Search

Canine polygenic obesity can be influenced by relatively recent mutations with large effects. We determined whether, as with monogenic diseases, long autozygous tracts may be disproportionately likely to harbor detrimental variants for additive polygenic obesity in Labrador retriever dogs. Both our detection of runs of homozygosity (ROH) and our preliminary association study were based on whole-genome sequencing of 28 obese and 22 healthy dogs. We detected and analyzed the distribution of 19,655 ROH. We observed 237 and 98 ROH-harboring genotypes associated with obesity and increased body mass, respectively. We found no evidence that long ROH tend to harbor genotypes linked to obesity or increased body weight, and we concluded that data on ROH overlapping GWAS signals for canine obesity are unlikely to help prioritize candidate genes for validation studies.

This study aimed to systematically review the literature to determine the clinical utility and perspectives of diffusion tensor imaging (DTI) in the management of patients with brainstem cavernous malformations (BSCMs). PubMed, Embase, and Cochrane were searched for English-language articles published until May 10, 2021. Clinical studies and case series describing DTI-based evaluation of patients with BSCMs were included. Fourteen articles were included. Preoperative DTI enabled to adjust the surgical approach and choose a brainstem safe entry zone in deep-seated BSCMs. Preoperatively lower fractional anisotropy (FA) of the corticospinal tract (CST) correlated with the severity of CST injury and motor deficits. Postoperatively increased FA and decreased apparent diffusion coefficient (ADC) corresponded with the normalization of the perilesional CST, indicating motor improvement. The positive (PPV) and negative predictive value (NPV) of qualitative DTI ranged from 20 to 75% and from 66.6 to 100%, respectively. The presence of preoperative and postoperative motor deficits was associated with a higher preoperative resting motor threshold (RMT) and lower FA. A higher preoperative CST score was indicative of a lower preoperative and follow-up Medical Research Council (MRC) grade. DTI facilitated the determination of a surgical trajectory with minimized risk of WMTs' damage. Preoperative FA and RMT might indicate the severity of preoperative and postoperative motor deficits. Preoperative CST score can reliably reflect patients' preoperative and follow-up motor status. Due to high NPV, normal CST morphology might predict intact neurological outcomes. Contrarily, sparse and relatively low PPV limits the reliable prediction of neurological deficits.

Purpose Brainstem abscess is a rare condition accounting for merely 1% of brain abscesses incidence in the pediatric population. This study aimed to present a single patient with a pontine abscess and review the literature to highlight clinical features, diagnosis, and management of brainstem abscess. Methods The PubMed database was screened for English-language articles concerning pediatric brainstem abscess. We, therefore, identified 22 publications, which concisely depict 23 cases. Our study reports on the 24th pediatric patient diagnosed with that entity. All included reports were analyzed in terms of clinical presentation, diagnosis, management, and outcomes of described patients. Results There was slight women predominance (15:9), with a mean age of occurrence 6.4 years, ranging from 7 months to 16 years. Pons was the most common location of brainstem abscess, occurring in 75% of patients. Clinically, they mostly presented with cranial nerves palsy (79.2%), hemiparesis (66.7%), and pyramidal signs (45.8%). The classic triad of symptoms, including fever, headache, and the focal neurologic deficit was present in 20.8% of patients. Positive pus cultures were obtained in 61.1%. Streptococci and Staphylococci were the most frequently identified pus microorganisms. Outcomes were satisfactory, with a 79.2% rate of general improvement. Conclusions Neurosurgical aspiration is a safe and beneficial therapeutic method. It should always be considered and should promptly be performed when the conservative treatment is not successful and clinical deterioration occurs. Prognosis in pediatric brainstem abscess is generally favorable. Most patients recover with minor neurologic deficits or improve completely.

