Identification and characterization of human HES2, HES3, and HES5 genes in silico.
MMTV induces the mouse mammary tumor through the dysregulation of Notch, Wnt, or Fgf signaling pathway. Activation of Notch signaling pathway leads to transcriptional activation of Hes family genes through the interaction between Notch intracellular domain and RBPSUH (CSL). Hes family proteins are mammalian homologs of Drosophila Hairy and Enhancer of split. Hes family of transcriptional repressors with basic Helix-loop-helix (bHLH) and Orange domains are implicated in the cell fate determination of stem cells (or precursor cells) by suppressing the expression of tissue-specific transcriptional activators. Human HES1, HES4, HES6, and HES7 genes have been reported by other groups. Here, we identified and characterized human HES2, HES3 and HES5 genes by using bioinformatics. FLJ33803 (AK091122.1) was the representative human HES2 cDNA. HES2 gene, encoding a 173-aa protein, was located within human genome sequence AL031848.11. HES3 gene, encoding a 186-aa protein, was identified within human genome sequence AL031847.17. HES5 gene, encoding a 166-aa protein, was identified within human genome sequence AL139246.20. HES2 and HES3 genes were mapped to human chromosome 1p36.31, while HES5 gene to 1p36.32. HES2 mRNA was expressed in placenta, pancreatic cancer, colon cancer with RER, cervical cancer, and in head and neck tumors. HES5 mRNA was expressed in fetal heart, and brain tumors. Human HES family proteins were found consisting of bHLH, Orange, Proline-rich domains, and WRPW motif. Phylogenetic analyses revealed that HES family proteins were distantly related except a paralog pair of HES1 and HES4. HES family genes are pharmacogenomic targets in the field of regenerative medicine and oncology.


m-Calpain implication in cell cycle during muscle precursor cell activation.
Milli-calpain, a member of the ubiquitous cysteine protease family, is known to control late events of cell-cell fusion in skeletal muscle tissue through its involvement in cell membrane and cytoskeleton component reorganization. In this report, we describe the characterization of m-calpain compartmentalization and activation during the initial steps of muscle precursor cell recruitment and differentiation. By immunofluorescence analysis, we show that m-calpain is present throughout the cell cycle in the nucleus of proliferating myoblast C2 cells. However, when myoblasts enter a quiescent/G0 stage, m-calpain staining is detected only in the cytoplasm. Moreover, comparison of healthy and injured muscle shows distinct m-calpain localization in satellite stem cells. Indeed, m-calpain is not found in quiescent satellite cells, but following muscle injury, when satellite cells start to proliferate, m-calpain appears in the nucleus. To determine the implication of m-calpain during the cell cycle progression, quiescent myoblasts were forced to re-enter the cell cycle in the presence or not of the specific calpain inhibitor MDL 28170. We demonstrate that this calpain inhibitor blocks the cell cycle, prevents accumulation of MyoD in the G1 phase and enhances Myf5 expression. These data support an important new role for m-calpain in the control of muscle precursor cell activation and thus suggest its possible implication during the initial events of muscle regeneration.


A randomized, double-blind, placebo-controlled trial of the safety of vaginal recombinant human relaxin for cervical ripening.
To assess the safety of vaginal recombinant human relaxin in pregnant women treated before the induction of labor and to collect preliminary data on the efficacy of recombinant human relaxin in promoting cervical ripening. In a multi-center, randomized, double-blind placebo-controlled trial, 40 women were studied before induction of labor because of post-dates. The women were randomized to receive either 1.5 mg recombinant human relaxin in 3% methylcellulose gel or gel only, placed into the posterior vaginal fornix after a cervical assessment on the evening before scheduled induction. If a subject did not go into spontaneous labor overnight, another cervical assessment was performed 15 hours following treatment, immediately before the standard induction regimen of the hospital. No important maternal or fetal-neonatal complications could be attributed to the drug. The differences between the recombinant human relaxin group and the placebo group for all the outcome measures of efficacy did not achieve statistical significance. Placebo patients were more likely to report moderate or strong uterine contractions in the first 4 hours following treatment than were the recombinant human relaxin-treated patients. The use of recombinant human relaxin at a dose of 1.5 mg was not associated with any significant maternal or fetal-neonatal complications. The relatively small number of subjects in this study was chosen deliberately because this was the first use of the drug in pregnant subjects. Assessment of efficacy will require studies that include more patients and a range of relaxin doses.


