Terminal Peptide Research Articles

Association between non-alcoholic fatty liver disease and bone turnover markers in southwest China.

Non-alcoholic fatty liver disease (NAFLD) is not considered only a liver disease but also associated with an increased risk of extra-hepatic diseases including bone metabolism disorders. In our study, we aim to explore the changes of several bone turnover markers (BTMs) under different fat deposition and stiffness levels of the liver. We analyzed the physical examination data of 3353 subjects from February 2018 to June 2021 in this study. The steatosis and stiffness of liver were quantitatively detected using the fat attenuation parameter (FAP) and liver stiffness measurements (LSM) of transient elastography (TE). Serum 25-hydroxyvitamin D3 (25(OH)D3), osteocalcin, carboxy-terminal collagen crosslinks (CTX), amino terminal elongation peptide of total type 1 procollagen (P1NP) were tested. Clinical and other biochemical data were also collected. With the increasing of FAP, the levels of 25(OH)D3 and osteocalcin decreased, the difference was statistically significant. No correlation was found between LSM and all the four BTMs. Logistic regression analysis revealed that FAP ≥ 244dB/m was negatively correlated with 25(OH)D3 (in both males and females) and osteocalcin (only in males). No correlation was found between FAP ≥ 244dB/m and P1NP or CTX. The degree of liver adipose deposition was found to be negatively associated with the serum levels of 25(OH)D3 (in both males and females) and osteocalcin (only in males) in southwest China.

Synchronized diaphragmatic stimulation for heart failure using the VisONE system: a first-in-patient study.

AimsSynchronized diaphragmatic stimulation (SDS) modulates intrathoracic and intra‐abdominal pressures with favourable effects on cardiac function for patients with a reduced left ventricular ejection fraction (LVEF) and heart failure (HFrEF). VisONE‐HF is a first‐in‐patient, observational study assessing the feasibility and 1 year effects of a novel, minimally invasive SDS device.Methods and resultsThe SDS system comprises a pulse generator and two laparoscopically delivered, bipolar, active‐fixation leads on the inferior diaphragmatic surface. Fifteen symptomatic men with HFrEF and ischaemic heart disease receiving guideline‐recommended therapy were enrolled (age 60 [56, 67] years, New York Heart Association class II [53%] /III [47%], LVEF 27 [23, 33] %, QRSd 117 [100, 125] ms, & N terminal pro brain natriuretic peptide [NT‐proBNP] 1779 [911, 2,072] pg/mL). Implant success was 100%. Patients were evaluated at 3, 6, and 12 months for device‐related or lead‐related complications, quality of life (SF‐36 QOL), 6 min hall walk distance (6MHWd), and by echocardiography. No implant procedure or SDS‐related adverse event occurred, and patients were unaware of diaphragmatic stimulation. By 12 months, left ventricular end‐systolic volume decreased (136 [123, 170] mL to 98 [89, 106] mL; P = 0.05), 6MHWd increased (315 [300, 330] m to 340 [315, 368] m; P = 0.004), and SF‐36 QOL improved (physical scale 0 [0, 0] to 25 [0, 50], P = 0.006; emotional scale 0 [0, 33] to 33 [33, 67], P = 0.001). Although neither reached statistical significance, LVEF decreased (28 [23, 40]% vs. 34 [29, 38]%; P = ns) and NT‐proBNP was lower (1784 [920, 2540] pg/mL vs. 1492 [879, 2028] pg/mL; P = ns).ConclusionsThese data demonstrate the feasibility of laparoscopic implantation and delivery of SDS without raising safety concerns. These encouraging findings should be investigated further in adequately powered randomized trials.

Impact of B-lines-guided intensive heart failure management on outcome of discharged heart failure patients with residual B-lines.

