Structure and function of the N-terminal extension of the formin INF2

In INF2—a formin linked to inherited renal and neurological disease in humans—the DID is preceded by a short N-terminal extension of unknown structure and function. INF2 activation is achieved by Ca2+-dependent association of calmodulin (CaM). Here, we show that the N-terminal extension of INF2 is organized into two α-helices, the first of which is necessary to maintain the perinuclear F-actin ring and normal cytosolic F-actin content. Biochemical assays indicated that this helix interacts directly with CaM and contains the sole CaM-binding site (CaMBS) detected in INF2. The residues W11, L14 and L18 of INF2, arranged as a 1-4-8 motif, were identified as the most important residues for the binding, W11 being the most critical of the three. This motif is conserved in vertebrate INF2 and in the human population. NMR and biochemical analyses revealed that CaM interacts directly through its C-terminal lobe with the INF2 CaMBS. Unlike control cells, INF2 KO cells lacked the perinuclear F-actin ring, had little cytosolic F-actin content, did not respond to increased Ca2+ concentrations by making more F-actin, and maintained the transcriptional cofactor MRTF predominantly in the cytoplasm. Whereas expression of intact INF2 restored all these defects, INF2 with inactivated CaMBS did not. Our study reveals the structure of the N-terminal extension, its interaction with Ca2+/CaM, and its function in INF2 activatio

MEG spectral analysis in subtypes of mild cognitive impairment

Mild cognitive impairment (MCI) has been described as an intermediate stage between normal aging and dementia. Previous studies characterized the alterations of brain oscillatory activity at this stage, but little is known about the differences between single and multidomain amnestic MCI patients. In order to study the patterns of oscillatory magnetic activity in amnestic MCI subtypes, a total of 105 subjects underwent an eyes-closed resting-state magnetoencephalographic recording: 36 healthy controls, 33 amnestic single domain MCIs (a-sd-MCI), and 36 amnestic multidomain MCIs (a-md-MCI). Relative power values were calculated and compared among groups. Subsequently, relative power values were correlated with neuropsychological tests scores and hippocampal volumes. Both MCI groups showed an increase in relative power in lower frequency bands (delta and theta frequency ranges) and a decrease in power values in higher frequency bands (alpha and beta frequency ranges), as compared with the control group. More importantly, clear differences emerged from the comparison between the two amnestic MCI subtypes. The a-md-MCI group showed a significant power increase within delta and theta ranges and reduced relative power within alpha and beta ranges. Such pattern correlated with the neuropsychological performance, indicating that the a-md-MCI subtype is associated not only with a "slowing" of the spectrum but also with a poorer cognitive status. These results suggest that a-md-MCI patients are characterized by a brain activity profile that is closer to that observed in Alzheimer disease. Therefore, it might be hypothesized that the likelihood of conversion to dementia would be higher within this subtype

Multiobjective-Optimized Design of a New UWB Antenna for UWB Applications

A multiobjective genetic algorithm has been applied to design a new printed, bow-tie antenna for ultrawideband applications, that is, ground penetrating radar, short range and high data rate communications, and so forth. The ultrawideband performance with respect to antenna impedance and gain is achieved by an optimized resistive loading profile and flare angle. A low-cost prototype is manufactured and numerical simulations are validated with measurements

CD38 Deficiency Ameliorates Chronic Graft-Versus-Host Disease Murine Lupus via a B-Cell-Dependent Mechanism