The floating anchored craniotomy.
The "floating anchored" craniotomy is a technique utilized at our tertiary neurosurgery institution in which a traditional decompressive craniectomy has been substituted for a floating craniotomy. The hypothesized advantages of this technique include adequate decompression, reduction in the intracranial pressure, obviating the need for a secondary cranioplasty, maintained bone protection, preventing the syndrome of the trephined, and a potential reduction in axonal stretching. The bone plate is re-attached via multiple loosely affixed vicryl sutures, enabling decompression, but then ensuring the bone returns to its anatomical position once cerebral edema has subsided. From the analysis of 57 consecutive patients analyzed at our institution, we have found that the floating anchored craniotomy is comparable to decompressive craniectomy for intracranial pressure reduction and has some significant theoretical advantages. Despite the potential advantages of techniques that avoid the need for a second cranioplasty, they have not been widely adopted and have been omitted from trials examining the utility of decompressive surgery. This retrospective analysis of prospectively collected data suggests that the floating anchored craniotomy may be applicable instead of decompressive craniectomy.


Interrogating cyclic AMP signaling using optical approaches.
Optical reporters for cAMP represent a fundamental advancement in our ability to investigate the dynamics of cAMP signaling. These fluorescent sensors can measure changes in cAMP in single cells or in microdomains within cells as opposed to whole populations of cells required for other methods of measuring cAMP. The first optical cAMP reporters were FRET-based sensors utilizing dissociation of purified regulatory and catalytic subunits of PKA, introduced by Roger Tsien in the early 1990s. The utility of these sensors was vastly improved by creating genetically encoded versions that could be introduced into cells with transfection, the first of which was published in the year 2000. Subsequently, improved sensors have been developed using different cAMP binding platforms, optimized fluorescent proteins, and targeting motifs that localize to specific microdomains. The most common sensors in use today are FRET-based sensors designed around an Epac backbone. These rely on the significant conformational changes in Epac when it binds cAMP, altering the signal between FRET pairs flanking Epac. Several other strategies for optically interrogating cAMP have been developed, including fluorescent translocation reporters, dimerization-dependent FP based biosensors, BRET (bioluminescence resonance energy transfer)-based sensors, non-FRET single wavelength reporters, and sensors based on bacterial cAMP-binding domains. Other newly described mammalian cAMP-binding proteins such as Popdc and CRIS may someday be exploited in sensor design. With the proliferation of engineered fluorescent proteins and the abundance of cAMP binding targets in nature, the field of optical reporters for cAMP should continue to see rapid refinement in the coming years.


Immunopathogenesis in Trypanosoma cruzi infection: a role for suppressed macrophages and apoptotic cells.
During Trypanosoma cruzi infection, macrophages phagocytose parasites and remove apoptotic cells through efferocytosis. While macrophage 1 (M1) produces proinflammatory cytokines and NO and fights infection, M2 macrophages are permissive host cells that express arginase 1 and play a role in tissue repair. The regulation of M1 and M2 phenotypes might either induce or impair macrophage-mediated immunity towards parasite control or persistence in chronic Chagas disease. Here, we highlight a key role of macrophage activation in early immune responses to T. cruzi that prevent escalating parasitemia, heart parasitism, and mortality during acute infection. We will discuss the mechanisms of macrophage activation and deactivation, such as T cell cytokines and efferocytosis, and how to improve macrophage-mediated immunity to prevent parasite persistence, inflammation, and the development of chagasic cardiomyopathy. Potential vaccines or therapy must enhance early T cell-macrophage crosstalk and parasite control to restrain the pathogenic outcomes of parasite-induced inflammation in the heart.