Because of its longevity and enormous information density, DNA is considered a promising data storage medium. In this work, we provide instructions for archiving digital information in the form of DNA and for subsequently retrieving it from the DNA. In principle, information can be represented in DNA by simply mapping the digital information to DNA and synthesizing it. However, imperfections in synthesis, sequencing, storage and handling of the DNA induce errors within the molecules, making error-free information storage challenging. The procedure discussed here enables error-free storage by protecting the information using error-correcting codes. Specifically, in this protocol, we provide the technical details and precise instructions for translating digital information to DNA sequences, physically handling the biomolecules, storing them and subsequently re-obtaining the information by sequencing the DNA. Along with the protocol, we provide computer code that automatically encodes digital information to DNA sequences and decodes the information back from DNA to a digital file. The required software is provided on a Github repository. The protocol relies on commercial DNA synthesis and DNA sequencing via Illumina dye sequencing, and requires 1-2 h of preparation time, 1/2 d for sequencing preparation and 2-4 h for data analysis. This protocol focuses on storage scales of ~100 kB to 15 MB, offering an ideal starting point for small experiments. It can be augmented to enable higher data volumes and random access to the data and also allows for future sequencing and synthesis technologies, by changing the parameters of the encoder/decoder to account for the corresponding error rates.

To investigate laboratory parameters as predictors of overall survival (OS) for hepatocellular carcinoma (HCC) treated with radioembolization and develop/validate a scoring system.With IRB approval, we included all patients with baseline alpha-fetoprotein (AFP) 100 ng/dL from our prospectively acquired HCC radioembolization database. Neutrophil-lymphocyte ratio, albumin-bilirubin (ALBI), and AFP were measured at baseline and at 1-, 3-, and 6-month post-radioembolization Landmarks. OS was assessed from these Landmarks. Univariate/multivariate analyses were performed to evaluate OS predictability of these parameters. Baseline Imaging, Laboratory, and Combination scoring systems were developed. Developing/validating groups were created to investigate/validate the score's OS predictability. Time-dependent receiver operating characteristics (ROC) were evaluated. Patients were stratified into groups I, II, and III by using 25th and 75th percentile cutoffs according to change in Laboratory Score from baseline.345/401 (86%), 238/401 (59%), and 167/401 (42%) patients had laboratory parameters available at the 1-, 3-, and 6-month Landmarks, respectively. ALBI and AFP were significant OS prognosticators at all Landmarks. The Laboratory Score [ALBI + (0.3 × LnAFP)] was developed/internally validated to predict OS from these Landmarks. Areas under the curve of time-dependent ROCs of the Baseline Imaging vs. Laboratory scores in predicting patient OS post 3 and 6 months Landmarks were 0.56 versus 0.82 and 0.57 versus 0.77, respectively. OS differences in groups I, II, and III according to change in Laboratory Score from baseline were significant (p 0.001).Post-radioembolization AFP and ALBI scores were significant OS prognosticators. A decrease in post-therapeutic Laboratory Score, which combines AFP and ALBI, correlates with an improved OS.

The volume of securely encrypted data transmission required by today’s network complexity of people, transactions and interactions increases continuously. To guarantee security of encryption and decryption schemes for exchanging sensitive information, large volumes of true random numbers are required. Here we present a method to exploit the stochastic nature of chemistry by synthesizing DNA strands composed of random nucleotides. We compare three commercial random DNA syntheses giving a measure for robustness and synthesis distribution of nucleotides and show that using DNA for random number generation, we can obtain 7 million GB of randomness from one synthesis run, which can be read out using state-of-the-art sequencing technologies at rates of ca. 300 kB/s. Using the von Neumann algorithm for data compression, we remove bias introduced from human or technological sources and assess randomness using NIST’s statistical test suite., Nature Communications, 11 (1), ISSN:2041-1723

Due to its longevity and enormous information density, DNA is an attractive medium for archival storage. The current hamstring of DNA data storage systems—both in cost and speed—is synthesis. The key idea for breaking this bottleneck pursued in this work is to move beyond the low-error and expensive synthesis employed almost exclusively in today’s systems, towards cheaper, potentially faster, but high-error synthesis technologies. Here, we demonstrate a DNA storage system that relies on massively parallel light-directed synthesis, which is considerably cheaper than conventional solid-phase synthesis. However, this technology has a high sequence error rate when optimized for speed. We demonstrate that even in this high-error regime, reliable storage of information is possible, by developing a pipeline of algorithms for encoding and reconstruction of the information. In our experiments, we store a file containing sheet music of Mozart, and show perfect data recovery from low synthesis fidelity DNA., Nature Communications, 11 (1), ISSN:2041-1723

Laser-mediated gene transfection into mammalian cells has recently emerged as a powerful alternative to more traditional transfection techniques. In particular, the use of a femtosecond-pulsed laser operating in the near-infrared (NIR) region has been proven to provide single-cell selectivity, localized delivery, low toxicity and consistent performance. This approach can easily be integrated with advanced multimodal live-cell microscopy and micromanipulation techniques. The efficiency of this technique depends on an understanding by the user of both biology and physics. Therefore, in this protocol we discuss the subtleties that apply to both fields, including sample preparation, alignment and calibration of laser optics and their integration into a microscopy platform. The entire protocol takes ~5 d to complete, from the initial setup of the femtosecond optical transfection system to the final stage of fluorescence imaging to assay for successful expression of the gene of interest.

