No description available.

The taste of sugar is one of the most basic sensory percepts for humans and other animals. Remarkably, animals can develop a strong preference for sugar even if lacking a functional sweet taste receptor, pointing to a detection mechanism independent of the sense of taste. Here we examined the neural basis for sugar preference and demonstrate that a population of neurons in the brainstem are activated via the gut-brain axis to create preference for sugar. These neurons are stimulated in response to sugar, but not to artificial sweeteners, and are activated by direct delivery of sugar into the gut. We demonstrate that these cells receive direct vagal inputs, which are necessary for their response to sugar. Using functional imaging we monitored the activity of the gut-brain axis, and identified the vagal neurons activated by intestinal delivery of glucose. We characterized the nature of their responses, establish their specificity, and identify the mechanism required for sugar sensation. Finally, we engineered animals where synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of a behavioral preference for sugar. Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for the behavioral differences of sweeteners versus sugar, and uncover an essential circuit underlying sugar’s highly appetitive effects.

No description available.

No description available.

Bakgrund: Kvinnliga idrottare drabbas i hög grad av främre korsbandsskador och under efterföljande rehabilitering har fysioterapeuten en viktig roll. En stor skillnad mellan kvinnor och män är menstruationscykeln. Den kvinnliga idrottaren påverkas av menstruationscykelns olika faser och intag av preventivmedel. Genom ett biopsykosocialt helhetsperspektiv kan en fysioterapeut ta hänsyn till flera olika faktorers påverkan på ett beteende. Detta kan möjliggöra vad som eventuellt kan påverka en elitidrottande kvinna kopplat till menstruationscykel under en pågående främre korsbandsrehabilitering.Syfte: Studiens syfte var att undersöka kvinnors upplevda motivation, self-efficacy och träningskvalité kopplat till menstruationscykeln under pågående främre korsbandsrehabilitering.Metod: Beskrivande fallstudier med deskriptiv och visuell analys. Sju kvinnliga elitidrottare som genomgick främre korsbandsrehabilitering rekryterades, varav en exkluderades. Datainsamlingen genomfördes med hjälp av ett frågeformulär och en dagbok. Datainsamlingen pågick i 33 dagar.Resultat: Resultatet visar att var och en av deltagarna upplevde variation i sina skattningar inom varje frågeställning under studiens gång. En deltagares variation kan eventuellt ha påverkats av menstruationscykeln och dess fluktuationer av hormoner.Slutsats: Uppsatsens resultat visar på variation av skattningar under menstruationscykeln hos samtliga deltagare. Denna studie kan dock inte påvisa om den påverkade faktorn är menstruationscykelns olika faser och intag av preventivmedel.Nyckelord: Främre korsbandsskada, fysioterapi, kvinnliga elitidrottare, rehabilitering, socialkognitiv teori

The Olfactory Epithelium (OE) is a specialized epithelial tissue inside the nasal cavity that is involved in the smell sensation. The OE maintains neuroregeneration, i.e. producing new olfactory sensory neurons, throughout the adult life via neural stem cell self-renewal, proliferation, neuronal differentiation and maturation. The neural stem cell niche regulates stem cell self-renewal and proliferation, and consists of stem cells, blood vessels and multiple extracellular matrix proteins (ECMs). ECMs regulate stem cell adhesion, proliferation, differentiation and migration via integrins. One of the main mediators of intracellular integrin signaling is the Focal Adhesion Kinase (FAK). Our previous studies found that FAK inhibition increased cell proliferation in adult mouse olfactory epithelium (OE) via up-regulation of Ciliary Neurotrophic Factor (CNTF). Now we continue to test whether FAK inhibition increases neuroregeneration through CNTF in the adult mouse OE using BrdU-chase pulse method. Adult male and female C57BL/6, CNTF wildtype and CNTF knockout (lack the CNTF gene) mice were systemically injected with PBS or FAK inhibitor (FAK14) for 3 days. During these 3 days, BrdU was injected into mice 4 h following PBS or FAK on each day. BrdU acts as a thymidine analog and is incorporated into DNA during DNA syntheses. Using immunohistochemistry with anti-BrdU antibody, BrdU+ cells can be visualized in the tissue. The BrdU+ cells are the ones who are replicating during the time frame when BrdU was given. 20 days after last BrdU injection, we fixed the mice via cardiac perfusion. The whole heads of mice was decalcified with EDTA and then frozen cross head sections including OE were cut using cryostat and mounted onto slides. The OE sections were then stained with anti-BrdU antibody followed by FITC-conjugated secondary antibody. The BrdU+ cells in the OE were counted in three sections (both left and right sides) per mouse and normalized to linear length of OE basement membrane. The results of the experiment showed that FAK 14 significantly increased BrdU+ stem cells and olfactory sensory neurons in the OE of C57BL/6 and CNTF wildtype mice but not knockout mice, indicating that FAK inhibition promotes olfactory stem cell self-renewal and neuroregeneration via CNTF. Collectively, this data indicates that FAK normally inhibits OE neuroregeneration by inhibiting CNTF expression and identifies the OE is a good model to study neuroregenerative mechanisms in the CNS.

