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1.
Cell ; 152(1-2): 316-26, 2013 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-23332763

RESUMEN

We propose a concept for the folding and self-assembly of the pore-forming TatA complex from the Twin-arginine translocase and of other membrane proteins based on electrostatic "charge zippers." Each subunit of TatA consists of a transmembrane segment, an amphiphilic helix (APH), and a C-terminal densely charged region (DCR). The sequence of charges in the DCR is complementary to the charge pattern on the APH, suggesting that the protein can be "zipped up" by a ladder of seven salt bridges. The length of the resulting hairpin matches the lipid bilayer thickness, hence a transmembrane pore could self-assemble via intra- and intermolecular salt bridges. The steric feasibility was rationalized by molecular dynamics simulations, and experimental evidence was obtained by monitoring the monomer-oligomer equilibrium of specific charge mutants. Similar "charge zippers" are proposed for other membrane-associated proteins, e.g., the biofilm-inducing peptide TisB, the human antimicrobial peptide dermcidin, and the pestiviral E(RNS) protein.


Asunto(s)
Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Proteínas de Transporte de Membrana/química , Proteínas de Transporte de Membrana/metabolismo , Secuencia de Aminoácidos , Bacillus subtilis/metabolismo , Toxinas Bacterianas/química , Proteínas de Escherichia coli/genética , Humanos , Proteínas de Transporte de Membrana/genética , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Péptidos/química , Péptidos/metabolismo , Pliegue de Proteína , Alineación de Secuencia , Proteínas Virales/química , Proteínas Virales/metabolismo
2.
Chemistry ; 30(22): e202400066, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38366887

RESUMEN

Photoisomerizable peptides are promising drug candidates in photopharmacology. While azobenzene- and diarylethene-containing photoisomerizable peptides have already demonstrated their potential in this regard, reports on the use of spiropyrans to photoregulate bioactive peptides are still scarce. This work focuses on the design and synthesis of a spiropyran-derived amino acid, (S)-2-amino-3-(6'-methoxy-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin-6-yl])propanoic acid, which is suitable for the preparation of photoisomerizable peptides. The utility of this amino acid is demonstrated by incorporating it into the backbone of BP100, a known membrane-active peptide, and by examining the photoregulation of the membrane perturbation by the spiropyran-containing peptides. The toxicity of the peptides (against the plant cell line BY-2), their bacteriotoxicity (E. coli), and actin-auxin oscillator modulation ability were shown to be significantly dependent on the photoisomeric state of the spiropyran unit.


Asunto(s)
Escherichia coli , Indoles , Nitrocompuestos , Péptidos , Benzopiranos/química , Aminoácidos
3.
Eur Radiol ; 34(3): 1556-1566, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37658140

RESUMEN

OBJECTIVE: Bioabsorbable magnesium-based alloy screws release gas upon resorption. The resulting findings in the adjacent soft tissues and joints may mimic infection. The aim of the study was to evaluate the ultrasound (US) findings in soft tissues and joints during screw resorption. METHODS: Prospectively acquired US studies from pediatric patients treated with magnesium screws were evaluated for screw head visibility, posterior acoustic shadowing, twinkling artifact, foreign body granuloma, gas (soft tissue, intra-articular), alterations of the skin and subcutaneous fat, perifascial fluid, localized fluid collections, hypervascularization, and joint effusion. RESULTS: Sixty-six US studies of 28 pediatric patients (nfemale = 9, nmale = 19) were included. The mean age of the patients at the time of surgery was 10.84 years; the mean time between surgery and ultrasound was 128.3 days (range = 6-468 days). The screw head and posterior acoustic shadowing were visible in 100% of the studies, twinkling artifact in 6.1%, foreign body granuloma in 92.4%, gas locules in soft tissue in 100% and intra-articular in 18.2%, hyperechogenicity of the subcutaneous fat in 90.9%, cobblestoning of the subcutaneous fat in 24.2%, loss of normal differentiation between the epidermis/dermis and the subcutaneous fat in 57.6%, localized fluid collection in 9.9%, perifascial fluid in 12.1%, hypervascularization in 27.3%, and joint effusion in 18.2%. CONCLUSION: US findings in pediatric patients treated with magnesium screws strongly resemble infection, but are normal findings in the setting of screw resorption. CLINICAL RELEVANCE STATEMENT: Bioabsorbable magnesium-based alloy screws release gas during resorption. The resulting US findings in the adjacent soft tissues and joints in pediatric patients may mimic infection, but are normal findings. KEY POINTS: • Bioabsorbable magnesium-based alloy screws release gas upon resorption. • The resulting ultrasound findings in children's soft tissues and joints closely resemble those of soft tissue infection or osteosynthesis-associated infection. • Be familiar with these ultrasound findings in order to avoid inadvertently misdiagnosing a soft tissue infection or osteosynthesis-associated infection.


