Reliable identification and collection of cells from bodily fluids is of growing interest for monitoring patient response to therapy and for early detection of disease or its recurrence. We describe ...a detection platform that combines microfluidics with surface-enhanced Raman spectroscopy (SERS) for the identification of individual mammalian cells continuously flowing in a microfluidics channel. A mixture of cancerous and noncancerous prostate cells was incubated with SERS biotags (SBTs) developed and synthesized by us, then injected into a flow-focused microfluidic channel, which forces the cells into a single file. The spectrally rich SBTs are based on a silver nanoparticle dimer core labeled with a Raman-active small reporter molecule paired with an affinity biomolecule, providing a unique barcode whose presence in a composite SERS spectrum can be deconvoluted. Individual cancer cells passing through the focused laser beam were correctly identified among a proportionally larger number of other cells by their Raman signatures. We examine two deconvolution strategies: principal component analysis and classical least-squares. The deconvolution strategies are used to unmix the overall spectrum to determine the relative contributions between two SBT barcodes, where one SBT barcode indicates neuropilin-1 overexpression, while a second SBT barcode is more universal and indicates unspecific binding to a cell's membrane. Highly reliable results were obtained for all of the cell mixture ratios tested, the lowest being 1 in 100 cells.
A linear array of periodically spaced and individually controllable skyrmions is introduced as a magnonic crystal. It is numerically demonstrated that skyrmion nucleation and annihilation can be ...accurately controlled by a nanosecond spin polarized current pulse through a nanocontact. Arranged in a periodic array, such nanocontacts allow the creation of a skyrmion lattice that causes a periodic modulation of the waveguide's magnetization, which can be dynamically controlled by changing either the strength of an applied external magnetic field or the density of the injected spin current through the nanocontacts. The skyrmion diameter is highly dependent on both the applied field and the injected current. This implies tunability of the lowest band gap as the skyrmion diameter directly affects the strength of the pinning potential. The calculated magnonic spectra thus exhibit tunable allowed frequency bands and forbidden frequency bandgaps analogous to that of conventional magnonic crystals where, in contrast, the periodicity is structurally induced and static. In the dynamic magnetic crystal studied here, it is possible to dynamically turn on and off the artificial periodic structure, which allows switching between full rejection and full transmission of spin waves in the waveguide. These findings should stimulate further research activities on multiple functionalities offered by magnonic crystals based on periodic skyrmion lattices.
In vivo tumor imaging with nanoprobes suffers from poor tumor specificity. Here, we introduce a nanosystem, which allows selective background quenching to gain exceptionally tumor-specific signals. ...The system uses near-infrared quantum dots and a membrane-impermeable etchant, which serves as a cation donor. The etchant rapidly quenches the quantum dots through cation exchange (ionic etching), and facilitates renal clearance of metal ions released from the quantum dots. The quantum dots are intravenously delivered into orthotopic breast and pancreas tumors in mice by using the tumor-penetrating iRGD peptide. Subsequent etching quenches excess quantum dots, leaving a highly tumor-specific signal provided by the intact quantum dots remaining in the extravascular tumor cells and fibroblasts. No toxicity is noted. The system also facilitates the detection of peritoneal tumors with high specificity upon intraperitoneal tumor targeting and selective etching of excess untargeted quantum dots. In vivo cation exchange may be a promising strategy to enhance specificity of tumor imaging.The imaging of tumors in vivo using nanoprobes has been challenging due to the lack of sufficient tumor specificity. Here, the authors develop a tumor-specific quantum dot system that permits in vivo cation exchange to achieve selective background quenching and high tumor-specific imaging.