AimsPulmonary congestion (PC) expressed by residual lung ultrasound B‐lines (LUS‐BL) could exist in some discharged heart failure (HF) patients, which is a known determinant of poor outcomes. Detection efficacy for PC is suboptimal with widely used imaging modalities, like X‐ray or echocardiography, while lung ultrasound (LUS) can sufficiently detect PC by visualizing LUS‐BL. In this trial, we sought to evaluate the impact LUS‐BL‐guided intensive HF management post‐discharge on outcome of HF patients discharged with residual LUS‐BL up to 1 year after discharge. IMP‐OUTCOME is a prospective, single‐centre, single‐blinded, randomized cohort study, which is designed to investigate if LUS‐BL‐guided intensive HF management post‐discharge in patients with residual LUS‐BL could improve the clinical outcome up to 1 year after discharge or not.Methods and resultsAfter receiving the standardized treatment of HF according to current guidelines, 318 patients with ≥3 LUS‐BL assessed by LUS within 48 h before discharge will be randomly divided into the conventional HF management group and the LUS‐BL‐guided intensive HF management group at 1:1 ratio. Patient‐related basic clinical data including sex, age, blood chemistry, imaging examination, and drug utilization will be obtained and analysed. LUS‐BL will be assessed at 2 month interval post‐discharge in both groups, but LUS‐BL results will be enveloped in the conventional HF management group, and diuretics will be adjusted based on symptom and physical examination results with or without knowing the LUS‐BL results. Echocardiography examination will be performed for all patients at 12 month post‐discharge. The primary endpoint is consisted of the composite of readmission for worsening HF and all‐cause death during follow up as indicated. The secondary endpoints consisted of the change in the New York Heart Association classification, Duke Activity Status Index, N terminal pro brain natriuretic peptide value, malignant arrhythmia event and 6 min walk distance at each designed follow up, echocardiography‐derived left ventricular ejection fraction, and number of LUS‐BL at 12 month post‐discharge. Safety profile will be recorded and managed accordingly for all patients.ConclusionsThis trial will explore the impact of LUS‐BL‐guided intensive HF management on the outcome of discharged HF patients with residual LUS‐BL up to 1 year after discharge in the era of sodium‐glucose cotransporter‐2 inhibitors and angiotensin receptor blocker‐neprilysin inhibitor.Trial Registration: ClinicalTrials.gov: NCT05035459

Characterization of critically ill patients with septic shock and sepsis-associated cardiomyopathy using cardiovascular MRI.

AimsSepsis‐induced cardiomyopathy is a major complication of septic shock and contributes to its high mortality. This pilot study investigated myocardial tissue differentiation in critically ill, sedated, and ventilated patients with septic shock using cardiovascular magnetic resonance (MR).Methods and resultsFifteen patients with septic shock were prospectively recruited from the intensive care unit. Individuals received a cardiac MR scan (1.5 T) within 48 h after initial catecholamine peak and a transthoracic echocardiography at 48 and 96 h after cardiac MR. Left ventricular ejection fraction was assessed using both imaging modalities. During cardiac MR imaging, balanced steady‐state free precession imaging was performed for evaluation of cardiac anatomy and function in long‐axis and short‐axis views. Native T1 maps (modified Look–Locker inversion recovery 5 s(3 s)3 s), T2 maps, and extracellular volume maps were acquired in mid‐ventricular short axis and assessed for average plane values. Patients were given 0.2 mmol/kg of gadoteridol for extracellular volume quantification and late gadolinium enhancement imaging. Critical care physicians monitored sedated and ventilated patients during the scan with continuous invasive monitoring and realized breathholds through manual ventilation breaks. Laboratory analysis included high‐sensitive troponine T and N terminal pro brain natriuretic peptide levels. Twelve individuals with complete datasets were available for analysis (age 59.5 ± 16.9 years; 6 female). Nine patients had impaired systolic function with left ventricular ejection fraction (LVEF) < 50% (39.8 ± 5.7%), and three individuals had preserved LVEF (66.9 ± 6.7%). Global longitudinal strain was impaired in both subgroups (LVEF impaired: 11.0 ± 1.8%; LVEF preserved: 16.0 ± 5.8%; P = 0.1). All patients with initially preserved LVEF died during hospital stay; in‐hospital mortality with initially impaired LVEF was 11%. Upon echocardiographic follow‐up, LVEF improved in all previously impaired patients at 48 (52.3 ± 9.0%, P = 0.06) and 96 h (54.9 ± 7.0%, P = 0.02). Patients with impaired systolic function had increased T2 times as compared with patients with preserved LVEF (60.8 ± 5.6 ms vs. 52.2 ± 2.8 ms; P = 0.02). Left ventricular GLS was decreased in all study individuals with impaired LVEF (11.0 ± 1.8%) and less impaired with preserved LVEF (16.0 ± 5.8%; P = 0.01). T1 mapping showed increased T1 times in patients with LVEF impairment as compared with patients with preserved LVEF (1093.9 ± 86.6 ms vs. 987.7 ± 69.3 ms; P = 0.03). Extracellular volume values were elevated in patients with LVEF impairment (27.9 ± 2.1%) as compared with patients with preserved LVEF (22.7 ± 1.9%; P < 0.01).ConclusionsSeptic cardiomyopathy with impaired LVEF reflects inflammatory cardiomyopathy. Takotsubo‐like contractility patterns occur in some cases. Cardiac MR is safely feasible in critically ill, sedated, and ventilated patients using extensive monitoring and experienced staff.Trial Registration: retrospectively registered (ISRCTN85297773)