Asunto(s)
Fracturas Óseas , Granuloma de Cuerpo Extraño , Infecciones de los Tejidos Blandos , Humanos , Masculino , Femenino , Niño , Magnesio , Implantes Absorbibles , Granuloma de Cuerpo Extraño/etiología , Infecciones de los Tejidos Blandos/etiología , Fracturas Óseas/etiología , Aleaciones , Fijación Interna de Fracturas/métodos , Tornillos Óseos/efectos adversos
4.
Appl Opt ; 63(9): 2167-2174, 2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38568568

RESUMEN

We report the results of fabricating fiber array unit (FAU) connectors using a near IR laser welding process, locking fibers in proper position on planar glass substrates and forming strong glass-to-glass bonds, followed by final assembly using lower coefficient of thermal expansion (CTE) epoxies. A thin metal film deposited on the glass substrate provides the absorption required to attain interfacial temperatures suitable for glass-to-glass bonding. This method allows the elimination of dedicated expensive V-groove plates while still maintaining very good fiber placement accuracy. The use of epoxy is minimized to simply securing macro packaging components and protecting fibers from environmental pressure, temperature, and humidity variation. The thermal expansion properties of the epoxy used were essential for the long-term FAU reliability.

5.
BMC Public Health ; 24(1): 2164, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39123183

RESUMEN

BACKGROUND: This study explores the health status differences between migrants and native Germans, focusing on potential disparities in their workloads. Physical and mental workloads can negatively impact individual health. Since various occupations come with distinct health-related patterns, occupational selection may contribute to systematic health disparities among socio-economic groups. Given the generally poorer health of migrants, they might experience systematic workload differences overall. METHODS: We suggest a conceptual framework for the empirical analysis based on the theory of health as a durable good with health consumption and health investment as key parameters. We quantify the role of work tasks, job requirements and working conditions on individual health based on detailed information from the BIBB/BAuA labour force survey 2012 and 2018. RESULTS: The empirical results reveal that migrants, i.e. foreigners and German citizens with a migration background, have a higher perception of workload and related health afflictions within the same occupation. Native Germans, on the other hand, experience a higher burden by high job requirements, both physically and mentally. The findings imply heterogeneous health impacts of work for migrants and native Germans due to differences in health consumption. CONCLUSIONS: The analysis shows that migrants report worse health than natives, with stronger negative effects of work-related conditions on their health, both physically and mentally. Women, in general, report poorer health conditions than men. The findings emphasize the importance of promoting human capital to reduce economic and health disparities, though caution is advised regarding affirmative actions for migrants; further research is needed to understand the underlying mechanisms and address these issues effectively.


Asunto(s)
Disparidades en el Estado de Salud , Migrantes , Carga de Trabajo , Humanos , Alemania , Femenino , Masculino , Carga de Trabajo/estadística & datos numéricos , Carga de Trabajo/psicología , Adulto , Migrantes/estadística & datos numéricos , Migrantes/psicología , Persona de Mediana Edad , Adulto Joven , Adolescente
6.
BMC Pediatr ; 24(1): 315, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38714956