Neuropilins (NRPs) are trans-membrane receptors involved in axon guidance and vascular development. Many growth factors and other signalling molecules bind to NRPs through a carboxy (C)-terminal, ...basic sequence motif (C-end Rule or CendR motif). Peptides with this motif (CendR peptides) are taken up into cells by endocytosis. Tumour-homing CendR peptides penetrate through tumour tissue and have shown utility in enhancing drug delivery into tumours. Here we show, using RNAi screening and subsequent validation studies, that NRP1-mediated endocytosis of CendR peptides is distinct from known endocytic pathways. Ultrastructurally, CendR endocytosis resembles macropinocytosis, but is mechanistically different. We also show that nutrient-sensing networks such as mTOR signalling regulate CendR endocytosis and subsequent intercellular transport of CendR cargo, both of which are stimulated by nutrient depletion. As CendR is a bulk transport pathway, our results suggest a role for it in nutrient transport; CendR-enhanced drug delivery then makes use of this natural pathway.
In this article, the influences of ortho‐fluoroazobenzenes (o‐Fbs) on liquid crystalline (LC) phase stability and actuation properties of liquid crystalline elastomers (LCEs) are presented. Such ...o‐Fbs find interest because they allow full photoswitching with visible light (no ultraviolet (UV) radiation). Novel o‐Fb monomers and crosslinkers are synthesized and characterized. Different amounts of an LC mixture are replaced with synthesized o‐Fbs successively and their influences on the LC phase stability in the cis and trans forms are observed through measuring the related clearing temperatures via polarized optical microscopy. LCE precursors containing 0, 1, 3, 5, 7, and 10 mol% o‐Fb monomer or crosslinker are aligned in a magnetic field and polymerized as films in the LC phase. Thermal and visible light–controlled photochemical 2D (planar) actuation properties of LCE samples are investigated and compared to LCEs containing a liquid crystalline non‐fluorinated azobenzene monomer as reference. It is shown that, while the favorable photochemistry is obtained, the integration of o‐Fbs is less effective for photoswitching of the LC phase, because i) less o‐Fbs can be integrated without destroying the LC phase and ii) the trans–cis isomerization is less effective in destroying the LC phase.
Novel ortho‐fluoroazobenzenes (o‐Fbs) are synthesized and their effects on liquid crystalline (LC) phase stabilities and planar actuation properties of liquid crystalline elastomers (LCEs) are investigated. It is shown that o‐Fbs drastically decrease the clearing temperatures of LC mixtures which limits their utilization. However, they are very useful for LCE applications where ultraviolet (UV) light has to be excluded.
Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances ...in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries.
We hypothesized that deficiency in 25-hydroxyvitamin D prior to hospital admission would be associated with sepsis in the critically ill.
Two-center observational study of patients treated in medical ...and surgical ICUs.
Two hundred nine medical and surgical intensive care beds in two teaching hospitals in Boston, MA.
Three thousand three hundred eighty-six patients, 18 years old or older, in whom 25-hydroxyvitamin D was measured prior to hospitalization between 1998 and 2011.
None.
: Preadmission 25-hydroxyvitamin D was categorized as deficiency in 25-hydroxyvitamin D (≤ 15 ng/mL), insufficiency (15-30 ng/mL), and sufficiency (≥ 30 ng/mL). The primary outcome was sepsis as defined by International Classification of Diseases, 9th Edition, Clinical Modification and validated by the 2001 Society of Critical Care Medicine/European Society of Intensive Care Medicine, American College of Chest Physicians, American Thoracic Society, and Surgical Infection Society international sepsis definitions conference guidelines. Logistic regression examined the presence of sepsis 3 days prior to critical care initiation to 7 days after critical care initiation. Adjusted odds ratios were estimated by multivariable logistic regression models. Preadmission 25-hydroxyvitamin D deficiency is predictive for the risk of sepsis. In the full cohort, 25-hydroxyvitamin D deficiency is a significant predictor for the risk of International Classification of Diseases, 9th Edition, Clinical Modification-defined sepsis following multivariable adjustment, including age, gender, race, type (surgical vs medical), and Deyo-Charlson index (adjusted odds ratio, 1.51 95% CI, 1.17-1.94; p = 0.001) relative to patients with 25-hydroxyvitamin D sufficiency. In a subset of cohort patients enriched for those with International Classification of Diseases, 9th Edition, Clinical Modification-diagnosed sepsis (n = 444), preadmission 25-hydroxyvitamin D deficiency is a significant predictor for the risk of conference guideline-defined sepsis following multivariable adjustment, including age, gender, race, type (surgical vs medical), and Acute Physiology and Chronic Health Evaluation II (adjusted odds ratio, 2.05 95% CI, 1.19-3.52; p = 0.009) relative to patients with 25-hydroxyvitamin D sufficiency. Furthermore, in cohort patients with International Classification of Diseases, 9th Edition, Clinical Modification-defined sepsis (n = 568), the multivariable adjusted risk of 90-day mortality was 1.6-fold higher in those with preadmission 25-hydroxyvitamin D values in the insufficient and deficient range, compared with those with preadmission vitamin D sufficiency (adjusted odds ratio, 1.63 95% CI, 1.11-2.39; p = 0.01).