© 2021 Martínez-Blanco, Domínguez-Pantoja, Botía-Sánchez, Pérez-Cabrera, Bello-Iglesias, Carrillo-Rodríguez, Martin-Morales, Lario-Simón, Pérez-Sánchez-Cañete, Montosa-Hidalgo, Guerrero-Fernández, Longobardo-Polanco, Redondo-Sánchez, Cornet-Gomez, Torres-Sáez, Fernández-Ibáñez, Terrón-Camero, Andrés-León, O’Valle, Merino, Zubiaur and Sancho.The absence of the mouse cell surface receptor CD38 in Cd38−/− mice suggests that this receptor acts as a positive regulator of inflammatory and autoimmune responses. Here, we report that, in the context of the chronic graft-versus-host disease (cGVHD) lupus inducible model, the transfer of B6.C-H2bm12/KhEg(bm12) spleen cells into co-isogenic Cd38−/− B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells, and T-bet+CD11chi B cells, were observed in Cd38−/− mice than in WT mice, while the expansion of Treg cells and Tfr cells was normal, suggesting that the ability of Cd38−/− B cells to respond to allogeneic help from bm12 CD4+ T cells is greatly diminished. The frequencies of T-bet+CD11chi B cells, which are considered the precursors of the autoantibody-secreting cells, correlate with anti-ssDNA autoantibody serum levels, IL-27, and sCD40L. Proteomics profiling of the spleens from WT cGVHD mice reflects a STAT1-driven type I IFN signature, which is absent in Cd38−/− cGVHD mice. Kidney, spleen, and liver inflammation was mild and resolved faster in Cd38−/− cGVHD mice than in WT cGVHD mice. We conclude that CD38 in B cells functions as a modulator receptor that controls autoimmune responses.S and MZ received financial support through “Proyecto del Plan Estatal”: SAF2017–89801-R. The IPBLN-CSIC Proteomics Unit belonged to ProteoRed-ISCIII (PRB2; PRB3) and was supported by grants PT13/0001/0011 (IPBLN-CSIC) and PT17/0019/0010 (CIB-CSIC; IPBLN-CSIC). RM: Project: SAF2017-82905-R. FO'V: Cátedra MIS IMPLANT-UGR. The stay of AC-G in Sancho’s lab was supported by a fellowship-contract JAE-Intro (CSIC). The stay of MD-P in Sancho’s lab was supported by a 1-year post-doctoral fellowship (Reference No. 502492) from the Consejo Nacional de Ciencia y Tecnología (CONACYT) of México. EA-L was recipient of a postdoctoral fellowship from the regional Andalusian Government

Accuracy and Survival Outcomes after National Implementation of Sentinel Lymph Node Biopsy in Early Stage Endometrial Cancer

Background. Sentinel lymph node (SLN) biopsy has recently been accepted to evaluate nodal status in endometrial cancer at early stage, which is key to tailoring adjuvant treatments. Our aim was to evaluate the national implementation of SLN biopsy in terms of accuracy to detect nodal disease in a clinical setting and oncologic outcomes according to the volume of nodal disease. Patients and Methods. A total of 29 Spanish centers participated in this retrospective, multicenter registry including patients with endometrial adenocarcinoma at preoperative early stage who had undergone SLN biopsy between 2015 and 2021. Each center collected data regarding demographic, clinical, histologic, therapeutic, and survival characteristics. Results. A total of 892 patients were enrolled. After the surgery, 12.9% were suprastaged to FIGO 2009 stages III-IV and 108 patients (12.1%) had nodal involvement: 54.6% macrometastasis, 22.2% micrometastases, and 23.1% isolated tumor cells (ITC). Sensitivity of SLN biopsy was 93.7% and false negative rate was 6.2%. After a median follow up of 1.81 years, overall surivial and disease-free survival were significantly lower in patients who had macrometastases when compared with patients with negative nodes, micrometastases or ITC. Conclusions. In our nationwide cohort we obtained high sensitivity of SLN biopsy to detect nodal disease. The oncologic outcomes of patients with negative nodes and low-volume disease were similar after tailoring adjuvant treatments. In total, 22% of patients with macrometastasis and 50% of patients with micrometastasis were at low risk of nodal metastasis according to their preoperative risk factors, revealing the importance of SLN biopsy in the surgical management of patients with early stage EC

Design, development and validation of a new laryngo-pharyngeal endoscopic esthesiometer and range-finder based on the assessment of air-pulse variability determinants

