Stem cells: Regenerating the skin of a young patient
Stem cells: Regenerating the skin of a young patient, Published online: 04 December 2017; doi:10.1038/nrg.2017.106
Stem cells: Regenerating the skin of a young patient
Am I ready for CRISPR? A user's guide to genetic screens
Am I ready for CRISPR? A user's guide to genetic screens, Published online: 04 December 2017; doi:10.1038/nrg.2017.97
The rapid development of CRISPR-based gene manipulation has enabled various approaches for high-throughput functional genomics. This Review guides users through the practicalities of CRISPR-based functional genomics screens, including study design options, best-practice approaches, pitfalls to avoid and data analysis strategies.
Pathogen genomics: Genomics in the time of cholera
Pathogen genomics: Genomics in the time of cholera, Published online: 04 December 2017; doi:10.1038/nrg.2017.105
Pathogen genomics: Genomics in the time of cholera
Gene expression: SPOTting single RNA molecules transcriptome-wide
Gene expression: SPOTting single RNA molecules transcriptome-wide, Published online: 04 December 2017; doi:10.1038/nrg.2017.107
Gene expression: SPOTting single RNA molecules transcriptome-wide
Membrane potentials of gastrointestinal (GI) muscles are important because voltage dependent Ca2+ channels in smooth muscle cells (SMC) provide the Ca2+ that triggers contraction. Regulation of membrane potential is complicated because SMC are electrically coupled to interstitial cells of Cajal (ICC) and PDGFRα+ cells. Activation of conductances in any of these cells affects the excitability of the syncytium. We explored the role of inward rectifier K+ conductances in colonic ICC that might contribute to regulation of membrane potential. ICC expressed Kcnj2 (Kir2.1), Kcnj4 (Kir2.3), Kcnj14 (Kir2.4) and Kcnj5 (Kir3.4), Kcnj8 (Kir 6.1) and Kcnj11 (Kir6.2). Voltage clamp experiments showed activation of inward current when extracellular K+ ([K+]o) was increased. The current was inwardly rectifying and inhibited by Ba2+ (10 μm) and ML-133 (10 μm). A similar current was not available in SMC. The current activated in ICC by elevated [K+]o was not affect by tertiapinQ, and Gβγ, dialyzed into cells, failed to activate a unique, tertiapinQ-sensitive conductance. Freshly dispersed ICC showed no evidence of functional KATP. Pinacidil failed to activate current and the inward current activated by elevated [K+]o was insensitive to glibenclamide. Under current clamp ML-133 caused depolarization of isolated ICC and of cells impaled with microelectrodes in intact muscle strips. These findings show that ICC, isolated freshly from colonic muscles, expressed a Ba2+-sensitive, inwardly rectifying K+ conductance. This conductance is due, most likely to the expression of multiple Kir2 family paralogues, and the inwardly rectifying conductance contributes to the regulation of resting potentials and excitability of colonic muscles.
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Intestinal anion secretion has been the focus of numerous investigations ever since the discovery of its essential role in diarrheal disease.
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Mid-portion Achilles tendinopathy (MAT) adversely affects free Achilles tendon (AT) structure and composition. However, it is not known how these pathological alterations associated with MAT change the normal three-dimensional (3D) morphology of free AT at rest and under load throughout the entire free tendon length. Here, we used 3D ultrasound to examine the effect of unilateral MAT on free tendon 3D morphology [length, cross-sectional area (CSA), antero-posterior (AP) diameter, and medio-lateral (ML) diameter] and volume at rest and during a sub-maximal (50%) voluntary isometric plantarflexion contraction bilaterally in individuals with unilateral MAT (n = 10) compared to a matched healthy control group (n = 10). The tendinopathic free AT had a greater CSA relative to the control tendons along the entire tendon length which was mainly driven by a greater tendon AP diameter. Under load, the tendinopathic tendon experienced greater longitudinal and transverse strains than the control tendons. In contrast to the control tendons, which experienced a reduction in tendon CSA and ML diameter and bulged along the AP axis and behaved iso-volumetrically under load, the tendinopathic tendon experienced a reduction in tendon CSA, AP diameter, ML diameter, and an overall volume reduction. Overall, these findings suggest that the magnitude of longitudinal strain and volume change and the corresponding magnitude and direction of transverse strain under load are altered in MAT compared to normal tendon. These findings are indicative of a fundamental reorganization of the tendon matrix and alterations in tendon fluid content and distribution under load in tendinopathic tendon.
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Spino-cerebral (projection) neurons localized in lamina I of the spinal gray substance play an important role in the transmission of pain-related information to the brain. We examined spontaneous excitatory postsynaptic currents (sEPSC) recorded from lamina I spino-pontine neurons in isolated preparations of the rat lumbar spinal cord; the respective neurons were retrogradely labeled by a fluorescent dye. We tried to find out how experimentally induced peripheral inflammation affects the amplitude/time characteristics of these currents. It was found that, in preparations obtained from animals with inflammation of hind limb tissues, the frequency and (to a lesser extent) amplitude of sEPSC in projection neurons are, on average, higher than those measured in neurons of the control animals. It is belived that such changes result mostly from plastic modifications of neuron-to-neuron interactions in neuronal networks of lamina II, which form main synaptic inputs to neurons of lamina I. Increased frequency and amplitude of sEPSC in lamina I neurons should lead to some facilitation of transmission of nociceptive information to the cerebral structures. Such hyperexcitability of lamina 1 projection neurons can provide a notable contribution to the development of hyperalgesia in chronic inflammatory states and to facilitation of generation of pain-related emotions.
