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Winterfest in Kennebunk

January 27 FROSTED! a freezing good time at7pm at The Boathouse Watefront Hotel – the kick-off event of Kennebunkport’s Paint the Town Red month, this 4th Annual Ice Bar party is Saturday, tickets are $55 in advance , forice bar with luge, light snacks, s’mores hot chocolate bars, entertainment, and two signature drink tickets.

January 27 FROSTED!

Feb 3 Bubbles Truffles with Chef Pierre Gignac –Join theChef from Ocean at Cape Arundel Inn, for sparkling wine and chocolate truffles, $40 pp, held at Grand Hotel 1-3pm.

Feb 3 Bubbles Truffles with Chef Pierre Gignac

Feb 3 TASTES OF ITALY + WINE PAIRING 3-5 at Ports of Italy . Chef German Luca shares four wines with travel tasting tips. $45

Feb 3 TASTES OF ITALY + WINE PAIRING

Feb 9 Worlds Collide Wine Tasting 5-7 at Old Vines Wine Bar $50 per person, includes six 3oz wine pours, light appetizers.

Feb 10 Soup Snow Stroll 9-11 Join Kennebunk Land Trust, Boulangerie, a Proper Bakery, and Ramblers Way for a snow shoe or walk at the Mousam River Wildlife Sanctuary then enjoy a warm drink, a cup of soup and sweets at Boulangerie.

Feb 10 Soup Snow Stroll

Feb 10 Wines Valentines 1-3, at Kennebunkport Inn enjoy wine tastings small plates with the culinary team at The Burleigh, $15.

Feb 10 Wines Valentines

Feb 10 MAKE THE PERFECT COCKTAIL 1-3 , Old Vines Wine Bar. $60 per person, includes three cocktails, light appetizers, reserve in advance. Old Vines Wine Bar .

Feb 10 MAKE THE PERFECT COCKTAIL

Feb 10 Date Skate 4-6 Skating at the Waterhouse Center with a live DJ.

Feb 10 Date Skate

Feb 10 Earth at Hidden Pond Pop Up Winter Dinner at 6, at Lodge on the Cove – Chef Joe Shafer debuts Earth’s 2018 menu in a Three-Course family-style dinner, $125.

Feb 10 Earth at Hidden Pond Pop Up Winter Dinner

Feb 10 TASTES OF ITALY + WINE PAIRING 3-5 at Ports of Italy . Chef German Luca shares four wines with travel tasting tips. $45

Feb. 13 14 FRENCH FAMILY DINNER 6 – 9at Old Vines Wine Bar . Chef Joel and his team will prepare a classic French four-course dinner, served family-style. $79.

Feb 15 Alisson’s Restaurant Choose Your Own Adventure Beer Dinner , with Orono Brewing Company t a do-what-you-want beer dinner! Offering Orono brews with suggested food pairings, all a la carte.

Feb 17 Drinking through the Decades1-3, at Kennebunkport Inn – learn to make five decades of cocktails at The Burleigh, $40.

Patient 1, a female, was born in 2011 in Sheffield, United Kingdom, to consanguineous Pakistanian parents (first cousins). There were two healthy brothers. An echogenic bowel was seen on the prenatal ultrasound, and no other problems were noted. The patient suffered from congenital diarrhea since the first days of life and failed to thrive. Severe diarrhea ameliorated when getting nil by mouth but recurred 2 days after any feed. A homozygous STXBP2 mutation, c.37+1G>A, affecting the canonical donor splice site of intron 1 and being absent from EXAC and dbSNP databases was identified in the patient, establishing the diagnosis of FHL5. Within the first year of life she underwent allogenic stem cell transplantation for hemophagocytic lymphohistiocytosis (HLH). Afterward, she required total parental nutrition. The patient died at the age of 13 months of unknown cause that was supposedly related to disease after transplant. Sequencing the whole-coding region and flanking splice sites revealed no concomitant mutations in the MYO5B or STX3 genes. At the MYO5B locus, heterozygosity for 8 common SNPs and a common 3-bp indel variant were observed, demonstrating that the patient was heterozygous at this locus. Given the parental consanguinity and the negative sequence analysis, the results from direct and indirect DNA testing likely exclude MYO5B from playing a role in the disease pathogenesis in this patient. There were no private or rare variants seen in the other MVID gene STX3 .

Patient 2, a male, was reported previously ( 12 ). He was born to healthy consanguineous Turkish parents. Two older siblings had died from HLH disease in their first years of life. His twin brother and an older sister were apparently healthy. He developed diarrhea, pancytopenia, and fever, with signs of sepsis and disseminated intravascular coagulation without the identification of an infectious agent at the age of 3 weeks. Bone marrow morphology revealed hemophagocytosis. He received a HSCT from his HLA-matched older healthy sister at the age of 6 months. Targeted sequence analysis of the STXBP2 gene revealed a homozygous 3-bp deletion in exon 9 (c.693_695delGAT; p.Ile232del) completely hampering the binding of Munc18 to Stx11, as described previously ( 3 ). Later, exome sequencing confirmed the presence of this STXBP2 mutation and indicated the presence of a 50% degree of chimerism. There were no private or rare variants seen in the MVID genes MYO5B and STX3 .