Effects of magnetic frustration in the model of nine-membered antiferromagnetic s = 3/2 molecular spin ring are investigated. We use a Heisenberg spin model with nearest-neighbor interactions, single-ion anisotropy and with tunable bond defect leading to continuously varying topology: from closed to open ring. In order to identify a frustrated phase we calculate the full energy spectrum of the model and a number of thermodynamic quantities at low temperature. The calculations are performed by means of numerically exact methods: quantum transfer matrix and exact diagonalization. It is shown that total and local magnetizations, nearest-neighbor spin correlations and spin fluctuations can serve as consistent frustration signatures. Magnetizations and spin-spin correlations are reduced in the frustrated phase whereas fluctuations and correlations of fluctuations increase. The ground state in a frustrated phase is a m = 1/2 doublet and in the non-frustrated phase a m = 3/2 doublet. In the system studied bipartiteness is not opposite to frustration as there are regions in the parameter space for which the system is neither bipartite nor frustrated.

It is now generally accepted that proteins are the primary targets of general anesthetics. However, the demonstration that the activity of a protein is altered by general anesthetics at clinically relevant concentrations in vitro does not provide direct evidence that this target mediates pharmacological actions of general anesthetics. Here we report on advances that have been made in identifying the contribution of individual ligand-gated ion channels to defined anesthetic endpoints using molecular mouse genetics.Gamma-aminobutyric acid (GABA)(A) receptor subtypes defined by the presence of the α1, α4, α5, β2, and β3 subunits and two-pore domain potassium channels (TASK-1, TASK-3, and TREK) have been discovered to mediate, at least in part, the hypnotic, immobilizing or amnestic actions of intravenous and volatile general anesthetics. Moreover, using tissues from genetically modified mice, specific functions of GABA(A) receptor subtypes in cortical and spinal neuronal networks were identified.Genetically modified mice have been very useful for research on mechanisms of anesthesia and have contributed to the functional identification of general anesthetic targets and of the role of these targets in neuronal networks.

CDKN2A gene belongs to the genes involved in cell cycle regulation. When is absent or inactivated by mutation or promoter hypermethylation a cell may undertake an uncontrolled proliferation. Inactivation of CDKN2A gene is observed in many human malignancies, including larynx cancer. In this study we investigated mutations in exon 1 and exon 2 of CDKN2A gene in a large group of 390 laryngeal cancers. We found 40 different alterations (17%) and nearly half of them was not described previously. Out of these alterations two transversions in codon 108: c.322G>C (Asp108His) and c.322G>T (Asp108Tyr) as well as a G>A transition in codon 110 (Trp110X) were found more frequently (altogether: 7 cases in codon 108 and 10 cases in codon 110). This result, concerning the location of these codons in the ankyrin repeat structures, may suggest that these two codons may be critical hot-spots in larynx carcinogenesis.

We study numerically the temporal and spatial dynamics of light in Bragg gratings in highly nonlinear photonic crystal fibre for a CW input signal. Our numerical model is based on the plane wave mode solver and a set of nonlinear coupled-mode equations which we solve using a variation of implicit fourth order Runge-Kutta method. We observe not only bistability of the intensity versus transmitted and reflected light but also complex dynamics. We demonstrate that for values of input intensity above the bistable region the steady state may undergo a supercritical Hopf bifurcation. For some ranges of the input intensity we also observe a coexistence of two periodic attractors. The dynamics found, in particular the features in the bifurcation diagram, strongly depend on the parameters of the fibre. Consequently, we suggest that by proper design of the photonic crystal in the cladding we can adjust such nonlinear features of the Bragg gratings as the width of the bistable region, the intensity at which the bifurcation occurs and also the characteristics of the dynamics at high values of input intensity.