25-hydroxyvitamin D deficiency prior to hospital admission is a significant predictor of sepsis in the critically ill. Additionally, patients with sepsis who are not vitamin D sufficient have an increased risk of mortality following critical care initiation.
Objective To evaluate studies assessing the effectiveness of a bundle of nasal decolonization and glycopeptide prophylaxis for preventing surgical site infections caused by Gram positive bacteria ...among patients undergoing cardiac operations or total joint replacement procedures. Design Systematic review and meta-analysis. Data sources PubMed (1995 to 2011), the Cochrane database of systematic reviews, CINAHL, Embase, and clinicaltrials.gov were searched to identify relevant studies. Pertinent journals and conference abstracts were hand searched. Study authors were contacted if more data were needed. Eligibility criteria Randomized controlled trials, quasi-experimental studies, and cohort studies that assessed nasal decolonization or glycopeptide prophylaxis, or both, for preventing Gram positive surgical site infections compared with standard care. Participants Patients undergoing cardiac operations or total joint replacement procedures. Data extraction and study appraisal Two authors independently extracted data from each paper and a random effects model was used to obtain summary estimates. Risk of bias was assessed using the Downs and Black or the Cochrane scales. Heterogeneity was assessed using the Cochran Q and I2 statistics. Results 39 studies were included. Pooled effects of 17 studies showed that nasal decolonization had a significantly protective effect against surgical site infections associated with Staphylococcus aureus (pooled relative risk 0.39, 95% confidence interval 0.31 to 0.50) when all patients underwent decolonization (0.40, 0.29 to 0.55) and when only S aureus carriers underwent decolonization (0.36, 0.22 to 0.57). Pooled effects of 15 prophylaxis studies showed that glycopeptide prophylaxis was significantly protective against surgical site infections related to methicillin (meticillin) resistant S aureus (MRSA) compared with prophylaxis using β lactam antibiotics (0.40, 0.20 to 0.80), and a non-significant risk factor for methicillin susceptible S aureus infections (1.47, 0.91 to 2.38). Seven studies assessed a bundle including decolonization and glycopeptide prophylaxis for only patients colonized with MRSA and found a significantly protective effect against surgical site infections with Gram positive bacteria (0.41, 0.30 to 0.56). Conclusions Surgical programs that implement a bundled intervention including both nasal decolonization and glycopeptide prophylaxis for MRSA carriers may decrease rates of surgical site infections caused by S aureus or other Gram positive bacteria.
Although lynxes and domestic cats are both felids, their luteal life cycles differ. As in many species, corpora lutea (CLs) of domestic cats regress after pregnancy or pseudopregnancy. By contrast, ...CLs of lynxes do not functionally regress following the cycle of their formation. They stay physiologically active and persist for several years. To obtain an improved understanding of the life cycle of both species, we comparatively studied the CLs of these species in detail. In this review, we summarize the similarities and differences of their CLs regarding sex steroid and prostaglandin generation and receptors. The most evident differences were visible in the CLs of lynxes, which persist from previous cycles, compared with CLs of lynxes and domestic cats from the recent luteal cycle. We assume that these differences could indicate processes ensuring long-term luteal survival and functionality, for example, by high estrogen production/metabolism or by antioxidative effects.
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