Exploring Structural Insights of Aß42 and α-Synuclein Monomers and Heterodimer: A Comparative Study Using Implicit and Explicit Solvent Simulations.

Protein misfolding, aggregation, and fibril formation play a central role in the development of severe neurological disorders, including Alzheimer's and Parkinson's diseases. The structural stability of mature fibrils in these diseases is of great importance, as organisms struggle to effectively eliminate amyloid plaques. To address this issue, it is crucial to investigate the early stages of fibril formation when monomers aggregate into small, toxic, and soluble oligomers. However, these structures are inherently disordered, making them challenging to study through experimental approaches. Recently, it has been shown experimentally that amyloid-ß 42 (Aß42) and α-synuclein (α-Syn) can coassemble. This has motivated us to investigate the interaction between their monomers as a first step toward exploring the possibility of forming heterodimeric complexes. In particular, our study involves the utilization of various Amber and CHARMM force-fields, employing both implicit and explicit solvent models in replica exchange and conventional simulation modes. This comprehensive approach allowed us to assess the strengths and weaknesses of these solvent models and force fields in comparison to experimental and theoretical findings, ensuring the highest level of robustness. Our investigations revealed that Aß42 and α-Syn monomers can indeed form stable heterodimers, and the resulting heterodimeric model exhibits stronger interactions compared to the Aß42 dimer. The binding of α-Syn to Aß42 reduces the propensity of Aß42 to adopt fibril-prone conformations and induces significant changes in its conformational properties. Notably, in AMBER-FB15 and CHARMM36m force fields with the use of explicit solvent, the presence of Aß42 significantly increases the ß-content of α-Syn, consistent with the experiments showing that Aß42 triggers α-Syn aggregation. Our analysis clearly shows that although the use of implicit solvent resulted in too large compactness of monomeric α-Syn, structural properties of monomeric Aß42 and the heterodimer were preserved in explicit-solvent simulations. We anticipate that our study sheds light on the interaction between α-Syn and Aß42 proteins, thus providing the atom-level model required to assess the initial stage of aggregation mechanisms related to Alzheimer's and Parkinson's diseases.

Paradoxical Activation of a Type VI Secretion System Phospholipase Effector by Its Cognate Immunity Protein.

Type VI secretion systems (T6SSs) deliver cytotoxic effector proteins into target bacteria and eukaryotic host cells. Antibacterial effectors are invariably encoded with cognate immunity proteins that protect the producing cell from self-intoxication. Here, we identify transposon insertions that disrupt the tli immunity gene of Enterobacter cloacae and induce autopermeabilization through unopposed activity of the Tle phospholipase effector. This hyperpermeability phenotype is T6SS dependent, indicating that the mutants are intoxicated by Tle delivered from neighboring sibling cells rather than by internally produced phospholipase. Unexpectedly, an in-frame deletion of tli does not induce hyperpermeability because Δtli null mutants fail to deploy active Tle. Instead, the most striking phenotypes are associated with disruption of the tli lipoprotein signal sequence, which prevents immunity protein localization to the periplasm. Immunoblotting reveals that most hyperpermeable mutants still produce Tli, presumably from alternative translation initiation codons downstream of the signal sequence. These observations suggest that cytosolic Tli is required for the activation and/or export of Tle. We show that Tle growth inhibition activity remains Tli dependent when phospholipase delivery into target bacteria is ensured through fusion to the VgrG ß-spike protein. Together, these findings indicate that Tli has distinct functions, depending on its subcellular localization. Periplasmic Tli acts as a canonical immunity factor to neutralize incoming effector proteins, while a cytosolic pool of Tli is required to activate the phospholipase domain of Tle prior to T6SS-dependent export. IMPORTANCE Gram-negative bacteria use type VI secretion systems deliver toxic effector proteins directly into neighboring competitors. Secreting cells also produce specific immunity proteins that neutralize effector activities to prevent autointoxication. Here, we show the Tli immunity protein of Enterobacter cloacae has two distinct functions, depending on its subcellular localization. Periplasmic Tli acts as a canonical immunity factor to block Tle lipase effector activity, while cytoplasmic Tli is required to activate the lipase prior to export. These results indicate Tle interacts transiently with its cognate immunity protein to promote effector protein folding and/or packaging into the secretion apparatus.

Paradoxical activation of a type VI secretion system (T6SS) phospholipase effector by its cognate immunity protein.

