Photonically active bowtie nanoassemblies with chirality continuum.

Chirality is a geometrical property described by continuous mathematical functions1-5. However, in chemical disciplines, chirality is often treated as a binary left or right characteristic of molecules rather than a continuity of chiral shapes. Although they are theoretically possible, a family of stable chemical structures with similar shapes and progressively tuneable chirality is yet unknown. Here we show that nanostructured microparticles with an anisotropic bowtie shape display chirality continuum and can be made with widely tuneable twist angle, pitch, width, thickness and length. The self-limited assembly of the bowties enables high synthetic reproducibility, size monodispersity and computational predictability of their geometries for different assembly conditions6. The bowtie nanoassemblies show several strong circular dichroism peaks originating from absorptive and scattering phenomena. Unlike classical chiral molecules, these particles show a continuum of chirality measures2 that correlate exponentially with the spectral positions of the circular dichroism peaks. Bowtie particles with variable polarization rotation were used to print photonically active metasurfaces with spectrally tuneable positive or negative polarization signatures for light detection and ranging (LIDAR) devices.

Structure of the Arabidopsis thaliana glutamate receptor-like channel GLR3.4.

Glutamate receptor-like channels (GLRs) play vital roles in various physiological processes in plants, such as wound response, stomatal aperture control, seed germination, root development, innate immune response, pollen tube growth, and morphogenesis. Despite the importance of GLRs, knowledge about their molecular organization is limited. Here we use X-ray crystallography and single-particle cryo-EM to solve structures of the Arabidopsis thaliana GLR3.4. Our structures reveal the tetrameric assembly of GLR3.4 subunits into a three-layer domain architecture, reminiscent of animal ionotropic glutamate receptors (iGluRs). However, the non-swapped arrangement between layers of GLR3.4 domains, binding of glutathione through S-glutathionylation of cysteine C205 inside the amino-terminal domain clamshell, unique symmetry, inter-domain interfaces, and ligand specificity distinguish GLR3.4 from representatives of the iGluR family and suggest distinct features of the GLR gating mechanism. Our work elaborates on the principles of GLR architecture and symmetry and provides a molecular template for deciphering GLR-dependent signaling mechanisms in plants.

Alterations in compositional and cellular properties of the subchondral bone are linked to cartilage degeneration in hip osteoarthritis.

OBJECTIVE: The subchondral bone is an emerging regulator of osteoarthritis (OA). However, knowledge of how specific subchondral alterations relate to cartilage degeneration remains incomplete. METHOD: Femoral heads were obtained from 44 patients with primary OA during total hip arthroplasty and from 30 non-OA controls during autopsy. A multiscale assessment of the central subchondral bone region comprising histomorphometry, quantitative backscattered electron imaging, nanoindentation, and osteocyte lacunocanalicular network characterization was employed. RESULTS: In hip OA, thickening of the subchondral bone coincided with a higher number of osteoblasts (controls: 3.7 ± 4.5 mm-1, OA: 16.4 ± 10.2 mm-1, age-adjusted mean difference 10.5 mm-1 [95% CI 4.7 to 16.4], p < 0.001) but a similar number of osteoclasts compared to controls (p = 0.150). Furthermore, higher matrix mineralization heterogeneity (CaWidth, controls: 2.8 ± 0.2 wt%, OA: 3.1 ± 0.3 wt%, age-adjusted mean difference 0.2 wt% [95% CI 0.1 to 0.4], p = 0.011) and lower tissue hardness (controls: 0.69 ± 0.06 GPa, OA: 0.67 ± 0.06 GPa, age-adjusted mean difference -0.05 GPa [95% CI -0.09 to -0.01], p = 0.032) were detected. While no evidence of altered osteocytic perilacunar/canalicular remodeling in terms of fewer osteocyte canaliculi was found in OA, specimens with advanced cartilage degeneration showed a higher number of osteocyte canaliculi and larger lacunocanalicular network area compared to those with low-grade cartilage degeneration. Multiple linear regression models indicated that several subchondral bone properties, especially osteoblast and osteocyte parameters, were closely related to cartilage degeneration (R2 adjusted = 0.561, p < 0.001). CONCLUSION: Subchondral bone properties in OA are affected at the compositional, mechanical, and cellular levels. Based on their strong interaction with cartilage degeneration, targeting osteoblasts/osteocytes may be a promising therapeutic OA approach. DATA AND MATERIALS AVAILABILITY: All data are available in the main text or the supplementary materials.