B-39 | BNP as a biomarker for pulmonary hypertension in a pediatric population

Amino terminal pro B-type natriuretic peptide (NT-proBNP) and brain B-type natriuretic peptide (BNP) are used as lab markers of cardiac wall tension and early studies indicate that it may be useful as a screening or surveillance test for pediatric pulmonary hypertension. This study is a prospective study of whether the serum level of BNP or NT-pro-BNP was associated with the severity and reactivity of pulmonary hypertension during catheterization of a population of pediatric patients with known or suspected pulmonary hypertension.

Early effects of ovariectomy on bone microstructure, bone turnover markers and mechanical properties in rats

BackgroundFragility fracture is one of the most serious consequences of female aging, which can increase the risk of death. Therefore, paying attention to the pathogenesis of postmenopausal osteoporosis (PMOP) is very important for elderly women.Methods and materialsForty 12-week-old female rats were divided into two groups including the ovariectomy (OVX) group and the control group. Four rats in each group were selected at 1, 4, 8, 12 and 16 weeks after operation. Vertebral bones and femurs were dissected completely for micro-Computed Tomography (micro-CT) scanning, biological modulus detection and histomorphological observation.ResultsIn OVX group, bone volume/total volume (BV/TV), bone trabecular connection density (Conn.D) and trabecular bone number (Tb.N) decreased significantly with time (P < 0.05). The elastic modulus of femur in OVX group was lower than that in control group, but there was no significant difference between them (P > 0.05). Over time, the tartrate resistant acid phosphatase (TRAP), osteocalcin (BGP), type I procollagen amino terminal propeptide (PINP) and type I collagen carboxy terminal peptide (CTX-I) in OVX group increased significantly (P < 0.05). The micrographs of the OVX group showed sparse loss of the trabecular interconnectivity and widening intertrabecular spaces with time.ConclusionThe bone loss patterns of vertebral body and femur were different in the early stage of estrogen deficiency. The bone turnover rate of OVX rats increased, however the changes of biomechanical properties weren’t obvious.

Reduced Circulating Levels of miR-491-5p and miR-485-3p Are Associated with the Occurrence of Vertebral Fractures in Postmenopausal Women with Osteoporosis.

Objective Postmenopausal women experiences osteoporotic structural damage and bone fragility resulting from reduced bone formation and increased bone resorption. Osteoporosis frequently affects the vertebral column and causes compression fractures. This study aims to characterize roles of miRNAs in osteoporosis and subsequent incidence risk of vertebral fractures for postmenopausal women. Methods. Differentially expressed miRNAs between osteoporotic patients with vertebral fractures and osteoporotic patients without fracture were identified. This retrospective study included 78 osteoporotic patients with vertebral fractures and 82 osteoporotic patients without vertebral fractures. The plasma levels of bone metabolic markers, 25-hydroxyvitamin D (25-(OH)VitD), propeptide of type I procollagen (PINP), and β-Carboxyl terminal peptide (β-CTx), were detected using the patented electro-chemiluminescence (ECLIA) method. The expression levels of miR-491-5p and miR-485-3p were determined by qRT-PCR. Pearson correlation analysis was carried out to assess the relationship between miR-491-5p, miR-485-3p, and bone metabolic markers. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to evaluate the performance of miR-491-5p and miR-485-3p in diagnosing the occurrence of vertebral fractures in osteoporotic patients.Results: The plasma levels of PINP and β-CTx were elevated but the plasma level of 25-(OH)VitD was declined in osteoporotic patients with vertebral fractures when comparable to those without (< 0.05). The plasma expression levels of miR-491-5p and miR-485-3p were declined osteoporotic patients with vertebral fractures when comparable to those without (< 0.001). Pearson correlation analysis revealed that the relative expression level of miR-491-5p was negatively correlated with the level of 25-(OH)VitD (r = -0.518, < 0.001) but positively correlated with the levels of PINP (r = 0.547, < 0.001) and β-CTx (r = 0.380, < 0.001). We also observed a negative correlation between the relative expression level of miR-485-3p and 25-(OH)VitD (r = -0.388, < 0.001), a positive correlation between miR-485-3p and PINP (r = 0.422,< 0.001). ROC curves for prediction of vertebral fracture following osteoporosis in postmenopausal women by miR-491-5p expression yielded 0.866 AUC and by miR-485-3p expression produced 0.848 AUC. Conclusion The data suggest that downregulated expressions of miR-491-5p and miR-485-3p may be involved in the occurrence of vertebral fractures in postmenopausal women with osteoporosis.