BACKGROUND: Laryngo-pharyngeal mechano-sensitivity (LPMS) is involved in dysphagia, sleep apnea, stroke, irritable larynx syndrome and cough hypersensitivity syndrome among other disorders. These conditions are associated with a wide range of airway reflex abnormalities. However, the current device for exploring LPMS is limited because it assesses only the laryngeal adductor reflex during fiber-optic endoscopic evaluations of swallowing and requires a high degree of expertise to obtain reliable results, introducing intrinsic expert variability and subjectivity. METHODS: We designed, developed and validated a new air-pulse laryngo-pharyngeal endoscopic esthesiometer with a built-in laser range-finder (LPEER) based on the evaluation and control of air-pulse variability determinants and on intrinsic observer variability and subjectivity determinants of the distance, angle and site of stimulus impact. The LPEER was designed to be capable of delivering precise and accurate stimuli with a wide range of intensities that can explore most laryngo-pharyngeal reflexes. RESULTS: We initially explored the potential factors affecting the reliability of LPMS tests and included these factors in a multiple linear regression model. The following factors significantly affected the precision and accuracy of the test (P < 0.001): the tube conducting the air-pulses, the supply pressure of the system, the duration of the air-pulses, and the distance and angle between the end of the tube conducting the air-pulses and the site of impact. To control all of these factors, an LPEER consisting of an air-pulse generator and an endoscopic laser range-finder was designed and manufactured. We assessed the precision and accuracy of the LPEER's stimulus and range-finder according to the coefficient of variation (CV) and by looking at the differences between the measured properties and the desired values, and we performed a pilot validation on ten human subjects. The air-pulses and range-finder exhibited good precision and accuracy (CV < 0.06), with differences between the desired and measured properties at <3 % and a range-finder measurement error of <1 mm. The tests in patients demonstrated obtainable and reproducible thresholds for the laryngeal adductor, cough and gag reflexes. CONCLUSIONS: The new LPEER was capable of delivering precise and accurate stimuli for exploring laryngo-pharyngeal reflexes

Sometimes Sperm Whales (Physeter macrocephalus) Cannot Find Their Way Back to the High Seas: A Multidisciplinary Study on a Mass Stranding

BACKGROUND: Mass strandings of sperm whales (Physeter macrocephalus) remain peculiar and rather unexplained events, which rarely occur in the Mediterranean Sea. Solar cycles and related changes in the geomagnetic field, variations in water temperature and weather conditions, coast geographical features and human activities have been proposed as possible causes. In December 2009, a pod of seven male sperm whales stranded along the Adriatic coast of Southern Italy. This is the sixth instance from 1555 in this basin. METHODOLOGY/PRINCIPAL FINDINGS: Complete necropsies were performed on three whales whose bodies were in good condition, carrying out on sampled tissues histopathology, virology, bacteriology, parasitology, and screening of veins looking for gas emboli. Furthermore, samples for age determination, genetic studies, gastric content evaluation, stable isotopes and toxicology were taken from all the seven specimens. The animals were part of the same group and determined by genetic and photo-identification to be part of the Mediterranean population. Causes of death did not include biological agents, or the "gas and fat embolic syndrome", associated with direct sonar exposure. Environmental pollutant tissue concentrations were relatively high, in particular organochlorinated xenobiotics. Gastric content and morphologic tissue examinations showed a prolonged starvation, which likely caused, at its turn, the mobilization of lipophilic contaminants from the adipose tissue. Chemical compounds subsequently entered the blood circulation and may have impaired immune and nervous functions. CONCLUSIONS/SIGNIFICANCE: A multi-factorial cause underlying this sperm whales' mass stranding is proposed herein based upon the results of postmortem investigations as well as of the detailed analyses of the geographical and historical background. The seven sperm whales took the same "wrong way" into the Adriatic Sea, a potentially dangerous trap for Mediterranean sperm whales. Seismic surveys should be also regarded as potential co-factors, even if no evidence of direct impact has been detected