RESUMEN

BACKGROUND: Ultrasound (US) is often the first method used to look for brain or cerebrospinal fluid (CSF) space pathologies. Knowledge of normal CSF width values is essential. Most of the available US normative values were established over 20 years ago, were obtained with older equipment, and cover only part of the age spectrum that can be examined by cranial US. This prospective study aimed to determine the normative values of the widths of the subarachnoid and internal CSF spaces (craniocortical, minimal and maximal interhemispheric, interventricular, and frontal horn) for high-resolution linear US probes in neurologically healthy infants and children aged 0-19 months and assess whether subdural fluid collections can be delineated. METHODS: Two radiologists measured the width of the CSF spaces with a conventional linear probe and an ultralight hockey-stick probe in neurologically healthy children not referred for cranial or spinal US. RESULTS: This study included 359 neurologically healthy children (nboys = 178, 49.6%; ngirls = 181, 50.4%) with a median age of 46.0 days and a range of 1-599 days. We constructed prediction plots, including the 5th, 50th, and 95th percentiles, and an interactive spreadsheet to calculate normative values for individual patients. The measurements of the two probes and the left and right sides did not differ, eliminating the need for separate normative values. No subdural fluid collection was detected. CONCLUSION: Normative values for the widths of the subarachnoid space and the internal CSF spaces are useful for evaluating intracranial pathology, especially when determining whether an increase in the subarachnoid space width is abnormal.


Asunto(s)
Espacio Subaracnoideo , Ultrasonografía , Humanos , Lactante , Estudios Prospectivos , Masculino , Femenino , Valores de Referencia , Recién Nacido , Ultrasonografía/métodos , Espacio Subaracnoideo/diagnóstico por imagen , Líquido Cefalorraquídeo/diagnóstico por imagen
7.
Biophys J ; 122(11): 2125-2146, 2023 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-36523158

RESUMEN

The twin arginine translocase (Tat) exports folded proteins across bacterial membranes. The putative pore-forming or membrane-weakening component (TatAd in B. subtilis) is anchored to the lipid bilayer via an unusually short transmembrane α-helix (TMH), with less than 16 residues. Its tilt angle in different membranes was analyzed under hydrophobic mismatch conditions, using synchrotron radiation circular dichroism and solid-state NMR. Positive mismatch (introduced either by reconstitution in short-chain lipids or by extending the hydrophobic TMH length) increased the helix tilt of the TMH as expected. Negative mismatch (introduced either by reconstitution in long-chain lipids or by shortening the TMH), on the other hand, led to protein aggregation. These data suggest that the TMH of TatA is just about long enough for stable membrane insertion. At the same time, its short length is a crucial factor for successful translocation, as demonstrated here in native membrane vesicles using an in vitro translocation assay. Furthermore, when reconstituted in model membranes with negative spontaneous curvature, the TMH was found to be aligned parallel to the membrane surface. This intrinsic ability of TatA to flip out of the membrane core thus seems to play a key role in its membrane-destabilizing effect during Tat-dependent translocation.


Asunto(s)
Proteínas de Escherichia coli , Proteínas de Transporte de Membrana , Proteínas de Transporte de Membrana/química , Membrana Dobles de Lípidos/química , Espectroscopía de Resonancia Magnética , Proteínas de Escherichia coli/metabolismo
8.
Proc Natl Acad Sci U S A ; 117(47): 29637-29646, 2020 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-33154156

RESUMEN

Pinholin S2168 triggers the lytic cycle of bacteriophage φ21 in infected Escherichia coli Activated transmembrane dimers oligomerize into small holes and uncouple the proton gradient. Transmembrane domain 1 (TMD1) regulates this activity, while TMD2 is postulated to form the actual "pinholes." Focusing on the TMD2 fragment, we used synchrotron radiation-based circular dichroism to confirm its α-helical conformation and transmembrane alignment. Solid-state 15N-NMR in oriented DMPC bilayers yielded a helix tilt angle of τ = 14°, a high order parameter (Smol = 0.9), and revealed the azimuthal angle. The resulting rotational orientation places an extended glycine zipper motif (G40xxxS44xxxG48) together with a patch of H-bonding residues (T51, T54, N55) sideways along TMD2, available for helix-helix interactions. Using fluorescence vesicle leakage assays, we demonstrate that TMD2 forms stable holes with an estimated diameter of 2 nm, as long as the glycine zipper motif remains intact. Based on our experimental data, we suggest structural models for the oligomeric pinhole (right-handed heptameric TMD2 bundle), for the active dimer (right-handed Gly-zipped TMD2/TMD2 dimer), and for the full-length pinholin protein before being triggered (Gly-zipped TMD2/TMD1-TMD1/TMD2 dimer in a line).