Patients with Periprosthetic Femoral Hip Fractures are Commonly Classified as Having Osteoporosis Based on DXA Measurements.

Periprosthetic femoral hip fractures are subject to an increasing incidence and are often considered to be related to osteoporosis. However, there are no available studies that have determined the frequency of osteoporosis in affected patients using gold standard dual-energy X-ray absorptiometry (DXA). In this retrospective comparative study, we analyzed the DXA results of 40 patients with periprosthetic femoral hip fractures who were treated surgically in our department. DXA measurements were performed at the total hip and the lumbar spine to determine bone mineral density T-scores. Data were compared to two age-, sex-, and BMI-matched control groups in which patients underwent DXA prior to aseptic revision surgery for other causes or primary THA (consisting of 40 patients each). The mean T-score in the periprosthetic fracture cohort was significantly lower (- 1.78 ± 1.78) than that of the aseptic revision (- 0.65 ± 1.58, mean difference - 1.13 [95% CI - 1.88 to - 0.37]; p = 0.001) and the primary THA cohort (- 0.77 ± 1.34, mean difference - 1.01 [95% CI - 1.77 to - 0.26]; p = 0.005). Accordingly, osteoporosis was detected more frequently (45%) in the fracture cohort compared to patients undergoing aseptic revision (12.5%) and primary THA (10%). In conclusion, almost half of the patients with periprosthetic femoral hip fractures have osteoporosis according to DXA measurements. A regular assessment of bone health in THA enables identification of patients with osteoporosis who likely benefit from initiation of osteoporosis medication and cemented stem fixation.

How to get rich from inflation.

We seem to have rich experience across our visual field. Yet we are surprisingly poor at tasks involving the periphery and low spatial attention. Recently, Lau and collaborators have argued that a phenomenon known as "subjective inflation" allows us to reconcile these phenomena. I show inflation is consistent with multiple interpretations, with starkly different consequences for richness and for theories of consciousness more broadly. What's more, we have only weak reasons favouring any of these interpretations over the others. I provisionally argue for an interpretation on which subjective experience is genuinely rich, but (in peripheral/unattended areas) unreliable as a guide to the external world. The main challenge for this view is that it appears to imply that experience in the periphery is not just unreliable but unstable. However, I argue that this consequence, while initially appearing unintuitive, is in fact plausible.

A clinical risk score enables early prediction of dissatisfaction 1 year after total knee arthroplasty.

PURPOSE: Dissatisfaction after total knee arthroplasty (TKA) is a prevalent and clinically relevant problem that affects approximately 10%-20% of patients. The aim of this study is to identify factors associated with dissatisfaction 1 year after TKA. METHODS: A total of 236 patients undergoing TKA were included in this prospective cohort study. Demographic data, preoperative clinical parameters (e.g., axial alignment, osteoarthritis severity) and patient-reported outcome measures (PROMs) were collected preoperatively, at 1 month and 1 year after TKA, encompassing the Knee Society Score (KSS) and Knee injury and Osteoarthritis Outcome Score (KOOS). The primary outcome was dissatisfaction 1 year after TKA, defined as ≤20 points on the KSS satisfaction scale. A risk score based on multiple regression and area under the curve (AUC) analyses was calculated to predict dissatisfaction. RESULTS: One year after TKA, 16% of the patients were dissatisfied. Dissatisfied patients were significantly younger (p = 0.023) and had a higher body mass index (BMI) (p = 0.007). No differences were observed in preoperative objective (p = 0.903) and functional KSS (p = 0.346), pain (p = 0.306), osteoarthritis severity (p = 0.358), axial knee alignment (p = 0.984) or psychological distress (p = 0.138). The likelihood of dissatisfaction at 1 year was 3.0, 4.0, 7.4, 4.3 and 2.8 times higher amongst patients aged <63.5 years, with a BMI > 30.1 kg/m2, a KOOSPain < 50%, a KSSFunction < 42 points and a KSSExpectation < 9 points (all at 1 month), respectively. Using these variables, a risk score with a maximum of 7 points was developed, demonstrating a high predictive value for dissatisfaction (AUC: 0.792 [95% confidence interval: 0.700-0.884], p < 0.001). CONCLUSION: Dissatisfaction 1 year after TKA can be predicted by a weighted risk score that includes patient age, BMI, pain, subjective functionality and unmet expectation 1 month postoperatively. Using the risk score, early detection of dissatisfaction has the potential to enable targeted interventions and improve patients' quality of life. LEVEL OF EVIDENCE: Level II, Prognostic study.