We analyze theoretically the coupling properties of Bragg gratings written in highly birefringent photonic crystal fibers with doped core and show how they can be tuned by the parameters of a microstructured fiber. We apply the coupled mode theory combined with a fully vectorial mode solver based on the plane-wave method. The results indicate large differences in interaction with the grating for the two linearly polarized fundamental modes. We show fiber designs, which provide single-mode operation with high birefringence and at the same time a high coupling efficiency of the grating. Such features can be used in fiber sensors, fiber laser configurations or to introduce a polarization dependent feedback in a long external cavity system with a semiconductor laser.

In this paper we are modeling the interplay of material and form birefringence in photonic crystal fibers. We introduce an efficient numerical method for the calculation of the modal structure. Our approach relies solving the fully vectorial wave equation for the transverse magnetic field and the respective propagation constants using a plane wave expansion. The method accounts for a simple form of material anisotropy. Our analysis is relevant to certain application areas, and in particular to fiber sensing, where material birefringence arises for instance due to transversally applied mechanical stress. We analyze the influence of material birefringence on the modal birefringence and the state of polarization of the fundamental mode.

Almost a century ago, Meyer and Overton discovered a linear relationship between the potency of anaesthetic agents to induce general anaesthesia and their ability to accumulate in olive oil. Similar correlations between anaesthetic potency and lipid solubility were later reported from investigations on various experimental model systems. However, exceptions to the Meyer-Overton correlation exist in all these systems, indicating that lipid solubility is an important, but not the sole determinant of anaesthetic action. In the mammalian central nervous system, most general anaesthetics act at multiple molecular sites. It seems likely that not all of these effects are involved in anaesthesia. GABAA- and NMDA-receptor/ion channels have already been identified as relevant targets. However, further mechanisms, such as a blockade of Na+ channels and an activation of K+ channels, also come into play. A comparison of different anaesthetics seems to show that each compound has its own spectrum of molecular actions and thus shows specific, fingerprint-like effects on different levels of neuronal activity. This may explain why there is no known compound that specifically antagonises general anaesthesia. General anaesthesia is a multidimensional phenomenon. Unconsciousness, amnesia, analgesia, loss of sensory processing and the depression of spinal motor reflexes are important components. It was not realised until very recently that different molecular mechanisms might underlie these different components. These findings challenge traditional views, such as the assumption that one anaesthetic can be freely replaced by another.

Wild pear (Pyrus pyraster, syn. P. communis var. pyraster) is thought to be one of the species that gave rise to all other members of the genus Pyrus, although intraspecific hybridizations with cultivated varieties could cause the disappearance of original species characteristics. S-RNase alleles from 7 different wild pear individuals, collected from various regions of Poland, were cloned on the basis of the PCR method and nucleotide sequence analyses. The hypervariable (HV) region is responsible for allele-specific S-RNase activity in the self-incompatibility mechanism. The high level of polymorphism of its sequences may constitute a source of valuable phylogenetic information. From all individuals, 14 sequences were obtained successfully, and 9 of them were novel alleles. Phylogenetic analysis of these alleles was based on the amino acid sequence interpretation of coding regions and intron nucleotide sequences. The research conducted on a limited pool of available P. pyraster alleles gives only an initial insight into possible S-RNase allele polymorphisms in wild populations. At this stage, the results do not confirm a strong influence of cultivated pear species on the wild pear.

A strong intramolecular hydrogen bond O-H⋯O, found by spectroscopic methods and proved by X-ray analysis, keeps the two planar fragments of the molecule twisted. The angle between the least-squares planes of these fragments is 38.2(1)°. The influence of the conformational rigidity of the molecule on the spectroscopic properties of the title compound is discussed in comparison with its methyl ether and free base.

The correlation between chemotherapy-induced toxicity and treatment outcome in cancer patients has not been studied thoroughly. Our aim was to evaluate whether there is any relationship between chemotherapy-induced leukopenia and response to treatment in small-cell lung cancer (SCLC). Data derived from records of 228 patients treated within two prospective multicentre phase II studies were analysed. In the first study (101 patients) chemotherapy included vincristine, epirubicin and cyclophosphamide and, in the second (127 patients), cyclophosphamide, etoposide and epirubicin; both regimens were given every 3 weeks. In the present analysis, the correlation between treatment outcome (response rate and survival) and highest scores of leukopenia within the first two and up to the fourth chemotherapy cycle, respectively, was evaluated. The objective response rate for the entire group was 66%; 53% in patients whose white blood cells remained normal and 85% in those who developed leukopenia within the first two cycles (P = 0.000). In multifactorial analysis, also including other treatment- and patient-related factors, independent correlation with response to chemotherapy was found for leukopenia (P = 0.001), chemotherapy regimen (P = 0.002) and the combined relative dose intensity (P = 0.018), but not for patient sex, age, performance status, pre-study weight loss, extent of disease and initial white blood cell count. Leukopenia within the first two cycles of chemotherapy was not correlated with survival, whereas such correlation for leukopenia occurring up to the fourth cycle was at the borderline level (P = 0.06). These findings suggest a relationship between chemotherapy-induced leukopenia and tumour response in SCLC.