Type VI secretion systems (T6SS) deliver cytotoxic effector proteins into target bacteria and eukaryotic host cells. Antibacterial effectors are invariably encoded with cognate immunity proteins that protect the producing cell from self-intoxication. Here, we identify transposon insertions that disrupt the tli immunity gene of Enterobacter cloacae and induce auto-permeabilization through unopposed activity of the Tle phospholipase effector. This hyper-permeability phenotype is T6SS-dependent, indicating that the mutants are intoxicated by Tle delivered from neighboring sibling cells rather than by internally produced phospholipase. Unexpectedly, an in-frame deletion of tli does not induce hyper-permeability because Δ tli null mutants fail to deploy active Tle. Instead, the most striking phenotypes are associated with disruption of the tli lipoprotein signal sequence, which prevents immunity protein localization to the periplasm. Immunoblotting reveals that most hyper-permeable mutants still produce Tli, presumably from alternative translation initiation codons downstream of the signal sequence. These observations suggest that cytosolic Tli is required for the activation and/or export of Tle. We show that Tle growth inhibition activity remains Tli-dependent when phospholipase delivery into target bacteria is ensured through fusion to the VgrG ß-spike protein. Together, these findings indicate that Tli has distinct functions depending on its subcellular localization. Periplasmic Tli acts as a canonical immunity factor to neutralize incoming effector proteins, while a cytosolic pool of Tli is required to activate the phospholipase domain of Tle prior to T6SS-dependent export.

Proteolytic processing induces a conformational switch required for antibacterial toxin delivery.

Many Gram-negative bacteria use CdiA effector proteins to inhibit the growth of neighboring competitors. CdiA transfers its toxic CdiA-CT region into the periplasm of target cells, where it is released through proteolytic cleavage. The N-terminal cytoplasm-entry domain of the CdiA-CT then mediates translocation across the inner membrane to deliver the C-terminal toxin domain into the cytosol. Here, we show that proteolysis not only liberates the CdiA-CT for delivery, but is also required to activate the entry domain for membrane translocation. Translocation function depends on precise cleavage after a conserved VENN peptide sequence, and the processed ∆VENN entry domain exhibits distinct biophysical and thermodynamic properties. By contrast, imprecisely processed CdiA-CT fragments do not undergo this transition and fail to translocate to the cytoplasm. These findings suggest that CdiA-CT processing induces a critical structural switch that converts the entry domain into a membrane-translocation competent conformation.

Content and delivery preferences for information to support the management of high blood pressure.

Blood pressure(BP) management interventions have been shown to be more effective when accompanied by appropriate patient education. As high BP remains poorly controlled, there may be gaps in patient knowledge and education. Therefore, this study aimed to identify specific content and delivery preferences for information to support BP management among Australian adults from the general public. Given that BP management is predominantly undertaken by general practitioners(GPs), information preferences to support BP management were also ascertained from a small sample of Australian GPs. An online survey of adults was conducted to identify areas of concern for BP management to inform content preferences and preferred format for information delivery. A separate online survey was also delivered to GPs to determine preferred information sources to support BP management. Participants were recruited via social media. General public participants (n = 465) were mostly female (68%), >60 years (57%) and 49% were taking BP-lowering medications. The management of BP without medications, and role of lifestyle in BP management were of concern among 30% and 26% of adults respectively. Most adults (73%) preferred to access BP management information from their GP. 57% of GPs (total n = 23) preferred information for supporting BP management to be delivered via one-page summaries. This study identified that Australian adults would prefer more information about the management of BP without medications and via lifestyle delivered by their GP. This could be achieved by providing GPs with one-page summaries on relevant topics to support patient education and ultimately improve BP management.

Current status of Phytophthora in Australia.

