Among the 22 fibroblast growth factors (FGFs), FGF21 has now emerged as a key metabolic regulator. However, the mechanism whereby FGF21 mediates its metabolic actions per se remains largely unknown. Here, we show that FGF21 represses mammalian target of rapamycin complex 1 (mTORC1) and improves insulin sensitivity and glycogen storage in a hepatocyte-autonomous manner. Administration of FGF21 in mice inhibits mTORC1 in the liver, whereas FGF21-deficient mice display pronounced insulin-stimulated mTORC1 activation and exacerbated hepatic insulin resistance (IR). FGF21 inhibits insulin- or nutrient-stimulated activation of mTORC1 to enhance phosphorylation of Akt in HepG2 cells at both normal and IR condition. TSC1 deficiency abrogates FGF21-mediated inhibition of mTORC1 and augmentation of insulin signaling and glycogen synthesis. Strikingly, hepatic βKlotho knockdown or hepatic hyperactivation of mTORC1/ribosomal protein S6 kinase 1 abrogates hepatic insulin-sensitizing and glycemic-control effects of FGF21 in diet-induced insulin-resistant mice. Moreover, FGF21 improves methionine- and choline-deficient diet-induced steatohepatitis. Conclusions: FGF21 acts as an inhibitor of mTORC1 to control hepatic insulin action and maintain glucose homeostasis, and mTORC1 inhibition by FGF21 has the therapeutic potential for treating IR and type 2 diabetes.

ObjectiveThis study aimed to explore the effects of lncRNA ANRIL on vascular endothelial growth factor (VEGF) and angiogenesis in diabetes mellitus (DM) combined with cerebral infarction (CI) through NF-κB signaling pathway.MethodsAdult male Wistar rats were randomly divided into control group and DM + CI group, and the DM + CI group were subdivided into Vector, shANRIL, PDTC, pcDNA-ANRIL, and pcDNA-ANRIL + PDTC groups. VEGF and FMS-like tyrosine kinase (FLT-1) expressions were measured by immunohistochemistry and endothelium dependent microvessel density (MVD) was detected by differentiation 31 (CD31) and para-amiuosalicylic acid (PAS) double staining. The qRT-PCR was applied to measure mRNA expressions of VEGF, FLT-1, Kinase insert domain protein receptor (FLK-1) and NF-κB, and Western blotting was conducted to detected expressions of VEGF, NF-κB and p-I?B/I?B.ResultsCompared with the control group, protein expressions of VEGF, NF-κB, p-I?B/I?B, expression of ANRIL, and mRNA expressions of VEGF, FLT-1 and NF-κB were increased in the DM + CI group. Compared with the Vector group, protein expressions of VEGF, NF-κB, p-I?B/I?B, expression of ANRIL, mRNA expressions of VEGF, FLT-1 and NF-κB, and endothelium dependent MVD were increased in the pcDNA-ANRIL group, while decreased in the shANRIL group and PDTC group. Compared with the pcDNA-ANRIL group, protein expressions of VEGF, NF-κB, p-I?B/I?B, expression of ANRIL, mRNA expressions of VEGF, FLT-1 and NF-κB, and endothelium dependent MVD were decreased in the pcDNA-ANRIL + PDTC group.ConclusionOverexpressed lncRNA ANRIL upregulates VEGF and promotes angiogenesis by activating NF-κB signaling pathway in DM + CI rats.

