Ligand entry in human ileal bile acid-binding protein is mediated by histidine protonation

Abstract Human ileal bile acid-binding protein (hI-BABP) has a key role in the intracellular transport of bile salts. To explore the role of histidine protonation in the binding process, the pH-dependence of bile salt binding and internal dynamics in hI-BABP was investigated using NMR spectroscopy and biophysical tools. Thermodynamic and kinetic measurements show an increase in the overall binding affinity and the association rate constant of the first binding step below the pKa of the histidines, suggesting that ligand binding is favoured by the protonated state. The overlap between residues exhibiting a high sensitivity to pH in their backbone amide chemical shifts and protein regions undergoing a global ms conformational exchange indicate a connection between the two processes. According to 15N NMR relaxation dispersion analysis, the slow motion is most pronounced at and above the pKa of the histidines. In agreement with the NMR measurements, MD simulations show a stabilization of the protein by histidine protonation. Hydrogen-bonding and van der Waals interactions mediating the flow of information between the C/D- and G/H-turn regions hosting the three histidines, suggest a complex way of pH-governed allosteric regulation of ligand entry involving a transition between a closed and a more open protein state

Analisis Hasil Dan Risiko Portofolio Optimal Saham Perbankan Di Bursa Efek Indonesia

Penelitian ini bertujuan untuk mengetahui saham-saham yang membentuk portofolio optimal dari saham-saham Perusahaan perbankan dengan model indeks tunggal, proporsi pada masing-masing saham yang membentuk portofolio optimal serta return ekspektasi dan risiko portofolio pada saham-saham yang optimal. Metode yang digunakan adalah model indeks tunggal. Hasil penelitian menunjukkan pada periode Januari 2009 – Desember 2014 di peroleh 8 saham yang memenuhi kriteria untuk membentuk portofolio optimal dengan menggunakan model indeks tunggal, yaitu MCOR (Bank Windu Kentjana International Tbk.) dengan proporsi 16,73%, SDRA (Bank Himpunan Saudara 1906 Tbk.) dengan proporsi 17,88%, BTPN (Bank Tabungan Pensiunan Nasional Tbk.) dengan proporsi 17,33%, BABP (Bank MNC Internasional Tbk.) dengan proporsi 3,61%, BBNI (Bank Negara Indonesia (Persero) Tbk.) dengan proporsi 24,47%, BBCA (Bank Central Asia Tbk.) dengan proporsi 17,4%, NISP (Bank NISP OCBC Tbk.) dengan proporsi 2,09% dan BMRI (Bank Mandiri (Persero) Tbk.) dengan proporsi 0,46%. Portofolio yang optimal tersebut menghasilkan tingkat pengembalian sebesar 4,47% per bulan dan risiko yang harus dihadapi dari hasil berinvestasi pada portofolio optimal tersebut adalah sebesar 14,62%

Temperature Dependence of Backbone Dynamics in Human Ileal Bile Acid-Binding Protein: Implications for the Mechanism of Ligand Binding

Human ileal bile acid-binding protein (I-BABP), a member of the family of intracellular lipid binding proteins plays a key role in the cellular trafficking and metabolic regulation of bile salts. The protein has two internal and, according to a recent study, an additional superficial binding site and binds di- and trihydroxy bile salts with positive cooperativity and a high degree of site-selectivity. Previously, in the apo form, we have identified an extensive network of conformational fluctuations on the millisecond time scale, which cease upon ligation. Additionally, ligand binding at room temperature was found to be accompanied by a slight rigidification of picosecond-nanosecond (ps-ns) backbone flexibility. In the current study, temperature-dependent N-15 NMR spin relaxation measurements were used to gain more insight into the role of dynamics in human I-BABP-bile salt recognition. According to our analysis, residues sensing a conformational exchange in the apo state can be grouped into two clusters with slightly different exchange rates. The entropy-enthalpy compensation observed for both clusters suggests a disorder-order transition between a ground and a sparsely populated higher energy state in the absence of ligands. Analysis of the faster, ps-ns motion of N-15-H-1 bond vectors indicates an unusual nonlinear temperature-dependence for both ligation states. Intriguingly, while bile salt binding results in a more uniform response to temperature change throughout the protein, the temperature derivative of the generalized order parameter shows different responses to temperature increase for the two forms of the protein in the investigated temperature range. Analysis of both slow and fast motions in human I-BABP indicates largely different energy landscapes for the apo and halo states suggesting that optimization of binding interactions might be achieved by altering the dynamic behavior of specific segments in the protein

