Laryngopharyngeal reflux disease:Updated examination of mechanisms,pathophysiology,treatment,and association with gastroesophageal reflux disease

Laryngopharyngeal reflux disease(LPRD)is an inflammatory condition in the laryngopharynx and upper aerodigestive tract mucosa caused by reflux of stomach contents beyond the esophagus.LPRD commonly presents with symptoms such as hoarseness,cough,sore throat,a feeling of throat obstruction,excessive throat mucus.This complex condition is thought to involve both reflux and reflex mechanisms,but a clear understanding of its molecular mechanisms is still lacking.Currently,there is no standardized diagnosis or treatment protocol.Therapeutic strategies for LPRD mainly include lifestyle modifications,proton pump inhibitors and endoscopic surgery.This paper seeks to provide a comprehensive overview of the existing literature regarding the mechanisms,pathophysiology and treatment of LPRD.We also provide an in-depth exploration of the association between LPRD and gastroesophageal reflux disease.

Laser ultrasonic testing for near-surface defects inspection of 316L stainless steel fabricated by laser powder bed fusion

The laser powder bed fusion(L-PBF)method of additive manufacturing(AM)is increasingly used in various industrial manufacturing fields due to its high material utilization and design freedom of parts.However,the parts produced by L-PBF usually contain such defects as crack and porosity because of the technological characteristics of L-PBF,which affect the quality of the product.Laser ultrasonic testing(LUT)is a potential technology for on-line testing of the L-PBF process.It is a non-contact and non-destructive approach based on signals from abundant waveforms with a wide frequency-band.In this study,a method of LUT for on-line inspection of L-PBF process was proposed,and a system of LUT was established approaching the actual environment of on-line detection to evaluate the method applicability for defects detection of L-PBF parts.The detection results of near-surface defects in L-PBF 316L stainless steel parts show that the crack-type defects with a sub-millimeter level within 0.5 mm depth can be identified,and accordingly,the positions and dimensions information can be acquired.The results were verified by X-ray computed tomography,which indicates that the present method exhibits great potential for on-line inspection of AM processes.

Adaptive strategy of Nitraria sibirica to transient salt,alkali and osmotic stresses via the alteration of Na+/K+fluxes around root tips

Nitraria sibirica Pall.is an important shrub with a strong salt-alkali tolerance,but the mechanism underlying this tolerance remains obscure.In this study,N.sibirica,with salt-sensitive Vigna radiata(Linn.)Wilczek as the control,was subjected to transient salt stress(100 mM NaCl),alkali stress(50 mM Na_(2)CO_(3)),and osmotic stress(175 mM mannitol).The ionic fluxes of Na^(+)and K^(+)in the root apical region were measured.Results show that,under salt and alkali stress,N.sibirica roots exhibited higher capacities to limit Na+influx and reduce K+efflux,thereby resulting in lower Na^(+)/K^(+)ratios compared with V.radiata roots.Alkali stress induced stronger Na^(+)influx and K+efflux in the root salt stress treatment;Na^(+)influx was mainly observed in the root cap,while K^(+)efflux was mainly observed in the elongation zone.While under osmotic stress,N.sibirica roots showed stronger Na+efflux and weaker K+efflux than V.radiata roots.Na+efflux was mainly observed in the root elongation zone,while K+efflux was in the root cap.These results reveal the ionic strategy of N.sibirica in response to transient salt,alkali,and osmotic stresses through the regulation of Na+/K+flux homeostasis.

Prior exposure to ciprofloxacin disrupts intestinal homeostasis and predisposes ayu(Plecoglossus altivelis)to subsequent Pseudomonas plecoglossicida-induced infection