Are Synovial Inflammatory Markers Increased in Patients Who Have Aseptic Total Hip Arthroplasty Dislocation Indicated for Revision?

BACKGROUND: Previous studies have speculated on elevated synovial inflammatory markers in patients undergoing surgical revision for total hip arthroplasty (THA) dislocation. However, this assumption is based on small patient series and a full investigation according to International Consensus Meeting (ICM) criteria has not yet been performed. METHODS: Patients who had aseptic THA dislocation indicated for revision surgery were identified retrospectively. Only patients who had available diagnostic workup according to ICM 2018 criteria, including preoperative and intraoperative parameters, were included. For comparison, we analyzed a matched cohort of patients indicated for aseptic THA revision for other conditions. The 2 cohorts each consisted of 55 patients and were not different regarding age, sex, BMI, or implant fixation. RESULTS: There was no difference in synovial white blood cell count (2,238 ± 2,544 versus 2,533 ± 3,448 c/µL; P = .601), alpha-defensin quotient (0.14 ± 0.11 versus 0.19 ± 0.28; P = .207), or polymorphonuclear neutrophil percentage (% PMN) (36.7 ± 22.6 versus 31.3 ± 24.5%; P = .312) between the groups. In the dislocation cohort, 20% of patients had a synovial white blood cell count of 3,000 c/µL or higher, compared with 18% in the control cohort. However, all patients in the dislocation cohort were below the cutoff for alpha-defensin or % PMN. CONCLUSION: In patients who have aseptic THA dislocation, synovial inflammatory markers are not elevated compared with patients undergoing aseptic revision for other complications. A detailed preoperative analysis of synovial inflammatory markers using ICM criteria appears critical in patients who have a THA dislocation to exclude periprosthetic joint infection. LEVEL OF EVIDENCE: Level III, retrospective, comparative study.

Comparison of Motion Grading in 1,000 Patients by First- and Second-Generation HR-pQCT: A Propensity Score Matched Cohort Study.

In-vivo bone microstructure measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) is gaining importance in research and clinical practice. Second-generation HR-pQCT (XCT2) shows improved image quality and shorter measurement duration compared to the first generation (XCT1). Predicting and understanding the occurrence of motion artifacts is crucial for clinical practice. We retrospectively analyzed data from HR-pQCT measurements at the distal radius and tibia of 1,000 patients (aged 20 to 89) evenly distributed between both generations of HR-pQCT. Motion artifacts were graded between 1 (no motion) and 5 (severe motion), with grades greater 3 considered unusable. Additionally, baseline characteristics and patients' muscle performance and balance were measured. Various group comparisons between the two generations of HR-pQCT and regression analyses between patient characteristics and motion grading were performed. The study groups of XCT1 and XCT2 did not differ by age (XCT1: 64.9 vs. XCT2: 63.8 years, p = 0.136), sex (both 74.5% females, p > 0.999), or BMI (both 24.2 kg/m2, p = 0.911) after propensity score matching. XCT2 scans exhibited significantly lower motion grading in both extremities compared to XCT1 (Radius: p < 0.001; Tibia: p = 0.002). In XCT2 motion-corrupted scans were more than halved at the radius (XCT1: 35.3% vs. XCT2: 15.5%, p < 0.001), and at the tibia the frequency of best image quality scans was increased (XCT1: 50.2% vs. XCT2: 63.7%, p < 0.001). The strongest independent predictor for motion-corrupted images is the occurrence of high motion grading at the other scanning site during the same consultation. The association between high motion grading in one scan and a corresponding high motion grading in another scan within the same session suggests a non-resting patient. Additionally, aged, female, and patients with smaller stature tend towards higher motion grading, requiring special attention to a correct extremity fixation.

GLUTAMATE RECEPTOR-LIKE channels are essential for chemotaxis and reproduction in mosses.

Glutamate receptors are well characterized channels that mediate cell-to-cell communication during neurotransmission in animals, but their functional role in organisms without a nervous system remains unclear. In plants, genes of the GLUTAMATE RECEPTOR-LIKE (GLR) family have been implicated in defence against pathogens, reproduction, control of stomata aperture and light signal transduction. However, the large number of GLR genes present in angiosperm genomes (20 to 70) has prevented the observation of strong phenotypes in loss-of-function mutants. Here we show that in the basal land plant Physcomitrella patens, mutation of the GLR genes GLR1 and GLR2 causes failure of sperm cells to target the female reproductive organs. In addition, we show that GLR genes encode non-selective Ca2+-permeable channels that can regulate cytoplasmic Ca2+ and are needed to induce the expression of a BELL1-like transcription factor essential for zygote development. Our work reveals functions for GLR channels in sperm chemotaxis and transcriptional regulation. Sperm chemotaxis is essential for fertilization in both animals and early land plants such as bryophytes and pteridophytes. Therefore, our results suggest that ionotropic glutamate receptors may have been conserved throughout plant evolution to mediate cell-to-cell communication during sexual reproduction.