Patient 3, a male, was born at term in 2014 as the second child of nonconsanguineous parents. His older brother was healthy. In the first week of life, he developed feeding problems, vomiting, and profuse watery diarrhea. During the first weeks, watery diarrhea persisted, and he was hospitalized three times because of dehydration, weight loss, and metabolic acidosis, despite elemental formula. Total parenteral nutrition was started, and an upper gastrointestinal endoscopy was performed at week 6 because of clinical suspicion of MVID. Duodenal biopsies revealed an intact brush-border membrane of the duodenum but subtle chronic inflammation, with microgranulomas in stomach and duodenum. At week 7, he deteriorated (fever, hepatosplenomegaly, pancytopenia, increased liver enzymes and ferritin) and was suspected of HLH. Treatment was started with dexamethasone, cyclosporin, and etoposide, with improvement of laboratory results as well as better tolerance of enteral feeding. Genetic analysis showed a homozygous c.902+5G>A mutation in STXBP2 , consistent with FHL type 5 ( 28 ). At 4 months of age he had an uncomplicated allogeneic HSTC (his brother was donor). Six months after the HSCT, he again developed feeding problems with vomiting, diarrhea, and failure to thrive. Enteral feeding by nasogastric tube was not tolerated, and a nasoduodenal tube had to be placed.

These results indicate a pivotal role of Munc18 for cognate t-/v-SNARE interaction and subsequent membrane fusion, e.g., cargo vesicles/Slp4a and the apical plasma membrane/Stx3. In respect to this, the Ile232del mutant of Munc18 rendered the protein dysfunctional regarding v-/t-SNARE–mediated membrane fusion.

Loss of Munc18 selectively disrupts apical cargo trafficking. In MVID, disturbed interaction of Slp4a/Stx3 in apical fusion processes was previously shown to impair the trafficking and localization of apical transmembrane transporters in enterocytes ( 26 ), e.g., sodium-hydrogen exchanger 3 (NHE3) and glucose transporter 5 (GLUT5), which are relevant for enterocyte physiology ( 35 37 ). Therefore, we further analyzed the localization of these proteins in Munc18-KO cells. Porous filter supports were used in order to allow establishment of enterocyte monolayer polarity. Indeed, loss of Munc18 resulted in a redistribution of normally apically destined NHE3 and GLUT5 proteins to a diffuse cytoplasmic localization ( Figure 6, A and B ). However, the localization of the brush-border enzyme dipeptidylpeptidase 4 (DPPIV) remained unaffected at the apical plasma membrane ( Sale Footlocker Philosophy Di Lorenzo Serafini striped sleeveless jumpsuit Lowest Price For Sale aTrDtAJN
).

Figure 6

Munc18 is pivotal for selective apical cargo transport of brush-border enzymes. () HS-NHE3 is found at the apical brush border in CaCo2 WT cells but redistributes toward the cytoplasm upon Munc18 deletion (gMunc18). () Apical GLUT5 mislocalizes in Munc18-KO cells, while DPPIV localizes correctly at the brush border. () NHE3 and DPPIV localize to the brush border in healthy duodenal enterocytes. NHE3, but not DPPIV, mislocalizes in FHL5 enterocytes. () Brush-border microvilli are indicated by actin staining. Scale bar: 10 μm.

Analogously, we analyzed the distribution of NHE3 and DPPIV in FHL5 duodenal biopsies. In patient 2, immunofluorescence microscopy showed NHE3 throughout the cytoplasm in contrast to age-matched controls, whereas DPPIV was found at the brush border in the FHL5 patient and control samples ( Frency amp; Mercury Its Life glasses Free Shipping Clearance Free Shipping Great Deals Supply DaM2uNKw
). Complementary immuno-EM investigation of samples from FHL5 patients 1, 2, and 4 identified NHE3 at the subapically clustering vesicles and tubules ( Prabal Gurung fringed sleeves top Pay With Visa Online Buy Cheap Popular Low Shipping Cheap Price 7s8YJEQcj
) and, to a minor extent, at the apical microvilli and the endoplasmatic reticulum. Moreover, Rab11 and Stx3 localized preferentially as well at the subapical vesicles and tubules in these FHL5 patient samples ( Supplemental Figure 2, D–I ), similar to the patterns reported in MVID patients ( 17 ). Control samples showed normal marker distribution ( Supplemental Figure 2, J–L ).

Collectively, mutations in Munc18 in FHL5 patients or loss of Munc18 in vitro resulted in disrupted SNARE-mediated apical fusion of cargo vesicles and, therefore, in a mislocalization of brush-border transporters relevant for physiological enterocyte function ( Ann Demeulemeester Norwood skirt Wide Range Of Clearance Excellent Outlet Sale j1Akzv
). Therefore, we propose that, in addition to the disturbed polarity of patients’ enterocytes, e.g., shortening or absence of brush-border microvilli, the disrupted trafficking of brush-border transporters, such as NHE3, might contribute to the enteropathy seen in patients.

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