Estimation of the plasma volume status of elderly patients with acute decompensated heart failure using bedside clinical, biological, and ultrasound parameters.

Assessment of intravascular volume status to ensure optimization before hospital discharge could significantly reduce readmissions. It is difficult to evaluate congestion on clinical signs during an episode of acute heart failure (ADHF) in elderly patients. There is an association between various volume overload parameters in patients older than 75 years. We performed a single-center prospective longitudinal study of patients older than 75 years hospitalized for acute heart failure. We analyzed the association between congestion assessment based on clinical signs, inferior vena cava (IVC) diameter measured by ultrasound, biological evaluation with N terminal pro brain natriuretic peptide (NT-proBNP), and estimated plasma volume (EPV) during decongestive therapy. We also monitored changes in renal function. Fifty consecutive ADHF patients (85.2 ± 5.9 years, 68% female) were included in the study. At admission, a dilated, noncompliant IVC was found in all patients. The strongest correlations between different parameters of volume overload estimation were found between IVC and jugular vein distention (r = .8; p < .001), then IVC and oedema (r = .6; p < .001), IVC and crackles (r = .3; p < .036), then IVC and NT-proBNP (r = .3; p = .02). There was no correlation between EPV and signs of congestion. Patients who had no congestive signs on clinical or IVC examination at Day 2, more often presented with acute renal failure. In ADHF patients older than 75 years, clinical and IVC evaluation of intravascular congestion correlate well. The concomitant assessment of clinical signs and IVC may prevent depletion-related renal failure.

Crystal structures of human neuropeptide Y (NPY) and peptide YY (PYY)

Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) form the evolutionarily conserved pancreatic polypeptide family. While the fold is widely utilized in nature, crystal structures remain elusive, particularly for the human forms, with only the structure of a distant avian form of PP reported. Here we utilize a crystallization chaperone (antibody Fab fragment), specifically recognizing the amidated peptide termini, to solve the structures of human NPY and human PYY. Intriguingly, and despite limited sequence identity (~50%), the structure of human PYY closely resembles that of avian PP, highlighting the broad structural conservation of the fold throughout evolution. Specifically, the PYY structure is characterized by a C-terminal amidated α-helix, preceded by a backfolded poly-proline N-terminus, with the termini in close proximity to each other. In contrast, in the structure of human NPY the N-terminal component is disordered, while the helical component of the peptide is observed in a four-helix bundle type arrangement, consistent with a propensity for multimerization suggested by NMR studies.

α2δ-1 protein promotes synaptic expression of Ca2+ permeable-AMPA receptors by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension.

Glutamate AMPA receptors (AMPARs) lacking GluA2 subunit are calcium permeable (CP-AMPARs), which are increased in the hypothalamic paraventricular nucleus (PVN) and maintain sympathetic outflow in hypertension. Here, we determined the role of α2δ-1, an NMDA receptor-interacting protein, in regulating synaptic CP-AMPARs in the hypothalamus in spontaneously hypertensive rats (SHR). Co-immunoprecipitation showed that levels of GluA1/GluA2, but not GluA2/GluA3, protein complexes in hypothalamic synaptosomes were reduced in SHR compared with Wistar-Kyoto rats (WKY). The level of GluA1/GluA2 heteromers in endoplasmic reticulum-enriched fractions of the hypothalamus was significantly lower in SHR than in WKY, which was restored by inhibiting α2δ-1 with gabapentin. Gabapentin also switched AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs) from inward rectifying to linear and attenuated the inhibitory effect of IEM-1460, a selective CP-AMPAR blocker, on AMPAR-EPSCs in spinally projecting PVN neurons in SHR. Furthermore, co-immunoprecipitation revealed that α2δ-1 directly interacted with GluA1 and GluA2 in the hypothalamus of rats and humans. Levels of α2δ-1/GluA1 and α2δ-1/GluA2 protein complexes in the hypothalamus were significantly greater in SHR than in WKY. Disrupting the α2δ-1-AMPAR interaction with an α2δ-1 C terminus peptide normalized GluA1/GluA2 heteromers in the endoplasmic reticulum of the hypothalamus diminished in SHR. In addition, α2δ-1 C terminus peptide diminished inward rectification of AMPAR-EPSCs and the inhibitory effect of IEM-1460 on AMPAR-EPSCs of PVN neurons in SHR. Thus, α2δ-1 augments synaptic CP-AMPARs by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension. These findings extend our understanding of the molecular basis of sustained sympathetic outflow in neurogenic hypertension.