With the rapid development of intensive farming,the aquaculture industry uses a great many antibiotics for the prevention and treatment of bacterial diseases.Despite their therapeutic functions,the overuse and accumulation of antibiotics also pose a threat to aquaculture organisms.In the present study,ayu(Plecoglossus altivelis)was used as a fish model to study the impacts of ciprofloxacin(CIP)overuse on intestinal homeostasis and immune response during subsequent Pseudomonas plecoglossicida infection.Based on 16S rRNA gene amplification and Illumina sequencing,we found that CIP pre-exposure caused significant variation in intestinal microbiota,including increased species richness,altered microbiota composition and interaction networks,and increased metabolic dysfunction.Furthermore,immunohistochemical analysis indicated that CIP pre-exposure resulted in severe mucosal layer damage,goblet cell reduction,and epithelial cell necrosis of the intestinal barrier in infected ayu.Quantitative real-time polymerase chain reaction(qRT-PCR)showed that disruption of intestinal homeostasis impaired systemic antiinfection immune responses in the intestine,gill,spleen,and head kidney,while inhibiting IL-1β,TNF-α,and IL-10 expression and promoting TGF-βexpression.Our findings indicated that CIP administration can directly affect intestinal microbiota composition and intestinal integrity in ayu fish.This perturbation of intestinal homeostasis is likely responsible for the lower survival rate of hosts following subsequent infection as the capacity to mount an effective immune response is compromised.This study also provides preliminary clues for understanding the effects of antibiotic overuse on higher vertebrates through trophic transfer.

Leukocyte cell-derived chemotaxin 2 inhibits development of atherosclerosis in mice

Leukocyte cell-derived chemotaxin 2 (LECT2), a multifunctional hepatokine, is involved in many pathological conditi ons. However, its role in atherosclerosis remains undefined. In this study, we admimistered vehicle or LECT2 to male Apoe^-/- mice fed a Western diet for 15 weeks. Atherosclerotic lesions were visualized and quantified with Oil-red O and hematoxylin staining. The mRNA expression levels of MCP-1, MMP-1, IL-8 IL-1β, and TNF-a were analyzed by quantitative real-time polymerase chain reaction. Serum TNF-a, IL-1β, IL-8, MCP-1, and MMP-1 concentrations were measured by en zyme-li nked immuno sorbent assay. CD68, CD31, and a-SMA, markers of macrophages, endothelial cells, and smooth muscle cells, respectively, were detected by immuno staining. Results showed that LECT2 reduced total cholesterol and low-density lipoprotein concentrations in serum and inhibited the development of atherosclerotic lesions, accompanied by reductions in inflammatory cytokines and lower MCP-1, MMP-1, TNF-a, IL-8, and IL-1β mRNA abundanee. Furthermore, LECT2 decreased CD68, but in creased cr SMA in atherosclerotic lesi ons, suggesting an in crease in smooth muscle cells and reduction in macrophages. In summary, LECT2 inhibited the development of atherosclerosis in mice, accompanied by reduced serum total cholesterol concentration and lower inflammatory responses.

TLR2 was overexpressed independent of IL-6 in patients with valvular atrial fibrillation

Toll-like receptor 2 （TLR2） has recently been shown to be up-regulated in patients with non-valvular atrial fi-brillation （AF）. The present study was aimed to determine whether the pathogenesis and development of AF is associated with the up-regulation of TLR2. Clinical data and right atrial appendage （RAA） specimens were col-lected from 20 patients with persisten AF （PeAF）, 15 patients with paroxysmal AF （PaAF） and 13 patients with no history of AF undergoing valvular replacement. The results showed that gene expression and protein content of TLR2 were increased in both the AF subgroups, compared with the sinus rhythm （SR） group. Between the two AF subgroups, PaAF had a higher TLR2 level than PeAF. However, no difference in interluekin （IL）-6 content was found among the three groups, and no correlation was found between TLR2 and IL-6 in PeAF patients （r = 0.090, P = 0.706）, PaAF patients （r = 0.408, P = 0.131） and AF patients （r = -0.301, P = 0.079）. Immunohistochemical analysis revealed that TLR2 was distributed in RAAs of AF patients and confirmed the immunoblotting results. In conclusion, we demonstrated that TLR2 was elevated in AF （especially PaAF） patients with valvular heart disease, further implicating inflammation involved in the pathogenesis and development of AF.

Prevalence and Spectrum of Complex Congenital Heart Disease in the Neonatal Intensive Care Unit at High Altitude in China