Calciphylaxis is a poorly-understood condition whose pathogenesis involves systemic calcification of arteries and arterioles. It is usually seen in patients end-stage renal disease, with an incidence of approximately 5% in dialysis patient and patients with calcium-phosphate dysregulations.1,2 However, there have also been reports of patients with biopsy-proven calciphylaxis with normal calcium-phosphate balance and renal function. We report a morbidly obese 45-year-old female with significant past medical history of necrotizing fasciitis with superimposed pseudomonas infections requiring multiple rounds of antibiotics and debridement. She presented to hospital due to chronic thigh wounds and debilitating pain. Patient developed tender and ulcerated lesions on her bilateral inner thighs spontaneously and was treated with trimethoprim-sulfamethoxazole and doxycycline. Wound cultures grew pseudomonas and Methicillin-Resistant Staphylococcus aureus. Rheumatologic work up including antinuclear antibody, rheumatoid factor, anti-double stranded DNA, anti-ribonucleoprotein and complement levels were all within normal limits except for elevated erythrocyte sedimentation rate and c-reactive protein. Patient was given multiple analgesics of which ketorolac helped the most. She was referred to dermatology after which excisional biopsy of wound was performed. Biopsy result revealed tissue necrosis and calciphylaxis. Patient was started on sodium thiosulfate (STS) infusions after discussing with dermatology and was discharged in stable conditions from hospital. The exact cause of calciphylaxis still remains unknown. It is thought to be due to intravascular calcium deposition in the media of the epidermal and subcutaneous arterioles causing medial calcification and intimal fibrosis of the arterioles resulting in thrombosis and occlusions. This leads to ischemic skin necrosis which is the most common clinical finding in calciphylaxis.3 For non-uremic calciphylaxis, there appears to be a predilection of Caucasian females, primary hyperparathyroidism, obesity, malignancy, connective tissue disease and vitamin D deficiency.4-5 Our patient had some of the risk factors including morbid obesity, middle aged Caucasian female and Vitamin D deficiency. Calciphylaxis has two-year mortality rate of 50-80% secondary to sepsis, hence preventing patients with known risk factors from developing calciphylaxis is imperative.6 The lesions of calciphylaxis are often debilitating and wound care with debridement of necrotic tissue as well as systemic antibiotics are of utmost importance, if indicated. In recent years, treatment include the use of STS, which chelate calcium from tissue deposits and bisphosphonates which are thought to help in removing arterial calcifications.7 It is important to understand that calciphylaxis may occur in patients without renal impairment and early interventions may be helpful to decrease debilitation and mortality.

No description available.

