Common structural traits for cystine knot domain of the TGFß superfamily of proteins and three-fingered ectodomain of their cellular receptors.

The transforming growth factor-ß (TGFß) superfamily of proteins and their receptors are crucial developmental factors for all metazoan organisms. Cystine-knot (CK) motif is a spatial feature of the TGFß superfamily of proteins whereas the extra-cellular domains (ectodomains) of their respective receptors form three-fingered protein domain (TFPD), both stabilized by tight cystine networks. Analyses of multiple sequence alignments of these two domains encoded in various genomes revealed that the cystines forming the CK and TFPD folds are conserved, whereas the remaining polypeptide patches are diversified. Orthologues of the human TGFßs and their respective receptors expressed in diverse vertebrates retain high sequence conservation. Examination of 3D structures of various TGFß factors bound to their receptors have revealed that the CK and TFPD domains display several similar spatial traits suggesting that these two different protein folds might have been acquired from a common ancestor.

Diagnosis and management of heart failure from hospital admission to discharge: A practical expert guidance.

Heart failure (HF) has high event rates, mortality, and is challenging to manage in clinical practice. Clinical management is complicated by complex therapeutic strategies in a population with a high prevalence of comorbidity and general frailty. In the last four years, an abundance of research has become available to support multidisciplinary management of heart failure from within the hospital through to discharge and primary care as well as supporting diagnosis and comorbidity management. Within the hospital setting, recent evidence supports sacubitril-valsartan combination in frail, deteriorating or de novo patients with LVEF≤40%. Furthermore, new strategies such as SGLT2 inhibitors and vericiguat provide further benefit for patients with decompensating HF. Studies with tafamidis report major clinical benefits specifically for patients with ATTR cardiac amyloidosis, a remaining underdiagnosed and undertreated disease. New evidence for medical interventions supports his bundle pacing to reduce QRS width and improve haemodynamics as well as ICD defibrillation for non-ischemic cardiomyopathy. The Mitraclip reduces hospitalisations and mortality in patients with symptomatic, secondary mitral regurgitation and ablation reduces mortality and hospitalisations in patients with paroxysmal and persistent atrial fibrillation. In end-stage HF, the 2018 French Heart Allocation policy should improve access to heart transplants for stable, ambulatory patients and, mechanical circulatory support should be considered to avoid deteriorating on the waiting list. In the community, new evidence supports that improving discharge education, treatment and patient support improves outcomes. The authors believe that this review fills the gap between the guidelines and clinical practice and provides practical recommendations to improve HF management.

Inhibition of FKBP rotamase activity by immunosuppressant FK506: twisted amide surrogate.

The immunosuppressive agents cyclosporin A and FK506 inhibit the transcription of early T cell activation genes. The binding proteins for cyclosporin A and FK506, cyclophilin and FKBP, respectively, are peptidyl-prolyl-cis-trans isomerases, or rotamases. One proposed mechanism for rotamase catalysis by cyclophilin involves a tetrahedral adduct of an amide carbonyl and an enzyme-bound nucleophile. The potent FKBP rotamase inhibitor FK506 has a highly electrophilic carbonyl that is adjacent to an acyl-pipicolinyl (homoprolyl) amide bond. Such a functional group would be expected to form a stabilized, enzyme-bound tetrahedral adduct. Spectroscopic and chemical evidence reveals that the drug interacts noncovalently with its receptor, suggesting that the alpha-keto amid of FK506 serves as a surrogate for the twisted amide of a bound peptide substrate.

The three-fingered protein domain of the human genome.

Extracellular domains of some cellular receptors expressed in the organisms at different levels of development belong to three-fingered protein (TFP) fold. The Homo sapiens genome encodes at least 45 genes containing from one to three TFP domains (TFPDs), namely diverse paralogues of the Ly6 gene, CD59 and the receptors of activins, bone morphogenetic proteins, Mullerian inhibiting substance and transforming growth factor-beta. C4.4a and urokinase/plasminogen activatory receptor contain two and three TFPD repeats, respectively. These diverse proteins have a low overall sequence similarity with each other and their hydrophobicity levels vary to a considerable degree. It is suggested that sequence differentiation within the TFPD led to distinct groups of proteins whose attributes were optimized to fit both the physicochemical properties specific to their functional microenvironment and selective targeting of their highly diversified extracellular cofactors.