Vancomycin-Loaded Furriness Amino Magnetic Nanospheres for Rapid Detection of Gram-Positive Water Bacterial Contamination.

Bacterial pathogens pose high threat to public health worldwide. Different types of nanomaterials have been synthesized for the rapid detection and elimination of pathogens from environmental samples. However, the selectivity of these materials remains challenging, because target bacterial pathogens commonly exist in complex samples at ultralow concentrations. In this study, we fabricated novel furry amino magnetic poly-L-ornithine (PLO)/amine-poly(ethylene glycol) (PEG)-COOH/vancomycin (VCM) (AM-PPV) nanospheres with high-loading VCM for vehicle tracking and the highly efficient capture of pathogens. The magnetic core was coated with organosilica and functionalized with cilia. The core consisted of PEG/PLO loaded with VCM conjugated to Gram-positive bacterial cell membranes, forming hydrogen bonds with terminal peptides. The characterization of AM-PPV nanospheres revealed an average particle size of 56 nm. The field-emission scanning electron microscopy (FE-SEM) micrographs showed well-controlled spherical AM-PPV nanospheres with an average size of 56 nm. The nanospheres were relatively rough and contained an additional 12.4 nm hydrodynamic layer of PLO/PEG/VCM, which provided additional stability in the suspension. The furry AM-PPV nanospheres exhibited a significant capture efficiency (>90%) and a high selectivity for detecting Bacillus cereus (employed as a model for Gram-positive bacteria) within 15 min, even in the presence of other biocompatible pathogens. Moreover, AM-PPV nanospheres rapidly and accurately detected B. cereus at levels less than 10 CFU/mL. The furry nano-design can potentially satisfy the increasing demand for the rapid and sensitive detection of pathogens in clinical and environmental samples.

Clinical characteristics of patients with acute pulmonary embolism in high altitude area of Yunnan province in China

Objective: To analyze the clinical features of patients with acute pulmonary embolism (APE) living in high altitude area of Yunnan province. Methods: This was a cross-sectional retrospective study. APE patients, hospitalized in our hospital between January 2017 and December 2019, were included. The selected patients were divided into low-risk group, medium-risk group and high-risk group according to risk stratification. The clinical data of patients, including demographic data, the main symptoms, risk factors of APE, heart rate and systolic blood pressure and laboratory testing results (D-dimer, cardiac troponin I (cTNI), N terminal B-type natriuretic peptide (NT-proBNP)) and echocardiography and electrocardiogram examination results, were obtained through the electronic medical record system. The clinical characteristics of selected patients were analyzed. Results: A total of 392 patients, aged (63.5±15.7) years, 224 males (57.14%), were included in this study and there were 59 low-risk, 304 medium-risk and 29 high-risk patients in this cohort. The main clinical manifestations were chest pain (157(40.05%)), dyspnea (107(27.30%)), hemoptysis (55(14.03%)), syncope as the first symptom (20(5.10%)), and only 6 cases (1.53%) presented with the typical "Virchow's triad". Most of the patients were accompanied by atypical chest tightness (223(56.89%)) and cough (208(53.06%)). The main risk factors were venous thrombosis of lower limbs (179(45.66%)), hypertension (138(35.20%)), surgery (63(16.07%)), and chronic obstructive pulmonary disease (COPD) (62(15.82%)). There were 57 cases (14.54%) of coronary heart disease, 57 cases (14.54%) of diabetes, 51 cases (13.01%) of cerebral infarction, 47 cases (12.00%) of advanced age, 15 cases (3.83%) of tumor, 7 cases (1.79%) of activity restriction, 6 cases (1.53%) of pregnancy and 4 cases (1.02%) of hormone use in this cohort. The proportion of lower extremity venous thrombosis was significantly higher in low-risk group than in medium-risk group (P<0.01), COPD was more common in high-risk and medium-risk groups than in low-risk group (P<0.01), hypertension was more common in high-risk group than in medium-and low-risk groups (P<0.01). The proportion of advanced age was significantly higher in medium-risk group than in low-risk group (P<0.01). There were no significant differences in RBC and hemoglobin level between low-, medium-and high-risk groups (P>0.05). The level of D-dimer was significantly higher in high-risk group than in medium-and low-risk groups (P<0.05). Levels of NT-proBNP and cTNI were significantly higher in high-risk group than in medium- and low-risk groups (P<0.05). Increased proportion of cTNI and NT-proBNP was significantly higher in high-risk group than in medium- and low-risk groups (P<0.05). There were 105 (26.79%) patients with pulmonary hypertension (PAH). The incidence of PAH was significantly higher in high-risk group than in low-risk group (P<0.01). There were 104 patients (26.53%) with right ventricular enlargement, and the incidence of right ventricular enlargement was significantly higher in high-risk group than in medium-and low-risk groups (P<0.01). Characteristic changes of electrocardiogram in patient with APE were T-wave inversion of limb leads (98(25.00%)), followed by SⅠQⅢTⅢ (83(21.17%)). Conclusions: The main clinical manifestations of APE in Yunnan high altitude area are chest pain and dyspnea, and syncope is the first symptom in some patients, but the typical "Virchow's triad" is rare. The most common risk factors are lower extremity venous thrombosis, hypertension, and COPD. Clinical symptoms, risk factors and laboratory examination results differ among patients with different risk stratification.