Background:Previous studies from high altitudes have reported significantly higher prevalence of congenital heart disease(CHD),consisting almost solely of simple CHD.Little is known about the occurrence of complex CHD.Neonates with complex CHD are likely admitted to NICU.We examined the prevalence and spectrum of complex CHD in NICU in order to depict a truer picture of CHD at high altitude.Methods:We reviewed charts of 4,214 neonates admitted to NICU in Qinghai province(average altitude 3,000 m).Echocardiography was performed in 1,943 babies when CHD was suspected based on clinical examinations.Results:CHD was diagnosed in 1,093(56.3%of echoed babies).Mild CHD in 96.8%(1058 babies).Moderate CHD in 0.8%(9)included 1(0.1%)large secundum atrial septal defect,3(0.3%)moderate pulmonary stenosis,2(0.2%)aortic stenosis and 3(0.3%)partial anomalous pulmonary venous connection.Severe CHD in 2.4%(26)included 6(0.5%)complete atrioventricular septal defect,5(0.5%)complete transposition of the great arteries,5(0.5%)hypoplastic right heart,3(0.3%)hypoplastic left heart,3(0.3%)double outlet right ventricle,3(0.3%)tetralogy of Fallot,2(0.2%)truncus arteriosus,2(0.2%)total anomalous pulmonary venous connection,2(0.2%)severe aortic stenosis,2(0.2%)interrupted aortic arch and 2(0.2%)severe pulmonary stenosis and 1(0.1%)single-ventricle abnormality.At two-years follow-up in 737(67.4%)patients,18(90%)with severe CHD and 38(5.3%)with mild and moderate CHD died,and 15 underwent cardiac surgery with 1 early death.Conclusions:At high altitude,a wide spectrum of CHD exists,with many heretofore unreported complex CHD.There is urgent need for routine echocardiography and early interventions in newborns particularly in NICU.

3D bioprinting of cell-laden nano-attapulgite/gelatin methacrylate composite hydrogel scaffolds for bone tissue repair

Bone tissue engineering(BTE)has proven to be a promising strategy for bone defect repair.Due to its excellent biological properties,gelatin methacrylate(GelMA)hydrogels have been used as bioinks for 3D bioprinting in some BTE studies to produce scaffolds for bone regeneration.However,applications for load-bearing defects are limited by poor mechanical properties and a lack of bioactivity.In this study,3D printing technology was used to create nano-attapulgite(nano-ATP)/GelMA composite hydrogels loaded into mouse bone mesenchymal stem cells(BMSCs)and mouse umbilical vein endothelial cells(MUVECs).The bioprintability,physicochemical properties,and mechanical properties were all thoroughly evaluated.Our findings showed that nano-ATP groups outperform the control group in terms of printability,indicating that nano-ATP is beneficial for printability.Additionally,after incorporation with nano-ATP,the mechanical strength of the composite hydrogels was significantly improved,resulting in adequate mechanical properties for bone regeneration.The presence of nano-ATP in the scaffolds has also been stud-ied for cell-material interactions.The findings show that cells within the scaffold not only have high viability but also a clear proclivity to promote osteogenic differentiation of BMSCs.Besides,the MUVECs-loaded composite hydrogels demonstrated increased angiogenic activity.A cranial defect model was also developed to evaluate the bone repair capability of scaffolds loaded with rat BMSCs.According to histo-logical analysis,cell-laden nano-ATP composite hydrogels can effectively im prove bone regeneration and promote angiogenesis.This study demonstrated the potential of nano-ATP for bone tissue engineering,which should also increase the clinical practicality of nano-ATP.

Anisotropy of microstructures and mechanical properties in FeCoNiCr_(0.5)high-entropy alloy prepared via selective laser melting

The anisotropy of microstructures and mechani-cal properties of FeCoNiCr_(0.5)high-entropy alloys(HEAs)prepared by selective laser melting(SLM)were investigated in this study.An anisotropic microstructure was obtained for the as-built FeCoNiCr_(0.5) HEA sample.Specifically,in the XOY plane(perpendicular to the building direction),the{110}texture is dominant,and the grain size is mostly between 40 and 60μm with equiaxial morphology.In the XOZ plane(parallel to the building direction),columnar grains have a length of 80-100μm,and there is no obvious preferred orientation in the structure.This structure leads to anisotropic tensile behavior in the sample where the yield strength,tensile strength,and elongation of FeCoNiCr_(0.5)HEA in the XOY plane are 528 MPa,546 MPa,and 49%,respectively,whereas those in the XOZ plane are 547 MPa,642 MPa,and 28%,respectively.The effect of deformation twins on the evolution of the work-hardening rate is also discussed,considering the anisotropy condition.