Asunto(s)
Bacteriófagos/metabolismo , Proteínas Virales/metabolismo , Dicroismo Circular , ADN/metabolismo , Escherichia coli/virología , Glicina/metabolismo , Membrana Dobles de Lípidos/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Proteínas de la Membrana/metabolismo , Conformación Proteica en Hélice alfa/fisiología
9.
Br J Haematol ; 196(2): 397-401, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34549417

RESUMEN

We examined heart rate variability (HRV) during exercise testing in 20 children with sickle cell anaemia (SCA) and 12 controls. Subjects achieved lower median HRV at peak exercise [standard deviation of R-wave to R-wave intervals (SDNN), 2·3 vs 2·9 ms, P = 0·027; logarithmic transformation of high frequency power (lnHF), 0·9 vs 1·3 ln(ms2 ), P = 0·047] and had lower post-exercise HRV across minute-by-minute analysis of recovery. After adjustment for haemoglobin, fitness and SCA status, subjects had lower HRV at the end of recovery with differences increasing as baseline HRV increased. Further investigation of HRV and exercise safety in SCA is warranted.


Asunto(s)
Anemia de Células Falciformes/fisiopatología , Ejercicio Físico , Frecuencia Cardíaca , Adolescente , Análisis de Varianza , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/diagnóstico , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Electrocardiografía , Índices de Eritrocitos , Ejercicio Físico/efectos adversos , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Adulto Joven
10.
Small ; 18(41): e2107308, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36074982

RESUMEN

A labeling strategy for in vivo 19 F-MRI (magnetic resonance imaging) based on highly fluorinated, short hydrophilic peptide probes, is developed. As dual-purpose probes, they are functionalized further by a fluorophore and an alkyne moiety for bioconjugation. High fluorination is achieved by three perfluoro-tert-butyl groups, introduced into asparagine analogues by chemically stable amide bond linkages. d-amino acids and ß-alanine in the sequences endow the peptide probes with low cytotoxicity and high serum stability. This design also yielded unstructured peptides, rendering all 27 19 F substitutions chemically equivalent, giving rise to a single 19 F-NMR resonance with <10 Hz linewidth. The resulting performance in 19 F-MRI is demonstrated for six different peptide probes. Using fluorescence microscopy, these probes are found to exhibit high stability and long circulation times in living zebrafish embryos. Furthermore, the probes can be conjugated to bovine serum albumin with only amoderate increase in 19 F-NMR linewidth to ≈30 Hz. Overall, these peptide probes are hence suitable for in vivo 19 F-MRI applications.


Asunto(s)
Asparagina , Albúmina Sérica Bovina , Alquinos , Amidas , Aminoácidos/química , Animales , Imagen por Resonancia Magnética , Péptidos/química , Pez Cebra , beta-Alanina
11.
Scand J Gastroenterol ; 57(10): 1250-1256, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35465817

RESUMEN

INTRODUCTION: Pancreatic exocrine insufficiency (PEI) results in maldigestion of fat, leading to steatorrhea, malabsorption and weight loss. Sjögren's syndrome (SS) is a chronic autoimmune rheumatic disease with unknown etiology. The exocrine pancreas and the salivary glands are functionally and histologically comparable, and pancreatic dysfunction in SS has been hypothesized. METHODS: Patients were recruited from the Department for Rheumatology at the Karolinska University Hospital in Stockholm, Sweden, between June and December 2019. PEI was assessed by fecal elastase-1 (FE-1) and 13C-mixed triglyceride breath test (13C-MTG-BT). The presence and severity of gastrointestinal symptoms were assessed by a well-established and validated survey based on a seven-point Likert scale. RESULTS: Fifty-seven patients with primary SS were included in the study, comprising 92% females with a median age of 63 years. In total, 87% of SS patients were tested for FE-1 and all had normal results. All patients who underwent a 13C-MTG-BT had a normal cumulative 13C-exhalation. Compared to the control group, significantly more patients suffered from gastrointestinal (GI) symptoms (p < .01). The same number of patients noted moderate to severe loose bowel movements or constipation (38%). Eleven GI symptom parameters were compared to controls and the highest odd ratios were noted for the following moderate to severe symptoms: bloating, feeling of incompletely emptied bowel after defecation and abdominal pain relieved by bowel action. CONCLUSION: In our study, most SS patients suffered from irritable bowel syndrome (IBS)-like GI symptoms that could not be attributed to PEI.