Early stages in the trifluoroethanol-induced unfolding of hen egg-white lysozyme and its complex with (GlcNAc)3.

The trifluoroethanol-induced unfolding of hen egg-white lysozyme was studied by circular dichroism. It was shown that if the H2O/trifluoroethanol ratio is above 10:1 (v/v), the unique three-dimensional structure of the protein is not affected, whereas within the ration 10:1-2.8:1 (v/v), this structure is partially unfolded. At the ratio 2.4:1 (v/v), the native conformation of lysozyme is completely disrupted and the conformational transition fits a two-state model. A similar effect was observed for the trifluoroethanol-induced unfolding of the lysozyme-(GlcNAc)3 complex. Within the H2O2 trifluoroethanol ratio 15:1-5.5:1 (v/v), the characteristic intensities of the Cotton effects which arise from the association of (GlcNAc)3 with the active site of lysozyme, diminished and approached those exhibited by lysozyme itself at the same H2O trifluoroethanol ratios. This shows that (GlcNAc)3 is released from the protein surface in early stages of the unfolding process. At the ratio 2.4:1 (v/v), the lysozyme-(GlcNAc)3 complex was completely disrupted and the protein unfolded. It is suggested that a considerable alteration in hydration of the lysozyme molecule caused by trifluoroethanol increases protein surface fluctuations, causing the release of (GlcNAc)3 from the active site of lysozyme.

Cyclophilin-B is an abundant protein whose conformation is similar to cyclophilin-A.

Cyclophilin-B (bCyP-20) was isolated in a relatively high quantity from calf brain and spleen tissues consecutively applying weak cation exchange, chromatofocusing and strong cation exchange chromatographies. Edman degradation yielded the N-terminal sequence NH2-DEKKKGPKVTVK- VYFDLRIGDEDIGRVVIGLFGKTVPKTVDNFVAL. Bovine cyclophilin-B possesses the peptidylproline cis-trans isomerase activity which is inhibited by nM concentrations of CsA. bCyP-20 has a strong tendency to bind to cation exchangers including DNA and heparin. It could be released from DNA affinity column at concentrations of NaCl higher than 200 mM. Circular dichroism spectroscopy revealed that bovine cyclophilin-A (bCyP-18) and bCyP-20 in aqueous solution have similar conformations.

Purification of macrophage migration inhibitory factor (MIF) from bovine brain cytosol.

Two isoforms of the macrophage migration inhibitory factor (MIF) have been isolated to homogeneity from bovine brain cytosol. In agreement with the cDNA sequence of their human counterpart, they both have an apparent molecular weight of 12 kDa and are characterized by the following N-terminal amino acid sequence NH2-PMFVVNTNVPRASVPDGLLSELTQQLAQATGKPPQYIAV-. CD spectra revealed that bovine MIF contains 42% (+/- 3%) alpha-helix and 21% (+/- 3%) beta-structure. CD-constrained prediction of the secondary structure assigned MIF to the alpha/beta-class of proteins.

On the localization of FKBP25 in T-lymphocytes.

Using polyclonal rabbit antibodies against bovine FKBP25, NEPHGE/SDS-PAGE and Western blotting we demonstrate that the rapamycin-specific immunophilin FKBP25 is present in T-lymphoma Jurkat cells. Subsequent fractionations of the soluble Jurkat cell proteins have revealed that FKBP25 predominantly occurs in the nuclear fraction. FKBP25 has the ability to bind to DNA. The FKBP25/DNA complex can be dissociated in the presence of a high salt concentration. FKBP12, which shares high amino acid sequence homology to the C-terminal domain of FKBP25, has no tendency to bind to DNA. CD-constrained predictions of the secondary structures in FKBP25 suggest that an amphipathic helix-loop-helix occurs in the N-terminal part of the protein and may account for its binding to DNA.

Study of the Raman scattering and infrared absorption spectra of branched polysaccharides.