With the critical role of aberrantly active Signal Transducer and Activator of Transcription (Stat) 3 protein in many human cancers, selective small-molecule inhibitors targeting the dimerization event which is required for stat3 activation, would be valuable as therapeutic agents. And the inhibitors will be useful chemical probes to clarify the complex biological functions of Stat3. By computational and structural analyses of the interaction between Stat3 and the lead dimerization disruptor, S3I-201, we have designed a diverse set of analogs. One of the most active analogs, S3I-201.1066 is derived to contain a cyclo-hexyl benzyl moiety on the amide nitrogen, which increases the binding to the Stat3 SH2 domain. Evidence is presented from in vitro biochemical and biophysical studies that S3I-201.1066 directly interacts with Stat3 or the SH2 domain, with an affinity (K[subscript D]) of 2.74 [micrometer], and disrupts the binding of Stat3 to the cognate pTyr-peptide, GpYLPQTV-NH2, with an IC₅₀ of 23 [micrometer]. Moreover, S3I-201.1066 selectively blocks the association of Stat3 with the epidermal growth factor receptor (EGFR), and inhibits Stat3 tyrosine phosphorylation and nuclear translocation in EGF-stimulated mouse fibroblasts. In cancer cells that harbor aberrant Stat3 activity, S3I-201.1066 inhibits constitutive Stat3 DNA-binding and transcriptional activities. By contrast, S3I-201.1066 has no effect on Src activation or the EGFR-mediated activation of the Erk1/2MAPK pathway. S3I-201.1066 selectively suppresses the viability, survival, and malignant transformation of the human breast and pancreatic cancer lines and the v-Src-transformed mouse fibroblasts harboring persistently active Stat3. Treatment with S3I-201.1066 on malignant cells harboring aberrantly active Stat3 down regulated the expression of c-Myc, Bcl-xL, Survivin, matrix metalloproteinase 9, and VEGF, which are known Stat3-regulated genes important in diverse tumor processes. The in vivo administration of S3I-201.1066 induced significant anti-tumor response in mouse models of human breast cancer, which correlates with the inhibition of constitutively active Stat3 and the suppression of known Stat3-regulated genes. Further computer-aided lead optimization derives higher-affinity (K[subscript D], 504 nM), orally bioavailable Stat3 SH2 domain-binding ligand, BP-1-102 as a structural analog of S3I-201.1066. The most significant modification is the pentafluorobenzene sulfonamide component of BP-1-102, which permits accessibility of a third sub-pocket of the Stat3 SH2 domain surface. BP-1-102-mediated inhibition of aberrantly-active Stat3 in human pancreatic cancer, Panc-1, breast cancer, MDA-MB-231, and prostate (DU145) cancer cells and in the mouse transformed fibroblasts harboring aberrantly-active Stat3. It also disrupts Stat3-NF[kappa]B cross-talk and suppresses the release of granulocyte colony-stimulating factor, soluble intercellular adhesion molecule-1, macrophage-migration-inhibitory factor/glycosylation-inhibiting factor, interleukin-1 receptor antagonist and the serine protease inhibitor (serpin) protein 1, and the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, and vascular endothelial growth factor expression in vitro and in vivo. Inhibition of tumor cell-associated constitutively-active Stat3 further suppresses focal adhesion kinase and paxillin induction, enhances E-cadherin expression, and down-regulates Kruüppel-like factor 8 expression. Consequently, BP-1-102 selectively suppresses anchorage-dependent and independent growth, survival, migration and invasion of Stat3-dependent tumor cells in vitro. Intravenous or oral gavage delivery of BP-1-102 furnishes micromolar or microgram levels in tumor tissues and inhibits growth of mouse xenografts of human breast and lung tumors. Computer-aided lead optimization has therefore derived a more suitable small-molecule inhibitor as a drug candidate. Our studies of the Stat3 SH2 protein surface and of the interactions between lead agents and the SH2 domain provided significant data to facilitate the structural optimization. From S2I-201 to S3I-201.1066 and to BP-1-102, we note the substantial gain in potency and efficacy, and the pharmacokinetic improvements. The oral bioavailability of BP-1-102 represents a substantial advancement in the discovery of small-molecule Stat3 inhibitors as novel anticancer agents.

The process of decoding is the most crucial determinant of the quality of protein synthesis. Ribosomal protein L9 was first implicated in decoding fidelity when a mutant version of L9 was found to increase the translation of a T4 phage gene. Later studies confirmed that the absence of L9 leads to increased translational bypassing, frameshifting, and stop codon readthrough. L9 is part of the large subunit of the prokaryotic ribosome and is located more than 90 Å from the site of decoding, making it difficult to envision how it might affect decoding and reading frame maintenance. Twenty years after the identification of L9's putative function, there is no mechanism for how a remotely located L9 improves translation fidelity. This mystery makes our picture of translation incomplete. Despite the high conservation of L9 in eubacteria, E.coli lacking L9 does not exhibit any obvious growth defects. Thus, the evolutionary advantage conferred by L9 in bacteria is masked under laboratory conditions. In order to uncover unique L9-dependent conditions, a library of E. coli mutants was screened to isolate those that rely on L9 for fitness. Interestingly, factors found to be synergistic with L9 had no known role in fidelity. Six independent mutants were isolated, each exhibiting a severe growth defect that is partially suppressed in the presence of L9. One class of L9-dependent mutations was present in an essential ribosome biogenesis factor, Der. Der's established function is in the maturation of the large ribosomal subunit. The identified mutations severely impaired the GTPase activity of Der. Interestingly, L9 did not directly compensate for the defective GTPase activity of mutant Der. The second class of L9-dependent mutations was present in EpmA and EpmB, factors required to post-translationally modify elongation factor, EF-P. EF-P's established function is in the translation of poly-proline containing proteins. EF-P deficient cells were nearly inviable in the absence of L9; however, L9 did not directly influence poly-proline translation. Therefore, in each case, L9 improved cell health without altering the activity of either Der or EF-P. Remarkably, the der mutants required only the N domain of L9, whereas the absence of active EF-P required full-length, wild-type L9 for growth complementation. Thus, each mutant class needed a different aspect of L9's unique architecture. In cells lacking either active EF-P or Der, there was a severe deficiency of 70S ribosomes and the indication of small subunit maturation defects, both of which worsened upon L9 depletion. These results strongly suggest that L9 plays a role in improving ribosome quality and abundance under certain conditions. Overall, the genetic screen lead to the discovery that bacteria need L9 when either of two important translation factors (Der or EF-P) is inactivated. This work has characterized the physiological requirement for L9 in each case and offers a new insight into L9's assigned role in translation fidelity.