Asunto(s)
Insuficiencia Pancreática Exocrina , Enfermedades Gastrointestinales , Síndrome de Sjögren , Insuficiencia Pancreática Exocrina/diagnóstico , Insuficiencia Pancreática Exocrina/epidemiología , Insuficiencia Pancreática Exocrina/etiología , Femenino , Enfermedades Gastrointestinales/epidemiología , Enfermedades Gastrointestinales/etiología , Humanos , Masculino , Persona de Mediana Edad , Elastasa Pancreática , Prevalencia , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/epidemiología , Triglicéridos
12.
Pediatr Radiol ; 52(12): 2368-2376, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35606529

RESUMEN

BACKGROUND: Resorption of magnesium-based alloy bioabsorbable screws produces hydrogen gas, which can be mistaken as a sign of infection and may affect the physis or fixed bone fragment. OBJECTIVE: We evaluated the temporal and spatial occurrence of gas and the occurrence of a breakage of the fixed bone fragment or screw following magnesium screw fixation. MATERIALS AND METHODS: Radiographs of paediatric patients treated with magnesium screws were retrospectively reviewed. Temporal occurrence and distribution of gas in the bone, the physis and soft tissues, breakage of the screw or fixed bone fragment and joint effusion were assessed. RESULTS: One hundred and three radiographs in 35 paediatric patients were reviewed (mean age: 10.6 years). Follow-up ranged from 1 to 730 days. Gas in the bone increases up to week 5, remains constant up to week 16 and then decreases. Gas in soft tissues, intra-articular gas and joint effusions gradually reduce over time. In 1/23 (4.3%) patients with an open physis, gas intrusion into the physis occurred. Breakage of the bone fragment fixated by the screw was observed in 4/35 (11.4%) patients within the first 6 weeks. Screw breakage was observed in 16/35 (45.7%) patients, with a median time to first detection of 300 days. CONCLUSION: Gas bubbles in bone and soft tissue are normal findings in the context of screw resorption and should not be confused with soft-tissue infection or osteomyelitis. Gas is rarely visible in the physis. Breakage of the fixed bone fragment and/or screw can occur.


Asunto(s)
Fracturas Óseas , Magnesio , Humanos , Niño , Implantes Absorbibles , Estudios Retrospectivos , Tornillos Óseos , Aleaciones , Fracturas Óseas/etiología
13.
Pediatr Radiol ; 52(13): 2584-2594, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35836016

RESUMEN

BACKGROUND: Exposure of the eye lens to ionizing radiation results in cataract. Several dose optimization techniques to protect the lens are available for computed tomography (CT). OBJECTIVE: The radiation dose to the eye lens, volume CT dose index (CTDIvol) and image quality of various methods of dose optimization were evaluated for pediatric head CT: automated tube current modulation (ATCM), automated tube voltage selection (ATVS), organ-based tube current modulation (OBTCM) and bismuth shielding. MATERIALS AND METHODS: An anthropomorphic phantom of a 5-year-old child was scanned with nine protocols: no dose optimization technique and then adding different dose optimization techniques alone and in combination. Dose to the eye, thyroid and breast were estimated using metal oxide semiconductor field effect transistor (MOSFET) dosimetry. CTDIvol, influence of timing of shield placement, image noise and attenuation values in 13 regions of interest of the head and subjective image quality were compared. RESULTS: The eye shield significantly reduced the eye lens dose when used alone, to a similar degree as when using all software-based techniques together. When used in combination with software-based techniques, the shield reduced the eye lens dose by up to 45% compared to the no dose optimization technique. Noise was significantly increased by the shield, most pronounced in the anterior portion of the eye. CONCLUSION: The combination of ATCM, ATVS, OBTCM and a bismuth shield, with the shield placed after acquiring the localizer image, should be considered to reduce the radiation dose to the eye lens in pediatric head CT.