The B7 family ligand HERV-H LTR–associating protein 2 (HHLA2) is an attractive target for cancer immunotherapy because of its coinhibitory function, overexpression in human cancers, and association with poor prognoses. However, the knowledge of the HHLA2 pathway is incomplete. HHLA2 has an established positive receptor transmembrane and immunoglobulin (Ig) domain containing 2 (TMIGD2) but a poorly characterized negative receptor human killer cell Ig-like receptor, three Ig domains, and long cytoplasmic tail (KIR3DL3). Here, KIR3DL3 and TMIGD2 simultaneously bound to different sites of HHLA2. KIR3DL3 was mainly expressed on CD56dim NK and terminally differentiated effector memory CD8+ T (CD8+ TEMRA) cells. KIR3DL3+ CD8+ TEMRA acquired an NK-like phenotype and function. HHLA2 engagement recruited KIR3DL3 to the immunological synapse and coinhibited CD8+ T and NK cell function and killing, inducing immune-evasive HHLA2+ tumors. KIR3DL3 recruited SHP-1 and SHP-2 to attenuate Vav1, ERK1/2, AKT, and NF-κB signaling. HHLA2+ tumors from human kidney, lung, gallbladder, and stomach were infiltrated by KIR3DL3+ immune cells. KIR3DL3 blockade inhibited tumor growth in multiple humanized mouse models. Thus, our findings elucidated the molecular and cellular basis for the inhibitory function of KIR3DL3, demonstrating that the KIR3DL3-HHLA2 pathway is a potential immunotherapeutic target for cancer.

We show that a random 4-regular graph asymptotically almost surely (a.a.s.) has chromatic number 3. The proof uses an efficient algorithm which a.a.s. 3-colours a random 4-regular graph. The analysis includes use of the differential equation method, and exponential bounds on the tail of random variables associated with branching processes. A substantial part of the analysis applies to random d-regular graphs in general. † Current address: Achlioptas and Moore [1] showed that P(χ = 3) for a random graph in G n,4 is bounded below by a positive constant. In this paper, we obtain results on a class of algorithms which colour d-regular graphs for general d and obtain in particular the following 'best possible' result for d = 4. Theorem 1.1. A random 4-regular graph a.a.s. has chromatic number 3.We also give a simple algorithm which a.a.s. colours a random 4-regular graph with three colours, based on a greedy colouring scheme (as proved in Theorem 10.1). Our analysis, expressed as it is in terms of k-colouring a random graph in G n,d for arbitrary fixed d, lays the groundwork for a more general result which will appear in a sequel to this paper. This paper contains those portions of the analysis for which the generalization to arbitrary d is trivial.For completeness, we point out that random 2-regular and 3-regular graphs are a.a.s. not bipartite, as shown by the distribution of short odd cycles (see, for example, Bollobás [3] or [12, Section 2]). Thus they a.a.s. have chromatic number 3. This is immediate for the 2-regular case; random 3-regular graphs have no K 4 a.a.s., and so Brooks' theorem reduces the upper bound to 3.Our starting point is an algorithm Colour(k) which greedily colours the vertices of a graph, using colours 1, . . . , k, in the following manner. At any point in the algorithm, the type of a vertex v is the pair (i, j) where i is the number of coloured neighbours and j is the number of colours, of 1, . . . , k, not available (i.e., already used on the neighbours of v). The algorithm takes as input an ordering of the possible types, as a list of priorities, and then repeatedly randomly chooses an uncoloured vertex of the highest-priority type and colours it with one of its available colours chosen at random. The algorithm fails if it runs out of available colours, but in that case, for convenience, we demand that it proceeds using a colour from one of the neighbours (so the resulting colouring is not proper). This algorithm does succeed, on random regular graphs, if k is large enough. However, we can improve upon this slightly. What we can do is eliminate the difficulty caused near the end of the algorithm by the occurrence of short odd cycles formed by the uncoloured vertices. If all vertices in such a cycle happen to have only the same two colours available, the algorithm will fail. This type of failure prevented Achlioptas and Moore [1], who analysed a related algorithm, from being able to show that a random 4-regular graph on n vertices is a.a.s. 3-colourable.As it turns out, a simple remedy, alg...