Among the most economically relevant and environmentally devastating diseases globally are those caused by Phytophthora species. In Australia, production losses in agriculture and forestry result from several well-known cosmopolitan Phytophthora species and infestation of natural ecosystems by Phytophthora cinnamomi have caused irretrievable loss to biodiversity especially in proteaceous dominated heathlands. For this review, all available records of Phytophthora in Australia were collated and curated, resulting in a database of 7 869 records, of which 2 957 have associated molecular data. Australian databases hold records for 99 species, of which 20 are undescribed. Eight species have no records linked to molecular data, and their presence in Australia is considered doubtful. The 99 species reside in 10 of the 12 clades recognised within the complete phylogeny of Phytophthora. The review includes discussion on each of these species' status and additional information provided for another 29 species of concern. The first species reported in Australia in 1900 was Phytophthora infestans. By 2000, 27 species were known, predominantly from agriculture. The significant increase in species reported in the subsequent 20 years has coincided with extensive surveys in natural ecosystems coupled with molecular taxonomy and the recognition of numerous new phylogenetically distinct but morphologically similar species. Routine and targeted surveys within Australian natural ecosystems have resulted in the description of 27 species since 2009. Due to the new species descriptions over the last 20 years, many older records have been reclassified based on molecular identification. The distribution of records is skewed toward regions with considerable activity in high productivity agriculture, horticulture and forestry, and native vegetation at risk from P. cinnamomi. Native and exotic hosts of different Phytophthora species are found throughout the phylogeny; however, species from clades 1, 7 and 8 are more likely to be associated with exotic hosts. One of the most difficult challenges to overcome when establishing a pest status is a lack of reliable data on the current state of a species in any given country or location. The database compiled here for Australia and the information provided for each species overcomes this challenge. This review will aid federal and state governments in risk assessments and trade negotiations by providing a comprehensive resource on the current status of Phytophthora species in Australia. Citation: Burgess TI, Edwards J, Drenth A, et al. 2021. Current status of Phytophthora in Australia. Persoonia 47: 151-177. https://doi.org/10.3767/persoonia.2021.47.05.

Current status of Phytophthora in Australia.

Among the most economically relevant and environmentally devastating diseases globally are those caused by Phytophthora species. In Australia, production losses in agriculture and forestry result from several well-known cosmopolitan Phytophthora species and infestation of natural ecosystems by Phytophthora cinnamomi have caused irretrievable loss to biodiversity especially in proteaceous dominated heathlands. For this review, all available records of Phytophthora in Australia were collated and curated, resulting in a database of 7 869 records, of which 2 957 have associated molecular data. Australian databases hold records for 99 species, of which 20 are undescribed. Eight species have no records linked to molecular data, and their presence in Australia is considered doubtful. The 99 species reside in 10 of the 12 clades recognised within the complete phylogeny of Phytophthora. The review includes discussion on each of these species' status and additional information provided for another 29 species of concern. The first species reported in Australia in 1900 was Phytophthora infestans. By 2000, 27 species were known, predominantly from agriculture. The significant increase in species reported in the subsequent 20 years has coincided with extensive surveys in natural ecosystems coupled with molecular taxonomy and the recognition of numerous new phylogenetically distinct but morphologically similar species. Routine and targeted surveys within Australian natural ecosystems have resulted in the description of 27 species since 2009. Due to the new species descriptions over the last 20 years, many older records have been reclassified based on molecular identification. The distribution of records is skewed toward regions with considerable activity in high productivity agriculture, horticulture and forestry, and native vegetation at risk from P. cinnamomi. Native and exotic hosts of different Phytophthora species are found throughout the phylogeny; however, species from clades 1, 7 and 8 are more likely to be associated with exotic hosts. One of the most difficult challenges to overcome when establishing a pest status is a lack of reliable data on the current state of a species in any given country or location. The database compiled here for Australia and the information provided for each species overcomes this challenge. This review will aid federal and state governments in risk assessments and trade negotiations by providing a comprehensive resource on the current status of Phytophthora species in Australia. Citation: Burgess TI, Edwards J, Drenth A, et al. 2021. Current status of Phytophthora in Australia. Persoonia 47: 151-177. https://doi.org/10.3767/persoonia.2021.47.05.

German Respiratory Society guidelines for diagnosis and treatment of adults suffering from acute, subacute and chronic cough.

The present 2019 S2k consensus guideline of the German Respiratory Society was written for pneumologists - in contrast to the more general predecessor's S3 guidelines from 2004 to 2010 -, since 2014 the German College of General Practitioners and Family Physicians (DEGAM) published their own cough guidelines. The guidelines contain 48 recommendations agreed upon the consensus and 16 statements, which are explained in the background text in the following nine chapters: epidemiology, physiology, classification, acute, subacute or chronic cough, diagnostics and therapy; an extra chapter was dedicated to chronic idiopathic/refractory cough. Further emphasis of the guidelines is the physiology of cough in anticipation of the introduction of new drugs, as well as detailed treatment for cough triggered by affectations of the upper respiratory tract or gastroesophageal reflux. The guideline should provide the pneumologist with the latest knowledge for neighboring disciplines required for diagnosis and therapy of cough. The clinical chapters also contain a short summary, practical recommendations and a bibliography of their own. Three new simplified algorithms for acute, subacute and chronic cough, round off the diagnostics chapter.