Asunto(s)
Bismuto , Protección Radiológica , Niño , Humanos , Preescolar , Dosis de Radiación , Protección Radiológica/métodos , Cabeza/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Fantasmas de Imagen
14.
Int J Mol Sci ; 23(9)2022 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-35562938

RESUMEN

The lateral pressure profile constitutes an important physical property of lipid bilayers, influencing the binding, insertion, and function of membrane-active peptides, such as antimicrobial peptides. In this study, we demonstrate that the lateral pressure profile can be manipulated using the peptides residing in different regions of the bilayer. A 19F-labeled analogue of the amphiphilic peptide PGLa was used to probe the lateral pressure at different depths in the membrane. To evaluate the lateral pressure profile, we measured the orientation of this helical peptide with respect to the membrane using solid-state 19F-NMR, which is indicative of its degree of insertion into the bilayer. Using this experimental approach, we observed that the depth of insertion of the probe peptide changed in the presence of additional peptides and, furthermore, correlated with their location in the membrane. In this way, we obtained a tool to manipulate, as well as to probe, the lateral pressure profile in membranes.


Asunto(s)
Membrana Dobles de Lípidos , Membrana Dobles de Lípidos/química , Espectroscopía de Resonancia Magnética/métodos
15.
Wirtschaftsdienst ; 102(2): 127-132, 2022.
Artículo en Alemán | MEDLINE | ID: mdl-35221388

RESUMEN

The amendment of the Infection Protection Act at the end of November 2021 made it possible to map vaccinated, recovered and tested employees at the firm-level for the first time after the start of vaccinations in Germany. The Employers' Associations of Lower Saxony (UVN), IHK Hannover, creditreform and the Institute for Economic Policy at Leibniz University Hanover conducted a short online survey on the vaccination and recovery status, the number of antigen rapid tests as well as the proportion of employees working from home. The results provide important indications about the general risk in everyday professional life, as well as the associated organisational effort in firms.

16.
Mol Pharmacol ; 100(5): 502-512, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34475108

RESUMEN

The activity of local anesthetics (LAs) has been attributed to the inhibition of ion channels, causing anesthesia. However, there is a growing body of research showing that LAs act on a wide range of receptors and channel proteins far beyond simple analgesia. The current concept of ligand recognition may no longer explain the multitude of protein targets influenced by LAs. We hypothesize that LAs can cause anesthesia without directly binding to the receptor proteins just by changing the physical properties of the lipid bilayer surrounding these proteins and ion channels based on LAs' amphiphilicity. It is possible that LAs act in one of the following ways: They 1) dissolve raft-like membrane microdomains, 2) impede nerve impulse propagation by lowering the lipid phase transition temperature, or 3) modulate the lateral pressure profile of the lipid bilayer. This could also explain the numerous additional effects of LAs besides anesthesia. Furthermore, the concepts of membrane-mediated activity and binding to ion channels do not have to exclude each other. If we were to consider LA as the middle part of a continuum between unspecific membrane-mediated activity on one end and highly specific ligand binding on the other end, we could describe LA as the link between the unspecific action of general anesthetics and toxins with their highly specific receptor binding. This comprehensive membrane-mediated model offers a fresh perspective to clinical and pharmaceutical research and therapeutic applications of local anesthetics. SIGNIFICANCE STATEMENT: Local anesthetics, according to the World Health Organization, belong to the most important drugs available to mankind. Their rediscovery as therapeutics and not only anesthetics marks a milestone in global pain therapy. The membrane-mediated mechanism of action proposed in this review can explain their puzzling variety of target proteins and their thus far inexplicable therapeutic effects. The new concept presented here places LAs on a continuum of structures and molecular mechanisms in between small general anesthetics and the more complex molecular toxins.


Asunto(s)
Potenciales de Acción/fisiología , Anestésicos Locales/metabolismo , Fenómenos Fisiológicos Celulares/fisiología , Microdominios de Membrana/metabolismo , Potenciales de Acción/efectos de los fármacos , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Animales , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Fenómenos Fisiológicos Celulares/efectos de los fármacos , Humanos , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/metabolismo , Membrana Dobles de Lípidos/metabolismo , Microdominios de Membrana/efectos de los fármacos , Estructura Secundaria de Proteína
17.
J Neurochem ; 156(6): 802-818, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33155274

RESUMEN

The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.