This work is supported by the UK Engineering Physical Sciences Research Council (EPSRC). A prevailing problem in neuroscience is the fast and targeted delivery of DNA into selected neurons. The development of an appropriate methodology would enable the transfection of multiple genes into the same cell or different genes into different neighboring cells as well as rapid cell selective functionalization of neurons. Here, we show that optimized femtosecond optical transfection fulfills these requirements. We also demonstrate successful optical transfection of channelrhodopsin-2 in single selected neurons. We extend the functionality of this technique for wider uptake by neuroscientists by using fast three-dimensional laser beam steering enabling an image-guided “point-and-transfect” user-friendly transfection of selected cells. A sub-second transfection timescale per cell makes this method more rapid by at least two orders of magnitude when compared to alternative single-cell transfection techniques. This novel technology provides the ability to carry out large-scale cell selective genetic studies on neuronal ensembles and perform rapid genetic programming of neural circuits. Publisher PDF

Methods Sixteen healthy subjects and 3 symptomatic PAD patients (ABI 0.4-0.9) underwent contrast-enhanced perfusion MRI of the calf before and after plantar-flexion exercise using an MR-compatible pedal at 50 rpm for up to 20 minutes or until limiting symptoms. Contrast-enhanced first-pass images were obtained on a 3T Siemens Trio scanner by infusion of 0.1mM/kg of gadolinium-DTPA followed by a 20 mL saline flush at 4 mL/ second. A spoiled gradient echo dual contrast sequence with slices positioned 32 mm apart allowed for simultaneous acquisition of arterial input and muscle perfusion images. Time-intensity curves (TIC) were generated using ARGUS software (Siemens) for arterial input and the muscle group with the highest signal intensity (tissue function, TF). PI was measured as ratio of the slopes of the TF TIC/arterial input TIC. PR was defined as exercise TF/resting TF. PIR was calculated as exercise PI/rest PI. Ten of the controls and all 3 patients underwent repeat studies on a separate day. For 7 controls and all patients, measurements were normalized to proton density.

Late gadolinium enhancement can identify focal fibrosis, but cannot evaluate diffuse myocardial fibrosis. Multiple methods have been used to determine the partition coefficient (λ) and volume of distribution (Vd) of gadolinium to quantify diffuse myocardial fibrosis, including first-pass and T1 mapping based techniques. These two techniques have not been directly compared in the same subjects.

The crystal structure of 5-hydroxy-9,10-dihydro-4-azaphenanthrene-4-oxide has been determined. The asymmetric unit contains three molecules which slightly differ in their geometries. The 2-phenylpyridine skeleton has been stiffened by linking in the 3,6′-positions with the-CH2-CH2-group and by the intramolecular hydrogen bond O-H⋯O. In consequence, a more planar conformation of the molecule is observed in comparison with the conformation of 2-(2-hydroxyphenyl)pyridine-1-oxide where the only flattening factor is the intramolecular hydrogen bond. NMR results confirm that the conformational rigidity persists in solution.

Orellanine hydrate crystallizes in the monoclinic space groupC2/c with unit cell parametersa=11.516(1) A,b=8.573(1) A,c=11.167(2) A,β=110.92(1)°. The finalR andRw equal 0.041 and 0.046, respectively. The water molecule in the hydrate binds bothN-oxide oxygens of the orellanine molecule by hydrogen bonds, thus fixing the conformation. The hydrate so formed occupies a special position on a twofold axis which passes through the midpoint of the C2-C2′ bond distance and the OW atom. Both of the hydroxy-groups participate also in intermolecular hydrogen bonds. As a consequence of the rigid hydrogen bonded network, the dihedral angle between these two pyridil rings of the orellanine molecule is equal to 90.20(5)°.