[Guidelines of the German Respiratory Society for Diagnosis and Treatment of Adults Suffering from Acute, Subacute and Chronic Cough]. / Leitlinie der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin zur Diagnostik und Therapie von erwachsenen Patienten mit Husten.

The present 2019 S2k consensus guideline of the German Respiratory Society was written - in contrast to the predecessor more general S3 guidelines from 2004 and 2010 - for pneumologists, since 2014 the German College of General Practitioners and Family Physicians (DEGAM) published his own cough guidelines.The guideline contains 48 recommendations agreed by consensus and 16 statements, which are explained in the background text in the following nine chapters: epidemiology, physiology, classification, acute, subacute or chronic cough, diagnostics and therapy; an extra chapter was dedicated to chronic idiopathic cough. Further emphasis of the guideline is the physiology of cough in anticipation of the introduction of new drugs, as well as detailed treatises on cough triggered by affections in the upper respiratory tract or by gastroesophageal reflux. The guideline should provide the pneumologist with the latest knowledge from neighboring disciplines required for diagnosis and therapy of cough. The clinical chapters also contain a short summary, practical recommendations and a bibliography of their own. Three new, simplified algorithms for acute, subacute and chronic cough round off the Diagnostics chapter.

Single-Procedure Outcomes and Quality-of-Life Improvement 12 Months Post-Cryoballoon Ablation in Persistent Atrial Fibrillation: Results From the Multicenter CRYO4PERSISTENT AF Trial.

OBJECTIVES: The CRYO4PERSISTENT AF (Cryoballoon Ablation for Early Persistent Atrial Fibrillation) trial aims to report long-term outcomes after a single pulmonary vein isolation (PVI)-only ablation procedure using the second-generation cryoballoon in persistent atrial fibrillation (PerAF) patients. BACKGROUND: Pulmonary vein isolation is recognized as the cornerstone of atrial fibrillation (AF) ablation, including ablation of PerAF. METHODS: The CRYO4PERSISTENT AF trial (NCT02213731) is a prospective, multicenter, single-arm trial designed to assess single-procedure outcomes of PVI using the cryoballoon. The primary endpoint was freedom from AF, atrial flutter, or atrial tachycardia ≥30 s after a 90-day blanking period. After enrollment, but before ablation, patients without 100% AF burden (18-h Holter monitoring or 3 consecutive electrocardiograms in a time frame ≥14 days) were excluded. Patients were followed at 3, 6, and 12 months, with 48-h Holter monitoring at 6 and 12 months. Quality of life and symptoms were evaluated at baseline and 12 months. Arrhythmia recurrence and adverse events were adjudicated by an independent committee. RESULTS: A total of 101 patients (62 ± 11 years of age, 74% men, left ventricular ejection fraction 56 ± 8%, left atrial diameter 43 ± 5 mm) meeting criteria, undergoing cryoballoon-based PVI, with follow-up data, were included. Kaplan-Meier estimate of freedom from AF, atrial flutter, or atrial tachycardia recurrence was 60.7% at 12 months. Compared with baseline, there were significantly fewer patients with arrhythmia-related symptoms at 12 months (16% vs. 92%; p < 0.0001). The symptom reduction was supported by significant improvement in 36-Item Short Form Health Survey composite scores and European Heart Rhythm Association score at 12 months. The only device related event was transient phrenic nerve injury in 2 (2%) patients, with resolution pre-discharge. CONCLUSIONS: Cryoballoon ablation for treatment of PerAF demonstrated 61% single-procedure success at 12 months post-ablation in addition to significant reduction in arrhythmia-related symptoms and improved quality of life. (Cryoballoon Ablation for Early Persistent Atrial Fibrillation [Cryo4 Persistent AF]; NCT02213731).

Interest of Anorectal Manometry During Long-term Follow-up of Patients Operated on for Hirschsprung's Disease.