Identification and Characterization of Differentially Expressed IgM Transcripts of Channel Catfish Vaccinated with Antigens of Virulent Aeromonas hydrophila

Channel catfish (Ictalurus punctatus) is the top species produced in US aquaculture and motile Aeromonas septicemia, caused by virulent Aeromonas hydrophila (vAh), is one of the most severe diseases that afflict catfish farms. Previously, vaccination of fish with extracellular proteins (ECP) of vAh was shown to produce a robust antibody-mediated immune response against vAh infection. In this study, we analyzed IgM transcripts that were differentially expressed in the head kidney and liver of ECP-immunized and mock-immunized (control) fish with emphasis on a variable domain of heavy chain. Quantitative PCR analysis indicated that immunized fish produced significantly more IgM transcripts than control fish. Full-length IgM heavy chain cDNA was cloned, which encoded typical IgM peptide, including signal peptide, variable domain (VH), constant domain (CH), and carboxyl terminal peptide. Great sequence diversity was revealed in a VH segment, with the third complementarity diversity region (CDR3) being most variable. Using germline VH gene grouping method, variants (clones) of VH characterized in this study belonged to nine VH families. The most unique variants (approximately 49%) were found in the VH2 family. Vaccinated fish apparently had more unique variants than in the control fish. There were 62% and 79% of unique variants in the head kidney and liver of vaccinated fish, respectively, while 44% and 27% unique variants in the head kidney and liver of control fish, respectively. Among the unique variants in VH2 family, approximately 87% of them were found in vaccinated fish. Two-dimensional gel electrophoresis of semi-purified IgM protein confirmed that matured IgM protein was as variable as IgM transcripts identified in this study, with isoelectric points crossing from 6 to 10. Results of this study provided insight into the molecular and genetic basis of antibody diversity and enriched our knowledge of the complex interplay between antigens and antibodies in Ictalurid catfish.

Structure and Peptidomes of Swine MHC Class I with Long Peptides Reveal the Cross-Species Characteristics of the Novel N-Terminal Extension Presentation Mode.

Antigenic peptide presentation by the MHC is essential for activating T cells. The current view is that the peptide termini are tethered within the closed Ag-binding groove of MHC class I (MHC-I). Recently, the N-terminal extension mode of peptide presentation has been observed in human MHC-I (HLA-I). In this study, we found that the N terminus of the long peptide can extend beyond the groove of swine MHC-I (SLA-1*0401), confirming that this phenomenon can occur across species. Removal of the N-terminal extra (P-1) residue of the RW12 peptide significantly reduced the folding efficiency of the complex, but truncation of the second half of the peptide did not. Consistent with previous reports, the second (P1) residue of the peptide is twisted, and its side chain is inserted into the A pocket to form two hydrogen bonds with polymorphic E63 and conserved Y159. Mutations of E63 disrupt the binding of the peptide, indicating that E63 is necessary for this peptide-binding mode. Compared with W167, which exists in most MHC-Is, SLA-I-specific S167 ensures an open N-terminal groove of SLA-1*0401, enabling the P-1 residue to extend from the groove. In this MHC class II-like peptide-binding mode, the A pocket is restrictive to the P1 residue and is affected by the polymorphic residues. The peptidomes and refolding data indicated that the open N-terminal groove of SLA-1*0401 allows one to three residues to extend out of the Ag-binding groove. These cross-species comparisons can help us better understand the characteristics of this N-terminal extension presentation mode.

