with breast cancer (BC). METHODS: The QLQ-C30, BR23, and EurQOL-EQ-5D were assessed at baseline and at the end of the first hospitalization. We used the then-test approach to characterize changes in internal standards by calculating the mean difference between the then-test (retrospective measure) and pre-test baseline QoL assessments. The Ideal Scale Approach was also used to assess changes in standards by comparing health and QoL expectancies between baseline and the end of the first hospitalization. Successive Comparison Approach was used to assess changes in values through the longitudinal assessment of the relative importance of EuroQOL dimensions. RESULTS: The results of this study showed that recalibration RS effects occurred early after the first hospitalization for 6/15 dimensions of QLQ-C30 (emotional, cognitive, fatigue, insomnia, appetite loss, diarrhea) and 2/8 of BR-23 (future perspective, systemic therapy side effects). Moreover, health and QoL expectancies changed between the baseline and the end of the first hospitalization, and changes in values were seen for the self-care and usual activities dimensions of the EuroQOL-EQ-5D. CONCLUSIONS: The occurrence of RS early after the first hospitalization suggests that it needs to be taken into account to interpret QoL changes in BC.

Various forms of organic and inorganic P fertilizers did not negatively affect soil- and root-inhabiting AM fungi in a maize-soybean rotation system.

Arbuscular mycorrhizal (AM) fungi are key components of most agricultural ecosystems. Therefore, understanding the impact of agricultural practices on their community structure is essential to improve nutrient mobilization and reduce plant stress in the field. The effects of five different organic or mineral sources of phosphorus (P) for a maize-soybean rotation system on AM fungal diversity in roots and soil were assessed over a 3-year period. Total DNA was extracted from root and soil samples collected at three different plant growth stages. An 18S rRNA gene fragment was amplified and taxa were detected and identified using denaturing gradient gel electrophoresis followed by sequencing. AM fungal biomass was estimated by fatty acid methyl ester analysis. Soil P fertility parameters were also monitored and analyzed for possible changes related with fertilization or growth stages. Seven AM fungal ribotypes were detected. Fertilization significantly modified soil P flux, but had barely any effect on AM fungi community structure or biomass. There was no difference in the AM fungal community between plant growth stages. Specific ribotypes could not be significantly associated to P treatment. Ribotypes were associated with root or soil samples with variable detection frequencies between seasons. AM fungal biomass remained stable throughout the growing seasons. This study demonstrated that roots and soil host distinct AM fungal communities and that these are very temporally stable. The influence of contrasting forms of P fertilizers was not significant over 3 years of crop rotation.

[Chronic lymphocytic leukemia]. / La leucémie lymphoïde chronique.

Chronic lymphocytic leukemia (CLL) is a low-grade B cell lymphoma with circulating cells, often revealed by hyperlymphocytosis. Its diagnosis and therapeutic indications (not systematic) have been defined in 2018. In fact, CLL can be separated in two entities differentiating themselves by their IGHV mutational status, but the search of other prognostic parameters like TP53 disruption is mandatory before treatment. Numerous genetic alterations and mutations exist in CLL. CLL cells are highly dependent from their b-cell receptor stimulation and from their microenvironment, which takes a central place in disease progression. Infections, dysimmune manifestations, cancers and Richter transformation are classic complications, and patients have poor vaccine response even without a treatment. Chemoimmunotherapy is being challenged by the new highly active drugs such as Bruton tyrosine-kinase inhibitors (ibrutinib, acalabrutinib) and by the association of venetoclax and anti-CD20. Future treatment strategies might integrate both new drugs and classical chemoimmunotherapy.

Muscle regeneration after high-dose radiation exposure: therapeutic potential of Hedgehog pathway modulation?

Purpose: Intentional or accidental exposure of relatively large as well as localized areas of the skin to ionizing radiation can lead to severe damage of many of its cellular components and cutaneous radiation syndrome. Patients can be treated with an invasive surgical procedure coupled with autologous cell therapy. However, this approach remains perfectible, especially for muscle repair. Indeed, a severe underlying muscle defect persists, in particular because of the damage to the satellite cells which ensure muscle regeneration. To overcome these shortcomings, a solution could be to develop new therapeutic strategies based on pharmacological treatments to improve post-irradiation muscle regeneration. In this study, we focus on the Hedgehog signaling pathway as a target, due to its involvement in myogenesis.Materials and methods: To evaluate the benefit of the pro-myogenic Hedgehog signaling pathway modulation, recombinant Sonic Hedgehog (rShh; agonist) or Cyclopamine (antagonist) were used in a stable cell line of mouse C2C12 myoblasts exposed to radiation (X-rays; 5 Gy). Our in vitro studies were carried out under either proliferation or differentiation conditions. Proliferation, migration, survival (apoptosis) and expression of myogenic genes/proteins were evaluated.Results: A high dose of radiation was shown to exert a serious negative impact in our in vitro model of mouse muscle progenitors after irradiation in proliferation or differentiation conditions. Interestingly, Hh pathway stimulation by rShh promotes the proliferation of myoblasts and their survival while its blockade by Cyclopamine significantly increases cell differentiation toward mature myotubes.Conclusion: These data suggest that, after irradiation, the sequence of activation and inhibition of the Hh pathway could allow rescue and proliferation of satellite cells, followed by their differentiation to regenerate new fibers. On the basis of these encouraging in vitro results, the second phase of our study will involve the in vivo validation of this treatment in a new murine model of ultra-localized muscle irradiation.