Black TiO_(2) nanoprobe-mediated mild phototherapy reduces intracellular lipid levels in atherosclerotic foam cells via cholesterol regulation pathways instead of apoptosis

Given that apoptosis increases the risk of plaque rupture, strategies that reduce intracellular lipid levels without killing foam cells are warranted for safe and effective treatment of atherosclerosis. In this study, a mild pho-totherapy strategy is carried out to achieve the hypothesis. Foam cell-targeted nanoprobes that allow photo-thermal therapy (PTT) and/or photodynamic therapy (PDT) were prepared by loading hyaluronan and porphine onto black TiO_(2) nanoparticles. The results showed that when temperatures below 45 ◦C, PTT alone and PTT +PDT significantly reduced the intracellular lipid burden without inducing evidently apoptosis or necrosis. In contrast, the use of PDT alone resulted in only a slight reduction in lipid levels and induced massive apoptosis or necrosis. The protective effect against apoptosis or necrosis after mild-temperature PTT and PTT + PDT was correlated with the upregulation of heat shock protein 27. Further, mild-temperature PTT and PTT + PDT attenuated intracellular cholesterol biosynthesis and excess cholesterol uptake via the SREBP2/LDLR pathway, and also triggered ABCA1-mediated cholesterol efflux, ultimately inhibiting lipid accumulation in foam cells. Our results offer new insights into the mechanism of lipid regulation in foam cells and indicate that the black TiO_(2) nanoprobes could allow safer and more effective phototherapy of atherosclerosis.

Up-regulation of miR-1245 by c-myc targets BRCA2 and impairs DNA repair

BRCA2,a clinical prognostic factor,is significantly up-regulated in mRNA level,while its protein expression is often decreased in sporadic breast cancer.However,how BRCA2 protein expressions are suppressed in these tumors remains unknown.In this study,we demonstrated that miR-1245 directly suppressed BRCA23′-UTR and translation,impaired homologous recombination(HR)-mediated repair,reduced DNA damage-induced Rad51 nuclear foci,and rendered cells hypersensitive to g-irradiation(IR),ul-timately inducing high chromosomal abnormalities in normal breast cells and breast cancer cells.Conversely,inhibiting miR-1245 in breast cancer cells enhanced BRCA2 levels and induced resistance to IR.Furthermore,we demonstrated that c-myc up-regulated miR-1245 expression via direct binding to the miR-1245 promoter,which led to down-regulation of BRCA2 and reduction in HR efficiency.Significantly,miR-1245 levels in primary breast tumors correlated with c-myc overexpression and BRCA2 suppression.These findings uncover a BRCA2 regulatory and signaling pathway in sporadic breast cancer and support a functionally and clinically relevant epigenetic mechanism in cancer pathogenesis.

Polydopamine nanoparticle-mediated mild photothermal therapy for inhibiting atherosclerotic plaque progression by regulating lipid metabolism of foam cells

Since apoptosis of foam,cells can induce plaque instability,reducing intracellular lipid content while protecting foam cells from apoptosis is beneficial for the safe and efficient therapy of atherosclerosis.In this study,osteopontin-coupled polydopamine(PDA-OPN)nanoparticles were synthesized and applied to target mild photothermal therapy(PTT)of atherosclerosis.The results from laser confocal microscopy indicate that PDA-OPN nanoparticles can be specially recognized and absorbed by foam cells.Under near-infrared laser irradiation,the mild photothermal generated by PDA-OPN decreases intracellular lipid accumulation but does not induce cell apoptosis.In vivo treatments demonstrate that mild PTT can substantially reduce plaque area and improve plaque stability by upregulating the expression of plaque fibrosis in ApoE^(−/−)mice.Our findings reinforce that the PDA-OPN nanoparticle-mediated mild PTT can inhibit atherosclerotic progression,which provides new insights for developing safe and effective treatment methods for atherosclerosis.

An experimental study on effects of temperature gradient on microstructure of a 308L stainless steel manufactured by directed energy deposition

The effect of spatial temperature gradient on the microstructural evolution of a 308L stainless steel during the directed energy deposition(DED)process was experimentally investigated.A novel cooling system was designed and incorporated to a DED system in order to control the temperature gradient along the deposition direction during solidification.During deposition,the workpiece was placed on a lifting platform,and as the deposition process proceeded,the platform and workpiece were gradually lowered into cooling water so that the temperature gradient along the deposition direction could be controlled and maintained stable during the deposition process.The microstructure characterization results indicated that a deposition strategy with higher G and G/R values(where G is temperature gradient and R is solidification rate)produced finer cellular grains that were better aligned with the deposition direction,while a deposition strategy with lower G and G/R values produced columnar grains with larger primary arm spacing and less aligned with the deposition direction.