A disulfide bridge allows for site-selective binding in liver bile acid binding protein thereby stabilising the orientation of key amino acid side chains

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Relevance of the protein macrodipole in the membrane-binding process. Interactions of fatty-acid binding proteins with cationic lipid membranes

The fatty acid-binding proteins L-BABP and Rep1-NCXSQ bind to anionic lipid membranes by electrostatic interactions. According to Molecular Dynamics (MD) simulations, the interaction of the protein macrodipole with the membrane electric field is a driving force for protein binding and orientation in the interface. To further explore this hypothesis, we studied the interactions of these proteins with cationic lipid membranes. As in the case of anionic lipid membranes, we found that both proteins, carrying a negative as well as a positive net charge, were bound to the positively charged membrane. Their major axis, those connecting the bottom of the β-barrel with the α-helix portal domain, were rotated about 180 degrees as compared with their orientations in the anionic lipid membranes. Fourier transform infrared (FTIR) spectroscopy of the proteins showed that the positively charged membranes were also able to induce conformational changes with a reduction of the β-strand proportion and an increase in α-helix secondary structure. Fatty acid-binding proteins (FABPs) are involved in several cell processes, such as maintaining lipid homeostasis in cells. They transport hydrophobic molecules in aqueous medium and deliver them into lipid membranes. Therefore, the interfacial orientation and conformation, both shown herein to be electrostatically determined, have a strong correlation with the specific mechanism by which each particular FABP exerts its biological function.Fil: Galassi, Vanesa Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Villarreal, Marcos Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Montich, Guillermo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentin

New Insight in Loss of Gut Barrier during Major Non-Abdominal Surgery

PG - e3954 AB - BACKGROUND: Gut barrier loss has been implicated as a critical event in the occurrence of postoperative complications. We aimed to study the development of gut barrier loss in patients undergoing major non-abdominal surgery. METHODOLOGY/PRINCIPAL FINDINGS: Twenty consecutive children undergoing spinal fusion surgery were included. This kind of surgery is characterized by long operation time, significant blood loss, prolonged systemic hypotension, without directly leading to compromise of the intestines by intestinal manipulation or use of extracorporeal circulation. Blood was collected preoperatively, every two hours during surgery and 2, 4, 15 and 24 hours postoperatively. Gut mucosal barrier was assessed by plasma markers for enterocyte damage (I-FABP, I-BABP) and urinary presence of tight junction protein claudin-3. Intestinal mucosal perfusion was measured by gastric tonometry (P(r)CO2, P(r-a)CO2-gap). Plasma concentration of I-FABP, I-BABP and urinary expression of claudin-3 increased rapidly and significantly after the onset of surgery in most children. Postoperatively, all markers decreased promptly towards baseline values together with normalisation of MAP. Plasma levels of I-FABP, I-BABP were significantly negatively correlated with MAP at (1/2) hour before blood sampling (-0.726 (p<0.001), -0.483 (P<0.001), respectively). Furthermore, circulating I-FABP correlated with gastric mucosal P(r)CO2, P(r-a)CO2-gap measured at the same time points (0.553 (p = 0.040), 0.585 (p = 0.028), respectively). CONCLUSIONS/SIGNIFICANCE: This study shows the development of gut barrier loss in children undergoing major non-abdominal surgery, which is related to preceding hypotension and mesenterial hypoperfusion. These data shed new light on the potential role of peroperative circulatory perturbation and intestinal barrier los

PENGARUH PENDAPATAN BUNGA KREDIT TERHADAP PROFITABILITAS PADA PERUSAHAAN JASA SEKTOR KEUANGAN YANG TERDAFTAR DI BURSA EFEK INDONESIA.