High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer.

BACKGROUND: A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy. METHODS: Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2), cyclophosphamide 500 mg m(-2) (FEC 100) followed by three cycles of docetaxel 100 mg m(-2) delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis. RESULTS: In March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%). CONCLUSION: Sequential dose-dense FEC 100 followed by docetaxel 100 mg m(-2) is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.

Diffusionless γ⇄α phase transition in polycrystalline and single-crystal cerium.

The cerium γ⇄α transition was investigated using high-pressure, high-temperature angle-dispersive x-ray diffraction measurements on both poly- and single-crystalline samples, explicitly addressing symmetry change and transformation paths. The isomorphic hypothesis of the transition is confirmed, with a transition line ending at a solid-solid critical point. The critical exponent is determined, showing a universal behavior that can be pictured as a liquid-gas transition. We further report an isomorphic transition between two single crystals (with more than 14% of volume difference), an unparalleled observation in solid-state matter interpreted in terms of dislocation-induced diffusionless first-order phase transformation.

A microrobotic platform actuated by thermocapillary flows for manipulation at the air-water interface.

Future developments in micromanufacturing will require advances in micromanipulation tools. Several robotic micromanipulation methods have been developed to position micro-objects mostly in air and in liquids. The air-water interface is a third medium where objects can be manipulated, offering a good compromise between the two previously mentioned ones. Objects at the interface are not subjected to stick-slip due to dry friction in air and profit from a reduced drag compared with those in water. Here, we present the ThermoBot, a microrobotic platform dedicated to the manipulation of objects placed at the air-water interface. For actuation, ThermoBot uses a laser-induced thermocapillary flow, which arises from the surface stress caused by the temperature gradient at the fluid interface. The actuated objects can reach velocities up to 10 times their body length per second without any on-board actuator. Moreover, the localized nature of the thermocapillary flow enables the simultaneous and independent control of multiple objects, thus paving the way for microassembly operations at the air-water interface. We demonstrate that our setup can be used to direct capillary-based self-assemblies at this interface. We illustrate the ThermoBot's capabilities through three examples: simultaneous control of up to four spheres, control of complex objects in both position and orientation, and directed self-assembly of multiple pieces.

Treating brain diseases using systemic parenterally-administered protein therapeutics: Dysfunction of the brain barriers and potential strategies.

The parenteral administration of protein therapeutics is increasingly gaining importance for the treatment of human diseases. However, the presence of practically impermeable blood-brain barriers greatly restricts access of such pharmaceutics to the brain. Treating brain disorders with proteins thus remains a great challenge, and the slow clinical translation of these therapeutics may be largely ascribed to the lack of appropriate brain delivery system. Exploring new approaches to deliver proteins to the brain by circumventing physiological barriers is thus of great interest. Moreover, parallel advances in the molecular neurosciences are important for better characterizing blood-brain interfaces, particularly under different pathological conditions (e.g., stroke, multiple sclerosis, Parkinson's disease, and Alzheimer's disease). This review presents the current state of knowledge of the structure and the function of the main physiological barriers of the brain, the mechanisms of transport across these interfaces, as well as alterations to these concomitant with brain disorders. Further, the different strategies to promote protein delivery into the brain are presented, including the use of molecular Trojan horses, the formulation of nanosystems conjugated/loaded with proteins, protein-engineering technologies, the conjugation of proteins to polymers, and the modulation of intercellular junctions. Additionally, therapeutic approaches for brain diseases that do not involve targeting to the brain are presented (i.e., sink and scavenging mechanisms).

Impact of UV Radiation on the Raman Signal of Cystine: Implications for the Detection of S-rich Organics on Mars.

Traces of life may have been preserved in ancient martian rocks in the form of molecular fossils. Yet the surface of Mars is continuously exposed to intense UV radiation detrimental to the preservation of organics. Because the payload of the next rovers going to Mars to seek traces of life will comprise Raman spectroscopy tools, laboratory simulations that document the effect of UV radiation on the Raman signal of organics appear critically needed. The experiments conducted here evidence that UV radiation is directly responsible for the increase of disorder and for the creation of electronic defects and radicals within the molecular structure of S-rich organics such as cystine, enhancing the contribution of light diffusion processes to the Raman signal. The present results suggest that long exposure to UV radiation would ultimately be responsible for the total degradation of the Raman signal of cystine. Yet because the degradation induced by UV is not instantaneous, it should be possible to detect freshly excavated S-rich organics with the Raman instruments on board the rovers. Alternatively, given the very short lifetime of organic fluorescence (nanoseconds) compared to most mineral luminescence (micro- to milliseconds), exploiting fluorescence signals might allow the detection of S-rich organics on Mars. In any case, as illustrated here, we should not expect to detect pristine S-rich organic compounds on Mars, but rather by-products of their degradation.