A novel unique terminal ampullae-expressed insulin-like peptide in male white shrimp, Penaeus vannamei

In crustaceans, sex differentiation is primarily regulated by insulin-like peptide which is expressed in male-specific androgenic gland. And, the insulin signaling pathway is crucial in gonad development and reproduction. However, the information of sexual regulatory genes, involved in sex differentiation of Penaeidea, is still fragmented. In the present study, a novel insulin-like peptide, termed Pv-ILP, was identified from the white shrimp Penaeus vannamei and the effect of Pv-ILP knockdown on sex differentiation was explored. Firstly, the predicted Pv-ILP protein consists of a signal peptide, B chain, C peptide, and A chain in order, and it has a similar structural organization as identified crustacean insulin-like androgenic gland hormones (IAGs). Secondly, Pv-ILP had a closer relative to P. vannamei and Penaeus mondon IAG and was subgrouped with Penaeidea by phylogenetic tree analysis. The multiple sequence alignment results indicated that Pv-ILP showed relatively high sequence similarity with other Penaeidae. Meanwhile, Pv-ILP was exclusively expressed in the terminal ampullae and gradually increased with individual development. On the other hand, Pv-ILP knockdown in undifferentiated postlarvae did not achieve sex reversal, which was different from that of IAGs in prawns. Significantly, one up-regulated nuclear receptor, two down-regulated transcripts, vitellogenin receptor, and guanylate cyclase, were focused as differentially expressed unigenes after Pv-ILP knockdown. These data provide a more theoretical basis for elucidating the sex differentiation mechanism of crustaceans.

PLC, PTH and NF-κB increased during orthodontic bone remodeling in chronic stress rats

This study was designed to investigate the potential effects of chronic stress on periodontal bone remodeling and its mechanism during orthodontic tooth movement in rats. Forty-eight male SD rats aged 8 weeks were randomly divided into control group and chronic stress group. Chronic unpredictable mild stress model (CUMS) was established in the stress group, which was validated by behavioral experiment as well as cortisol (CORT) and adrenocorticotropic hormone (ATCH) levels. Then, the two groups were further divided into three distinct groups, namely group with no orthodontic force, group with 30 g orthodontic force and group with 50 g orthodontic force respectively to construct orthodontic tooth movement model. The rats were sacrificed after 14 days and maxilla on the loading side was obtained to measure tooth movement distance. It was found that compared with the control group, the chronic stress group displayed increased parathyroid hormone (PTH), amino terminal peptide of type I procollagen (PINP) and c-terminal peptide of type I collagen branch (CTX) levels as measured by enzyme-linked immunosorbent assay (ELISA). Hematoxylin and Eosin (HE) and TRAP staining showed fewer osteoblasts and more number of osteoclasts. The results of western blot showed no significant change in expression of Adenylate cyclase (AC) but increased phospholipase C (PLC) levels were noted. In addition, increased NF-κB expression was observed by immunohistochemistry. Overall, chronic stress can affect bone remodeling during orthodontic tooth movement by increasing the content of PTH in the blood and increasing PLC and NF-κB.

The Utility of Plasma N- Terminal Brain Natriuretic peptide (NT- Pro BNP) as a Biomarker to Differentiate Cardio embolic Stroke from Non-Cardio embolic Stroke.

TITLE: The Utility of Plasma N- Terminal Brain Natriuretic Peptide (NT- Pro BNP) as a Biomarker to Differentiate Cardio embolic Stroke from Non-Cardio embolic Stroke. PURPOSE: To measure plasma NT-Pro BNP in patients with acute ischemic stroke and investigate whether the plasma NT- pro BNP level can be a useful bio marker to differentiate cardio embolic (CE) stroke from non-cardio embolic (NCE) stroke or not. STUDY DESIGN: In our analytic observational prospective study, 66 patients were enrolled within 24 hours of the onset of acute ischemic stroke and met inclusion and exclusion criteria. METHODOLOGY: Plasma NT-pro BNP level was performed in each patient. Clinical observations were recorded on special performa designed for the study. They were classified in to four groups: Cardioembolic (CE), Large artery atherosclerosis (LAA), Small-vessel disease (SVD) and other subtypes according to TOAST classification. Study outcome was measured by applying appropriate statistical tests at the end of all patient enrolments. RESULTS: Out of 66 patients, 21(31.81 %) were cardioembolic whereas 45 (68.18%) patients were in non-cardioembolic (NCE) group. The result showed that plasma NT pro BNP levels were significantly higher in CE group than NCE group (p value&lt;0.001). The optimal cut off point for NT pro BNP levels to differentiate CE stroke from NCE stroke was &gt; 594 pg./ml with 93.33% Specificity and 66.67% Sensitivity. CONCLUSION: As plasma biomarker NT-pro BNP has a good sensitivity, specificity and accuracy for early identification of cardio embolic stroke.