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We examined the effects of 2.0 μM curcumin, a known antioxidant, on the cultures of normal rat astrocytes and of those subjected to the action of 0.01 μM lipopolysaccharide, LPS. As was found, 24-h-long exposure of astrocytes to LPS resulted in a relatively mild decrease in the cell viability of astrocytes (a decrement of 22%). The action of curcumin significantly ameliorated this decrease. LPS induced significant upregulation of GFAP, NF-κB, and poly(ADP-ribose)polymerase (PARP) in activated astrocytes. Curcumin significantly decreased these effects (to 60, 71, and 89% as compared to those in astrocytes subjected to isolated action of LPS). Thus, curcumin significantly prevents the decrease in cell viability and moderates the cytoskeleton rearrangements and disorders in NF-κBdependent regulation in astrocytes activated by LPS.
We investigated whether indices of the reflex regulation of the cardiovascular system, i.e., muscle ergoreflex activity (ERGO) and characteristics of the autonomic balance, differ from each other while measured in the vertical vs. horizontal positions in healthy humans. Ten young healthy men (mean age 28 ± 1 years; BMI 23.6 ± 0.8 kg/m2) were examined. In each subject, the ERGO (ventilatory response to a control handgrip exercise, with repetitive isometric contractions at 50% of the maximal strength), baroreflex sensitivity (BRS, the sequence method), heart rate variability (HRV), and a few hemodynamic parameters were measured in two positions, horizontal and vertical. In the latter position, the heart rate, and diastolic and mean blood pressures (BP) were higher, while the stroke volume was smaller (all P < 0.05) with no differences in the systolic BP, cardiac output, and systemic vascular resistance (all P > 0.2). The HRV time domains, as well as BRS, decreased, whereas HRV-LF increased (all P < 0.05) in the vertical position as compared to the horizontal one. There were no differences between other HRV parameters (all P > 0.2) in the two examined positions. Minute ventilation during the exercise increased, while ERGO was reduced in the vertical position (all P < 0.05). Thus, the body position noticeably affects both reflex regulation of the cardiovascular system and autonomic balance. This observation has to be taken into account during physiological testing.
We examined the accessibility of influenza virus and diphtheria-tetanus toxin (DiTe) antigens to the choroid plexus (CP) within the postvaccination period and the expression of CD11b molecules (by immunohistochemistry). Eighteen Dark Agouti (DA) rats were divided into three groups: (i) animals administered with influenza vaccine (Flu), (ii) animals administered with DiTe vaccine (DiTe), and (iii) nontreated (Contr) animals. The serum antibody titers following influenza and diphtheria-tetanus vaccination were detected by the ELISA test. Immunohistochemical staining revealed a great number of viral antigen-positive and CD11b-positive brain cells in Flu rats compared to a very small number of the respective cells in DiTe animals and no staining in the Contr group. DiTe- and Flu-rats showed significant increases in the serum anti-tetanus toxoid and anti-influenza virus antibody levels compared to those in the Contr group. The results obtained attract attention towards the dynamic role of the CP in the immunosurveillance of the CNS. Based on the viral antigen deposits accumulated in the CP, it has been proposed that the latter can play an active role in modulation of the immune response after influenza vaccine immunization.
Perrault syndrome represents a genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females. Causative genes include HARS2, HSD17B4, CLPP, C10orf2, and LARS2. Some patients with Perrault syndrome exhibit neurologic features including learning disability, cerebellar ataxia, and peripheral neuropathy and are classified as type 2 and are clinically separate from those without neurological symptoms other than a hearing loss (type 1). To date, all reported patients with LARS2 mutations (15 patients in 8 families) have been classified as type 1. Here, we report female siblings with biallelic mutations in LARS2, p.Glu294Lys, and p.Thr519Met, who were classified as type 2. The proposita developed progressive sensorineural hearing loss at 18 months and pervasive developmental disorder at 8 years, with repetitive behavior, insistence on sameness, attention deficit, tic, irritability, and an ataxic gait. At age 15 years, she was diagnosed as having primary amenorrhea with elevated FSH and LH and a decreased estradiol; ultrasound and magnetic resonance imaging examinations revealed a small uterus and no detectable ovaries. The proposita's younger sister presented with neonatal sensorineural hearing loss and a mild delay in motor and speech development. She was diagnosed as having primary amenorrhea with endocrinologic and radiographic findings that were comparable to those of her sister. She had difficulty with reading comprehension, and had trouble with open-ended test questions at 12 years of age. We concluded that Perrault syndrome patients with LARS2 mutations are at risk for neurologic problems, despite previous notions otherwise.
By Cathy Dyson The Free Lance-Star via AP SPOTSYLVANIA, Va. — Patrick Jett had been waiting most of his young life for the moment he could climb into the front of an ambulance and respond to whatever emergency awaited. For two years, he'd been running calls with the Spotsylvania Volunteer Rescue Squad, responding to vehicle accidents or drug overdoses, general illnesses or diabetic reactions ...
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