BACKGROUND/AIMS: Although many advances in the management of Hirschsprung's disease have recently been achieved, postoperative outcomes of these patients remain difficult in a non-negligible number of cases. Therefore, this study aims at investigating characteristics of anorectal manometry and its relationship with postoperative outcomes during long-term follow-up in Hirschsprung patients. METHODS: Patients over 4 years of age operated on for Hirschsprung's disease were interviewed to complete detailed questionnaires on bowel function. The patients who consented to undergo an anorectal manometry during follow-up were enrolled in this study. We investigated their clinical characteristics, manometric findings, and their postoperative bowel function. RESULTS: Nineteen patients out of 53 patients (35.8%) were enrolled, 68.4% who were male. Mean age of patients at manometry was 11.3 ± 6.3 years. Twelve out of 19 patients (63.2%) were incontinent. The mean anal resting pressures of incontinent patients were significantly lower than continent patients (47 ± 12 mmHg versus 63 ± 11 mmHg, P < 0.05, t test). Due to neurological impairment, only 11 patients (57.9%) were able to perform a complete manometry. A dyssynergic defecation was found in 4 patients during strain tests. Maximum tolerated volume of the incontinent patients was significantly lower than that of the continent patients (97 ± 67 mL versus 181 ± 74 mL, P < 0.05, t test). CONCLUSION: Anorectal manometry is an objective method providing useful information that could guide a more adapted management in patients with defecation disorders after Hirschsprung's disease operation.

High probability of comorbidities in bronchial asthma in Germany.

Clinical experience has shown that allergic and non-allergic respiratory, metabolic, mental, and cardiovascular disorders sometimes coexist with bronchial asthma. However, no study has been carried out that calculates the chance of manifestation of these disorders with bronchial asthma in Saarland and Rhineland-Palatinate, Germany. Using ICD10 diagnoses from health care institutions, the present study systematically analyzed the co-prevalence and odds ratios of comorbidities in the asthma population in Germany. The odds ratios were adjusted for age and sex for all comorbidities for patients with asthma vs. without asthma. Bronchial asthma was strongly associated with allergic and with a lesser extent to non-allergic comorbidities: OR 7.02 (95%CI:6.83-7.22) for allergic rhinitis; OR 4.98 (95%CI:4.67-5.32) allergic conjunctivitis; OR 2.41 (95%CI:2.33-2.52) atopic dermatitis; OR 2.47 (95%CI:2.16-2.82) food allergy, and OR 1.69 (95%CI:1.61-1.78) drug allergy. Interestingly, increased ORs were found for respiratory diseases: 2.06 (95%CI:1.64-2.58) vocal dysfunction; 1.83 (95%CI:1.74-1.92) pneumonia; 1.78 (95%CI:1.73-1.84) sinusitis; 1.71 (95%CI:1.65-1.78) rhinopharyngitis; 2.55 (95%CI:2.03-3.19) obstructive sleep apnea; 1.42 (95%CI:1.25-1.61) pulmonary embolism, and 3.75 (95%CI:1.64-8.53) bronchopulmonary aspergillosis. Asthmatics also suffer from psychiatric, metabolic, cardiac or other comorbidities. Myocardial infarction (OR 0.86, 95%CI:0.79-0.94) did not coexist with asthma. Based on the calculated chances of manifestation for these comorbidities, especially allergic and respiratory, to a lesser extent also metabolic, cardiovascular, and mental disorders should be taken into consideration in the diagnostic and treatment strategy of bronchial asthma. BRONCHIAL ASTHMA: PREVALENCE OF CO-EXISTING DISEASES IN GERMANY: Patients in Germany with bronchial asthma are highly likely to suffer from co-existing diseases and their treatments should reflect this. Quoc Thai Dinh at Saarland University Hospital in Homburg, Germany, and co-workers conducted a large-scale study of patients presenting with bronchial asthma in the Saarland region between 2009 and 2012. Patients with asthma made up 5.4% of the region's total population, with a higher prevalence occurring in females. They found that bronchial asthma was strongly associated with allergic comorbidities such as rhinitis. Indeed, asthmatic patients had a seven times higher chance to suffer from allergic rhinitis than the rest of the population, and were at higher risk of respiratory diseases like pneumonia and obstructive sleep apnea syndrome. Further associations included cardiovascular, metabolic and mental disorders. Dinh's team call for asthma treatments to take such comorbidities into account.

Nonfluoroscopic Imaging as Guidance for Radiofrequency Ablation of Atrioventricular Nodal Reentrant Tachycardia after Mustard Repair.