Parathyroid hormone-related protein (PTHrP)-dependent modulation of gene expression signatures in cancer cells.

PTHrP is encoded by PTHLH gene which can generate by alternative promoter usage and splicing mechanisms at least three mature peptides of 139, 141 and 173 amino acids with distinct carboxy terminus. PTHrP may undergo proteolytic processing into smaller bioactive forms, comprising an amino terminus peptide, which is the mediator of the "classical" PTH-like effect, as well as midregion and carboxy terminus peptides that act as multifaceted critical regulator of proliferation, differentiation and apoptosis via the reprogramming of gene expression in normal and neoplastic cells. Moreover, a nuclear/nucleolar localization signal sequence is present in the [87-107] domain allowing PTHrP nuclear import and "intracrine" effect additional to the autocrine/paracrine one. Within the large number of data available in the literature on PTHrP bioactivities, the goal of this chapter is to pick up selected studies that report the detection of molecular signatures of cancer cell exposure to PTHrP, either as full-length protein or discrete peptides, demonstrated by individual gene or whole genome expression profiling, briefly recapitulating the biological implications associated with the specific gene activation or silencing.

Benefits of Angiotensin Receptor-Neprilysin Inhibitor in Heart Failure with Reduced Ejection Fraction: A Longitudinal Study

Introduction: Combination of Angiotensin Receptor and Neprilysin Inhibitors (ARNI) has become the mainstay drug in treatment of Heart Failure (HF) with reduced Ejection Fraction (HFrEF). However, there are very few studies to evaluate the extent and spectrum of benefit of ARNI therapy in Indian HFrEF patients. Aim: To observe the benefits of sacubitril/valsartan (ARNI) therapy on left ventricle function, parameters of cardiac remodelling, N terminal pro Brain-natriuretic peptide (NT-proBNP), rate of rehospitalisation for HF and detailed subgroup analysis in symptomatic HFrEF patients who are already receiving optimal medical therapy. Materials and Methods: This longitudinal study was conducted at Cardiology Department of Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India, from September 2018 to August 2020. Total 200 patients of HFrEF with previous echocardiographic records of past 6 months, who did not show any further improvement in left ventricle dysfunction or cardiac dimensions were included in the study. Patients were started on ARNI initially from 100 mg/day and up titrated to 400 mg/day. At each follow-up (6 weeks, 4 months, 6 months, 9 months and 1 year) clinical examination, New York Heart Association (NYHA) functional class, 2D Echocardiography and NT-ProBNP were done. Echocardiographic parameters of Cardiac Reverse Remodelling (CRR) i.e., Left Ventricular Ejection Fraction (LVEF), Left Ventricular End Diastolic Diameter (LVEDD), Left Ventricle End-Systolic Diameter (LVESD) were recorded at each follow-up. All categorical variables were shown in the form of frequency, mean with standard deviation and percentage. Intergroup comparison between different time periods was done by one-way Analysis of Variance (ANOVA) and paired t-test. A p-value &lt;0.05 was considered statistically significant. Results: Mean age of study population was 58.61±11.95 years, of whom 104 (59.77%) were males, and 70 (40.22%) were females. Mean LVEF increased from 30.42% at baseline to 45.98%, after 1 year (p-value &lt;0.05). There was reduction in mean LVEDD of 4.5 mm (p&lt;0.05) and LVESD of 3.86 mm (p-value &lt;0.05) at 1 year. These benefits of CRR were observed in all the subgroups of study population (including diabetics, hypertensive, tobacco users, age, gender). Reduction in NT-ProBNP from 1097.65±769.7 pg/mL at baseline to 127.28 pg/mL after 1 year with mean reduction of 970.37±731.33 pg/mL (p-value &lt;0.05). Rate of rehospitalisation for HF was 13.2% (N=23). A positive although weak correlation was seen between change in NT-ProBNP level and change in LVEF, LVEDD, LVESD as per spearman’s rank correlation coefficient. Conclusion: ARNI was well tolerated in this Indian population as 72% achieved maximum dose of 400 mg. There was significant improvement in LV systolic function and cardiac dimensions and benefits extended to different subgroups of HFrEF patients along with positive although weak correlation between fall in NT-ProBNP level and improvement in LV function and cardiac dimensions over and above optimal medical therapy.

Peptide based folding and function of single polymer chains

A modular synthetic strategy to fold single polymer chains upon deprotection of pendent cysteine terminal peptides is reported. The one step deprotection initiates both folding and catalytic activity of the macromolecular architectures.