Organizing and operating a one day clinic / theragnostic center.
The increasing success of recent nuclear medicine therapies, which followed the NETTER-1 and VISION trials, has boosted the interest for setting up and operating theragnostic centers. EANM, SNMMI and IAEA have recently published a joint guideline in order to assist nuclear medicine centers towards that path. The present paper will focus on the main points of these guidelines, with reference to the Greek radiation protection legislation.


High-resolution compact spectrometer based on periodic tapered coreless fiber.
This Letter proposes a method that balances miniaturization and high performance of fiber optic speckle spectrometers. The periodically tapered coreless fiber is used as the scattering element to excite more higher-order modes in the coreless fiber. As a result, a remarkable spectral resolution of 0.03 nm in the near-infrared spectrum can be achieved with a 5-cm-long fiber. Narrow linewidth and broadband spectra in the wavelength of 1540-1560 nm are reconstructed separately, demonstrating the excellent performance of the designed all-fiber spectrometer. The spectral resolution of our proposed spectrometer is comparable to that of a 2-m multimode fiber spectrometer and has a significant improvement in miniaturization.


Molecularly Imprinted Polymer Enables High-Efficiency Recognition and Trapping Lithium Polysulfides for Stable Lithium Sulfur Battery.
Using molecularly imprinted polymer to recognize various target molecules emerges as a fascinating research field. Herein, we applied this strategy for the first time to efficiently recognize and trap long-chain polysulfides (Li2Sx, x = 6-8) in lithium sulfur battery to minimize the polysulfide shuttling between anode and cathode, which enables us to achieve remarkable electrochemical performance including a high specific capacity of 1262 mAh g-1 at 0.2 C and superior capacity retention of over 82.5% after 400 cycles at 1 C. The outstanding performance is attributed to the significantly reduced concentration of long-chain polysulfides in electrolyte as evidenced by in situ UV/vis spectroscopy and Li2S nucleation tests, which were further confirmed by density functional theory calculations. The molecular imprinting is demonstrated as a promising approach to effectively prevent the free diffusion of long-chain polysulfides, providing a new avenue to efficiently recognize and trap lithium polysulfides for high-performance lithium sulfur battery with greatly suppressed shuttle effect.


Intradural Cauda Equina Metastases: A Systematic Review of Clinico-radiological Features, Management, and Treatment Outcomes.
Intradural cauda equina metastases (ICEM) are rare tumors that reduce functional status. Surgery and radiation are feasible and effective treatments but may have debilitating complications. We systematically reviewed the literature on ICEMs. PubMed, Scopus, Web of Science, and Cochrane were searched for studies reporting clinical data of patients with ICEMs. Clinical characteristics, management strategies, and treatment outcomes were analyzed. We included 40 studies comprising 123 patients. Median age was 57 years. The most frequent primary tumors were lung (18.7%), breast (13%), and renal carcinomas (11.4%). Median time from primary tumor diagnosis to ICEMs' presentation was 36 months. The most common presenting symptoms were lower back pain (74%) and motor deficits (62.6%), with acute cauda equina syndrome documented in 36 patients (29.3%). Most lesions were diagnosed at magnetic resonance imaging (56.9%) or computed tomography myelography (32.5%). All cases were treated with decompressive laminectomy and tumor resection, with partial resection (82.1%) more often than complete (15.4%). Adjuvant radiotherapy (83.7%) and/or chemotherapy (10.6%) were often administered. Most patients experienced post-treatment symptom improvement (86.2%) and favorable radiological response (82.9%). ICEM recurrences were reported in 4 cases (8.5%) with median local tumor control of 7 months. At last follow-up, most patients were dead (62.9%) with median overall-survival of 10 months. Patients with ICEMs have poor prognoses and significant tumor burden. Surgery and locoregional radiotherapy may offer optimal clinical and radiological outcomes but have a limited role in improving local tumor control and overall survival.