Most tachycardias in the pulmonary venous atrium are inaccessible by direct means and require either a retrograde approach or a transseptal approach for ablation. We present a case in which successful radiofrequency ablation of common atrioventricular nodal reentrant tachycardia was accomplished via a retrograde transaortic approach guided by nonfluoroscopic mapping with use of the NavX™ mapping system. The patient was a 49-year-old woman who at the age of 4 years had undergone Mustard repair for complete dextrotransposition of the great arteries. Three-dimensional reconstructions of the ascending aorta, right ventricle, systemic venous atrium, left ventricle, and superior vena cava-inferior vena cava baffle complex were created, and the left-sided His bundle was marked. After a failed attempt at ablation from the systemic venous side, we eliminated the atrioventricular nodal reentrant tachycardia by ablation from the pulmonary venous side. This case is, to our knowledge, the first report of successful radiofrequency ablation of common atrioventricular nodal reentrant tachycardia after Mustard repair for this congenital cardiac malformation in which ablation was guided by 3-dimensional nonfluoroscopic imaging. This imaging technique enabled accurate anatomic location of the ablation catheters in relation to the His bundle marked from the systemic venous side.

Local Effects on Airway Inflammation and Systemic Uptake of 5 nm PEGylated and Citrated Gold Nanoparticles in Asthmatic Mice.

Nanotechnology is showing promise in many medical applications such as drug delivery and hyperthermia. Nanoparticles administered to the respiratory tract cause local reactions and cross the blood-air barrier, thereby providing a means for easy systemic administration but also a potential source of toxicity. Little is known about how these effects are influenced by preexisting airway diseases such as asthma. Here, BALB/c mice are treated according to the ovalbumin (OVA) asthma protocol to promote allergic airway inflammation. Dispersions of polyethylene-glycol-coated (PEGylated) and citrate/tannic-acid-coated (citrated) 5 nm gold nanoparticles are applied intranasally to asthma and control groups, and (i) airway resistance and (ii) local tissue effects are measured as primary endpoints. Further, nanoparticle uptake into extrapulmonary organs is quantified by inductively coupled plasma mass spectrometry. The asthmatic precondition increases nanoparticle uptake. Moreover, systemic uptake is higher for PEGylated gold nanoparticles compared to citrated nanoparticles. Nanoparticles inhibit both inflammatory infiltrates and airway hyperreactivity, especially citrated gold nanoparticles. Although the antiinflammatory effects of gold nanoparticles might be of therapeutic benefit, systemic uptake and consequent adverse effects must be considered when designing and testing nanoparticle-based asthma therapies.

Transcriptional down-regulation of suppressor of cytokine signaling (SOCS)-3 in chronic obstructive pulmonary disease.

BACKGROUND: Tobacco is a leading environmental factor in the initiation of respiratory diseases and causes chronic obstructive pulmonary disease (COPD). Suppressor of cytokine signaling (SOCS) family members are involved in the pathogenesis of many inflammatory diseases and SOCS-3 has been shown to play an important role in the regulation, onset and maintenance of airway allergic inflammation indicating that SOCS-3 displays a potential therapeutic target for anti-inflammatory respiratory drugs development. Since chronic obstructive pulmonary disease (COPD) is also characterized by inflammatory changes and airflow limitation, the present study assessed the transcriptional expression of SOCS-3 in COPD. METHODS: Real-time PCR was performed to assess quantitative changes in bronchial biopsies of COPD patients in comparison to unaffected controls. RESULTS: SOCS-3 was significantly down-regulated in COPD at the transcriptional level while SOCS-4 and SOCS-5 displayed no change. CONCLUSIONS: It can be concluded that the presently observed inhibition of SOCS-3 mRNA expression may be related to the dysbalance of cytokine signaling observed in COPD.

[Pathophysiology, diagnostics and therapy of chronic cough: neuronal reflexes and antitussiva]. / Pathophysiologie, Diagnostik und Therapie von chronischem Husten: Neuronale Reflexe und Antitussiva.