THE EFFECT OF INTEREST INCOME CREDIT TO PROFITABILITY IN THE SERVICES OF THE FINANCIAL SECTOR THAT ARE LISTED IN THE INDONESIA STOCK EXCHANGE. Jurusan Pendidikan Akuntansi Fakultas Ekonomi. Universitas Negeri Makassar Jl. Pendidikan Makassar Email: [email protected] ABSTRAK Penelitian ini bertujuan untuk mengetahui pengaruh pendapatan bunga kredit terhadap profitabilitas pada perusahaan jasa sektor keuangan yang terdaftar di Bursa Efek Indonesia. Variabel dalam peneletian ini adalah pendapatan bunga kredit sebagai variabel bebasdan profitabilitas sebagai variabel terikat. Populasi dalam penelitian ini adalah perusahaan jasa sektor keuangan yang terdaftar (listing) di BEI selama periode 2014-2016 sejumlah 38 perusahaan, sedangkan pengambilan sampel menggunakan purposive sampling diperoleh 11 perusahaan. Teknik pengumpulan data menggunakan metode dokumentasi. Analisis data yang digunakan adalah regresi linear sederhana, korelasi product moment, dan uji-t. Hasil persamaan regresi Y = -6.468 + 0.629 X menunjukkan bahwa pendapatan bunga kredit berpengaruh signifikan terhadap profitabilitas dengan tingkat signifikansi <0,05. Korelasi antara pendapatan bunga kredit dan profitabilitas diperoleh koefisien r = 0,608 berada pada interval (0,60-0,799) dalam kategori kuat. Hasil uji-t menunjukkan nilai signifikansi 0,000 < α = 0,05 sehingga dapat disimpulkan bahwa pendapatan bunga kredit berpengaruh signifikan terhadap profitabilitas dan hipotesis diterima. Kata Kunci: Pendapatan Bunga Kredit, Profitabilitas

A KLK6 activity-based probe reveals a role for KLK6 activity in pancreatic cancer cell invasion

Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options. Serine hydrolases are known to mediate cancer progression and metastasis through initiation of signaling cascades and cleavage of extracellular matrix proteins, and the kallikrein-related peptidase (KLK) family of secreted serine proteases have emerging roles in pancreatic ductal adenocarcinoma (PDAC). However, the lack of reliable activity-based probes (ABPs) to profile KLK activity has hindered progress in validation of these enzymes as potential targets or biomarkers. Here, we developed potent and selective ABPs for KLK6 by using a positional scanning combinatorial substrate library and characterized their binding mode and interactions by X-ray crystallography. The optimized KLK6 probe IMP-2352 (kobs/I = 11,000 M–1 s–1) enabled selective detection of KLK6 activity in a variety of PDAC cell lines, and we observed that KLK6 inhibition reduced the invasiveness of PDAC cells that secrete active KLK6. KLK6 inhibitors were combined with N-terminomics to identify potential secreted protein substrates of KLK6 in PDAC cells, providing insights into KLK6-mediated invasion pathways. These novel KLK6 ABPs offer a toolset to validate KLK6 and associated signaling partners as targets or biomarkers across a range of diseases

Analisis Capital Asset Pricing Model (Capm) Terhadap Keputusan Investasi Saham (Studi Pada Perusahaan-Perusahaan Sektor Perbankan Di Bei Tahun 2009-2011)

This research aims to analyze the efficient clustering of stock as an alternative to stock investment decisions based on Capital Asset Pricing Model (CAPM). With the CAPM, investors can predict the stock with a small risk but generate huge profits based on the concept of risk and return.The method used in this research is descriptive method with a quantitative approach. The samples used were 18 stocks from the banking sector companies listed in Indonesia Stock Exchange continuously in the period 2009-2011 and only stocks that have positive individual stock returns (Ri) are taken.Analysis result showed that company stock of Bank Himpunan Saudara 1906 Tbk has the highest mean stock returns 6,7599535%. Bank Negara Indonesia (Persero) (BBNI) has the highest beta 1,931978114 including aggressively stocks because the beta value is more than one (β&gt; 1). Bank Negara Indonesia (Persero) (BBNI) has the highest expected rate of return 5,459%. There are 8 efficient stocks in the banking sector companies that have individual stock returns greater than the expected rate