Biomagnetic 3-dimensional spatial and temporal characterization of electrical activity of human stomach.
Biomagnetic measurements are based on the noninvasive recording of magnetic signals produced by biological sources such as nervous system and muscle. The aim of this study was to obtain multichannel magnetic field recordings from the human gastrointestinal tract and to localize the sources of these signals three-dimensionally. The magnetic field was recorded in eight human healthy subjects using a sensor array with 37 superconducting quantum interference devices (SQUIDs); an electrogastrogram was recorded simultaneously. Biomagnetic source localization was carried out with an iterative nonlinear optimization algorithm using the model of an equivalent current dipole (ECD) and correlated to magnetic resonance imaging (MRI) in four volunteers. Magnetogastrograms and electrogastrograms demonstrated a similar frequency distribution with a peak at 3/min. In all subjects the centers of the calculated dipoles plotted vs time showed a characteristic migration across the stomach area. One volunteer demonstrated tachygastric episodes, during which his magnetic field amplitudes increased fivefold and his dipole migration disappeared. In absence of an attack his recordings changed to normal. This demonstrates multichannel magnetic recordings can be used to localize the sources of the biomagnetic field, which could be useful for the understanding of motility disturbances.


Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols.
There are many advantages of direct nose-to-brain drug delivery in the treatment of neurological disorders. However, its application is limited by the extremely low delivery efficiency (< 1%) to the olfactory mucosa that directly connects the brain. It is crucial to develop novel techniques to deliver neurological medications more effectively to the olfactory region. The objective of this study is to develop a numerical platform to simulate and improve intranasal olfactory drug delivery. A coupled image-CFD method was presented that synthetized the image-based model development, quality meshing, fluid simulation, and magnetic particle tracking. With this method, performances of three intranasal delivery protocols were numerically assessed and compared. Influences of breathing maneuvers, magnet layout, magnetic field strength, drug release position, and particle size on the olfactory dosage were also numerically studied. From the simulations, we found that clinically significant olfactory dosage (up to 45%) were feasible using the combination of magnet layout and selective drug release. A 64 -fold higher delivery of dosage was predicted in the case with magnetophoretic guidance compared to the case without it. However, precise guidance of nasally inhaled aerosols to the olfactory region remains challenging due to the unstable nature of magnetophoresis, as well as the high sensitivity of olfactory dosage to patient-, device-, and particle-related factors.


The risk of second primary cancers due to peripheral photon and neutron doses received during prostate cancer external beam radiation therapy.
Out-of-field organs can be affected by secondary radiations originating from high energy linear accelerators, leading to an increased risk of carcinogenesis. The aim of this work was to determine the risk of second primary cancers (SPC) in the organs distal to the prostate during 3D conformal radiotherapy. Based on previously measured peripheral photon and neutron doses in a Rando phantom using an 18MV photon beam, SPC risks in the out-of-field organs were estimated using the linear-no-threshold and the competitive risk models. Whole body as well as organ specific risk coefficients were used to calculate the SPC risks in order to estimate upper and lower risk limits, given the uncertainties associated with the coefficients. The corresponding estimated average SPC risks ranged from 1.5±0.3% for thyroid to 4.5±4.2% for colon using whole body risk coefficients and 0.12±0.03% and 1.45±1.34%, respectively, using organ specific risk coefficients. The linear-no-threshold and the competitive risk models resulted in the same risk estimates (within the estimated errors) in the dose range received by out-of-field organs (≤1Gy). Distally located organs such as lungs, oesophagus, and thyroid received higher neutron versus photon dose. The findings have important radiation protection implications when using high energy linear accelerators, as radiation protective measures could be employed to minimize the secondary out-of-field radiation for patients undergoing high energy external beam irradiation of the prostate.