Cough is the number one symptom for patients to visit a physician worldwide. It is an important neuronal reflex which serves to protect the airways from inhaled exogenous microorganisms, thermal and chemical irritants. Moreover, it prevents the airways from mucus retention.The cough reflex is initiated by activation of different cough receptors. These cough receptors can be divided into three groups according to their electrophysiological properties: into the two Aδ-fiber types "rapid-adapting mechanoreceptor" (RAR) and "slow-adapting mechanoreceptor" (SAR), and the C-fiber receptor.The stimulus is detected by cough receptors which conduct the signal to the cerebral cough centre via vagal-sensory neurons. The cough itself is mediated by efferent motoneurons. Hence the cough reflex consists of 5 functionally sequential parts 1: the cough receptors 2, the primary afferent fibres of the N. vagus 345, N. trigeminus and N. glossopharyngeus 1, the cough centre in the medulla oblongata (N. tractus solitarius) 678, the afferent fibres of the N. phrenicus, spinal nerve and N. laryngeus recurrens, as well as the diaphragm and the abdominal, intercostal and laryngeal muscles. The cough receptors are mainly located in the larynx, trachea and main bronchi 2.The event of coughing can be divided into four subsequent parts: After the first phase of fast inspiration with an opened glottis, there is compression with a closed glottis and increasing tracheal pressure, acceleration and ultimately maximum expiration with an opened glottis 9. According to its characteristics, cough can be split into two distinct types, "aspiration cough", which is loud and involuntary, and "urge-to-cough sensation", which describes an irritant, scratchy, and controlled cough of slowly increasing intensity 10.Acute cough mostly develops because of infection of the respiratory system 111213 and ends spontaneously after 4 weeks. In contrast to this, bacterial infection with pathogens like Adenovirus, Bordetella pertussis and Mycoplasms can last up to 8 weeks 121314. In additional to the division of cough according to its cause, it can also be differentiated according to its manner: dry and mucus-producing cough.With this review we want to give an overview of neuronal processes and mechanisms, as well as diagnostics of and therapy for chronic cough. Thereby the focus is also placed on the efficiency of already established and potential future antitussive agents.

Characterization of MADS-domain transcription factor complexes in Arabidopsis flower development.

Floral organs are specified by the combinatorial action of MADS-domain transcription factors, yet the mechanisms by which MADS-domain proteins activate or repress the expression of their target genes and the nature of their cofactors are still largely unknown. Here, we show using affinity purification and mass spectrometry that five major floral homeotic MADS-domain proteins (AP1, AP3, PI, AG, and SEP3) interact in floral tissues as proposed in the "floral quartet" model. In vitro studies confirmed a flexible composition of MADS-domain protein complexes depending on relative protein concentrations and DNA sequence. In situ bimolecular fluorescent complementation assays demonstrate that MADS-domain proteins interact during meristematic stages of flower development. By applying a targeted proteomics approach we were able to establish a MADS-domain protein interactome that strongly supports a mechanistic link between MADS-domain proteins and chromatin remodeling factors. Furthermore, members of other transcription factor families were identified as interaction partners of floral MADS-domain proteins suggesting various specific combinatorial modes of action.

[Innervation of the airways in asthma bronchiale and chronic obstructive pulmonary disease (COPD)]. / Neuronale Kontrolle bei chronisch entzündlichen und obstruktiven Lungenerkrankungen wie Asthma bronchiale und COPD.

Airway nerves have the capacity to control airway functions via neuronal reflexes and through neuromediators and neuropeptides. Neuronal mechanisms are known to play a key role in the initiation and modulation of airway hyperresponsiveness and inflammation. Therefore, the nerve fibres may contribute to airway narrowing in asthma and COPD. In addition to the traditional transmitters such as norepinephrine in postganglionic sympathetic nerve fibres and acetylcholine in parasympathetic nerve fibres, a large number of neuropeptides have been identified to have different pharmacological effects on the muscle tone of the vessels and bronchi, mucus secretion and immune cells. Meanwhile, a broad range of stimuli including capsaicin, bradykinin, hyperosmolar saline, tobacco smoke, allergens, ozone, inflammatory mediators and even cold, dry air have been shown to activate sensory nerve fibres to release neuropeptides such as the tachykinins substance P (SP) and neurokinin A (NKA) to mediate neurogenic inflammation. Different aspects of the neurogenic inflammation have been well studied in animal models of chronic airway inflammation and anticholinergic agents such as ipratropium bromide (Atrovent (®)) and tiotropium bromide (Spiriva (®)) have been proved to be important when used as bronchodilators for the treatment of obstructive airway diseases such as COPD. However, little is known about the role of neurogenic airway inflammation in human diseases. In this review, we address the current knowledge of the airway sensory nerves in human asthma and COPD.