Collateral status is an independent predictor of stroke outcome. However, the spatiotemporal manner in which collateral flow maintains cerebral perfusion during cerebral ischemia is poorly understood. Diabetes exacerbates ischemic brain damage, although the impact of diabetes on collateral dynamics remains to be established. Using Doppler optical coherent tomography, a robust recruitment of leptomeningeal collateral flow was detected immediately after middle cerebral artery (MCA) occlusion in C57BL/6 mice, and it continued to grow over the course of 1 week. In contrast, an impairment of collateral recruitment was evident in the Type 2 diabetic db/db mice, which coincided with a worse stroke outcome compared with their normoglycemic counterpart db/ϩ, despite their equally well-collateralized leptomeningeal anastomoses. Similar to the wild-type mice, both db/ϩ and db/db mice underwent collateral growth 7 d after MCA stroke, although db/db mice still exhibited significantly reduced retrograde flow into the MCA territory chronically. Acutely induced hyperglycemia in the db/ϩ mice did not impair collateral flow after stroke, suggesting that the state of hyperglycemia alone was not sufficient to impact collateral flow. Human albumin was efficacious in improving collateral flow and outcome after stroke in the db/db mice, enabling perfusion to proximal MCA territory that was usually not reached by retrograde flow from anterior cerebral artery without treatment. Our results suggest that the impaired collateral status contributes to the exacerbated ischemic injury in mice with Type 2 diabetes, and modulation of collateral flow has beneficial effects on stroke outcome among these subjects.

Abstract. We propose a simple and optimized method for acquiring a wide velocity range of blood flow using Doppler optical microangiography. After characterizing the behavior of the scanner in the fast scan axis, a step-scanning protocol is developed by utilizing repeated A-scans at each step. Multiple velocity range images are obtained by the high-pass filtering and Doppler processing of complex signals between A-scans within each step with different time intervals. A phase variance mask is then employed to segment meaningful Doppler flow signals from noisy phase background. The technique is demonstrated by imaging in vivo mouse brain with skull left intact to provide bidirectional images of cerebral blood flow with high quality and wide velocity range. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

Moyamoya disease (MMD) involves progressive occlusion of the intracranial internal carotid artery resulting in formation of moyamoya-like vessels at the base of the brain. It can be characterized by hemorrhage or ischemia. Direct vascular bypass is the main and most effective treatment of MMD. However, patients with MMD differ from those with normal cerebral vessels. MMD patients have unstable intracranial artery hemodynamics and a poor blood flow reserve; therefore, during the direct bypass of superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis, perioperative risk factors and anesthesia can affect the hemodynamics of these patients. When brain tissue cannot tolerate a high blood flow rate, it becomes prone to hyperperfusion syndrome, which leads to neurological function defects and can even cause intracranial hemorrhage in severe cases. The brain tissue is prone to infarction when hemodynamic equilibrium is affected. In addition, bypass vessels become susceptible to occlusion or atrophy when blood resistance increases. Even compression of the temporalis affects bypass vessels. Because the STA is used in MMD surgery, the scalp becomes ischemic and is likely to develop necrosis and infection. These complications of MMD surgery are difficult to manage and are not well understood. To date, no systematic studies of the complications that occur after direct bypass in MMD have been performed, and reported complications are hidden among various case studies; therefore, this paper presents a review and summary of the literature in PubMed on the complications of direct bypass in MMD.

We report non-invasive 3D imaging of capillary blood flow within human finger cuticle by the use of Doppler optical microangiography (DOMAG) and ultra-high sensitive optical microangiography (UHS-OMAG) techniques. Wide velocity range DOMAG method is applied to provide RBC axial velocity mapping in capillary loops with ranges of ±0.9 mm/s and ±0.3 mm/s. Additionally, UHS-OMAG technique is engineered to acquire high resolution image of capillary morphology. The presented results are promising to facilitate clinical trials of treatment and diagnosis of various diseases such as diabetes, Raynaud's phenomenon, and connective tissue diseases by quantifying cutaneous blood flow changes within human finger cuticle. Maximum projection image of the bidirectional RBC axial velocity mapping in the human finger cuticle capillaries.