Asunto(s)
Amiloidosis Familiar/tratamiento farmacológico , Amiloidosis Familiar/genética , Prealbúmina/efectos de los fármacos , Amiloide/antagonistas & inhibidores , Amiloide/biosíntesis , Amiloide/genética , Amiloidosis Familiar/fisiopatología , Animales , Técnicas de Silenciamiento del Gen , Humanos , Prealbúmina/genética
18.
Appetite ; 156: 104858, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-32891676

RESUMEN

Negative affect and poor inhibitory control are related to disinhibited eating behaviors in youth and may contribute to the development and/or maintenance of obesity. Although few studies have jointly examined these constructs in youth, it has been theorized that poor inhibitory control may be driven by negative affect. If supported, impaired inhibitory control, driven by negative affect, could represent a modifiable neurocognitive treatment target for disinhibited eating. The current study examined whether inhibitory control mediates the relationship between negative affect and eating among youth. Youth (8-17 years) participated in a Food Go/No-Go neurocognitive task to measure inhibitory control as the percentage of commission errors. A composite negative affect score was created from self-report measures of anxiety and depression. A laboratory buffet meal modeled to simulate disinhibited eating was used to measure total and snack food intake. Cross-sectional mediation models with bias-corrected bootstrap confidence intervals (CI) were conducted using negative affect as the independent variable, inhibitory control as the mediator, and intake patterns as dependent variables. One-hundred-eighty-one youths (13.2 ± 2.7y; 55% female; BMIz 0.6 ± 1.0) were studied. Total Go/No-Go commission errors mediated the relationship between negative affect and total intake (95%CI = [0.3, 31.6]), but not snack intake (95%CI = [-2.5, 7.3]). Commission errors for Food-Go blocks significantly mediated the relationship between negative affect and total intake (95%CI = [7.7, 44.4]), but not snack intake (95%CI = [-3.4, 9.5]). Commission errors on Neutral-Go blocks did not significantly mediate any of these relationships. Negative affect may lead to poorer inhibitory control as well as a stronger approach tendency toward food, increasing the likelihood of engaging in disinhibited eating. Future research should determine if, in combination with approaches to reduce negative affect, improved inhibitory control could help prevent overeating in youths with depressive or anxiety symptoms.


Asunto(s)
Conducta Alimentaria , Bocadillos , Adolescente , Estudios Transversales , Ingestión de Alimentos , Ingestión de Energía , Femenino , Humanos , Hiperfagia , Masculino
19.
J Neuroeng Rehabil ; 18(1): 37, 2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33596942

RESUMEN

BACKGROUND: The foot progression angle is an important measure used to help patients reduce their knee adduction moment. Current measurement systems are either lab-bounded or do not function in all environments (e.g., magnetically distorted). This work proposes a novel approach to estimate foot progression angle using a single foot-worn inertial sensor (accelerometer and gyroscope). METHODS: The approach uses a dynamic step frame that is recalculated for the stance phase of each step to calculate the foot trajectory relative to that frame, to minimize effects of drift and to eliminate the need for a magnetometer. The foot progression angle (FPA) is then calculated as the angle between walking direction and the dynamic step frame. This approach was validated by gait measurements with five subjects walking with three gait types (normal, toe-in and toe-out). RESULTS: The FPA was estimated with a maximum mean error of ~ 2.6° over all gait conditions. Additionally, the proposed inertial approach can significantly differentiate between the three different gait types. CONCLUSION: The proposed approach can effectively estimate differences in FPA without requiring a heading reference (magnetometer). This work enables feedback applications on FPA for patients with gait disorders that function in any environment, i.e. outside of a gait lab or in magnetically distorted environments.


Asunto(s)
Análisis de la Marcha/instrumentación , Dispositivos Electrónicos Vestibles , Acelerometría/instrumentación , Adulto , Fenómenos Biomecánicos , Pie/fisiopatología , Humanos , Masculino
20.
Wirtschaftsdienst ; 101(4): 305-310, 2021.
Artículo en Alemán | MEDLINE | ID: mdl-33897059

RESUMEN

The low representation of women in leadership positions has induced the EU Commission to define measures and targets for gender equality. Almost simultaneously, the measures adopted in the coronavirus pandemic have led to profound changes in the organisation of work. These can slow or inhibit the process. This article provides an overview of the situation of women in leadership positions and the most important reasons for their underrepresentation. Special attention is paid to the effects of the COVID-19 measures in order to identify opportunities and risks. It becomes clear that the same measures entail both positive and negative effects through behavioural changes. Nevertheless, in the long term, women are likely to benefit significantly from the new conditions.

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