Raman scattering and infrared absorption spectra of glycogen and starch were recorded over the range of 4000 - 50 cm-1, and the observed bands were correlated with the vibrational modes. It was shown that the spectral regions within 1050 - 970 cm-1 and 900 - 780 cm-1, where the specific Raman scattering and infrared bands of solvated hydroxyl groups and glucosidic linkages are found, can be applied successfully in the studies on the conformation and structure of branched polysaccharides.

Analyses of infrared amide bands of chitin.

Infrared spectra of chitin isolated from various biological species were measured by Fourier transform technique. The recorded spectra were decomposed into component bands within 1500--1750 cm-1 and 3000--3500 cm-1 spectral regions; it allowed us to establish the precise position of amide I and amids II bands. It was shown that the positions of amide I and amide II bands are independent of the source from which chitin was isolated.

[Effect of the level and extent of a brain stem lesion on central hemodynamics in patients with an arterial aneurysm in the acute stage of a subarachnoid hemorrhage]. / Vliianie urovnia i stepeni porazheniia stvola golovnogo mozga na tsentral'nuiu gemodinamiku u bol'nykh s arterial'noi anevrizmoi v ostroi stadii subarakhnoidal'nogo krovoizliianiia.

Using the dye-dilution method (indigo carmine), the authors studied the central hemodynamics in 46 people, including 36 patients with arterial aneurysms in the acute period of subarachnoidal hemorrhage and 10 healthy subjects (a control group). Hyperkinetic, hypokinetic and normokinetic types of the central hemodynamics were specified. The hyperkinetic type was characteristic of patients in a satisfactory state and with injuries at the hypothalamo-diencephalic level. The hypokinetic type is characteristic of grave and very grave patients with injuries at the mesencephalodienchephalic and mesencephalo-bulbar levels and with severe damage to the brain stem.

[Features of central hemodynamics in patients with ischemic disorders of cerebrovascular circulation]. / Osobennosti tsentral'noi gemodinamiki u bol'nykh s ishemicheskimi narusheniiami mozgovogo krovoobrashcheniia.

Central hemodynamics was studied in 75 persons; 10 were healthy, 65 had abnormal tortuousness, stenosis, and thrombosis of the internal carotid arteries in the late post-stroke period. Twenty-one patients suffered from arterial hypertension. An increase in the cardiac output was revealed, which was associated with centripetal effects and was compensatory in character.

[State of central hemodynamics in cerebral arterial aneurysms in the acute period of subarachnoid hemorrhage]. / Sostoianie tsentral'noi gemodinamiki pri arterial'nykh anevrizmakh golovnogo mozga v ostrom periode subarakhnoidal'nogo krovoizliianiia.

Central hemodynamics was studied by the method of dye (indigo carmine) dilution in 44 persons, 34 of whom had saccular aneurysms of the cerebral arteries in the acute period of subarachnoid hemorrhage and 10 formed the control group. Central hemodynamics changed depending on the condition of the patient. In a satisfactory and moderately severe condition, the cardiac output (minute circulation, volume, stroke volume cardiac index) was increased. In a severe and extremely severe conditions, the values of the cardiac output and the volumes of circulating blood, plasma, and red cells were sharply reduced, while peripheral resistance was increased.

[Types of hemodynamic response in patients with severe injuries of the skull and brain during the postoperative period]. / Tipy gemodinamicheskikh reaktsii u bol'nykh s tiazheloi travmoi cherepa i golovnogo mozga v posleoperatsionnom periode.

The main values of central hemodynamics were studied in 20 patients in the acute period of injury with severe contusion of the brain and compression of intracranial hematoma. Three main types of circulatory reactions to the injury were revealed according to the values of the minute circulation volume. The hyperdynamic type of reaction was characterized by a rise of the main values of central hemodynamics; in the hypodynamic type of the circulatory reaction the cardiac output and the volume of circulating red cells were considerably reduced while the peripheral resistance was increased. The normodynamic type was characterized by essentially unchanged main values of central hemodynamics except for a reduced cardiac output and was interpreted as an inadequate reaction of circulation to the injury.