Enantiomeric discrimination by chiral electromagnetic resonance enhancement.

Circularly polarized light interacts preferentially with the biomolecules to generate spectral fingerprints reflecting their primary and secondary structure in the ultraviolet region of the electromagnetic spectrum. The spectral features can be transferred to the visible and near-infrared regions by coupling the biomolecules with plasmonic assemblies made of noble metals. Nanoscale gold tetrahelices were used to detect the presence of chiral objects that are 40 times smaller in size by using plane-polarized light of 550 nm wavelength. The emergence of chiral hotspots in the gaps between 80 nm long tetrahelices differentiate between weakly scattering S- vs R-molecules with optical constants similar to that of organic solvents. Simulations map the spatial distribution of the scattered field to reveal enantiomeric discrimination with selectivity up to 0.54.

Pulmonary Findings in Hospitalized COVID-19 Patients Assessed by Lung Ultrasonography (LUS) - A Prospective Registry Study.

PURPOSE: This prospective two-centre study investigated localisation-dependent lesion patterns in COVID-19 with standard lung ultrasonography (LUS) and their relationship with thoracic computed tomography (CT) and clinical parameters. MATERIALS AND METHODS: Between April 2020 and April 2021, 52 SARS-CoV-2-positive patients in two hospitals were examined by means of LUS for "B-lines", fragmented pleura, consolidation and air bronchogram in 12 lung regions and for pleural effusions. A newly developed LUS score based on the number of features present was correlated with clinical parameters (respiration, laboratory parameters) and the CT and analysed with respect to the 30- and 60-day outcome. All patients were offered an outpatient LUS follow-up. RESULTS: The LUS and CT showed a bilateral, partially posteriorly accentuated lesion distribution pattern. 294/323 (91%) of CT-detected lesions were pleural. The LUS score showed an association with respiratory status and C-reactive protein; the correlation with the CT score was weak (Spearman's rho = 0.339, p < 0.001). High LUS scores on admission were also observed in patients who were discharged within 30 days. LUS during follow-up showed predominantly declining LUS scores. CONCLUSION: The LUS score reflected the clinical condition of the patients. No conclusion could be made on the prognostic value of the LUS, because of the low event rate. The LUS and CT score showed no sufficient correlation. This is probably due to different physical principles, which is why LUS could be of complementary value.

Alzheimer's disease phenotypes show different sleep architecture.

INTRODUCTION: Sleep-wake disturbances are a prominent feature of Alzheimer's disease (AD). Atypical (non-amnestic) AD syndromes have different patterns of cortical vulnerability to AD. We hypothesized that atypical AD also shows differential vulnerability in subcortical nuclei that will manifest as different patterns of sleep dysfunction. METHODS: Overnight electroencephalography monitoring was performed on 48 subjects, including 15 amnestic, 19 atypical AD, and 14 controls. AD was defined based on neuropathological or biomarker confirmation. We compared sleep architecture by visual scoring and spectral power analysis in each group. RESULTS: Overall, AD cases showed increased sleep fragmentation and N1 sleep compared to controls. Compared to atypical AD groups, typical AD showed worse N3 sleep dysfunction and relatively preserved rapid eye movement (REM) sleep. DISCUSSION: Results suggest differing effects of amnestic and atypical AD variants on slow wave versus REM sleep, respectively, corroborating the hypothesis of differential selective vulnerability patterns of the subcortical nuclei within variants. Optimal symptomatic treatment for sleep dysfunction in clinical phenotypes may differ. HIGHLIGHTS: Alzheimer's disease (AD) variants show distinct patterns of sleep impairment. Amnestic/typical AD has worse N3 slow wave sleep (SWS) impairment compared to atypical AD. Atypical AD shows more rapid eye movement deficits than typical AD. Selective vulnerability patterns in subcortical areas may underlie sleep differences. Relatively preserved SWS may explain better memory scores in atypical versus typical AD.

Autonomic and Vascular Responses during Reactive Hyperemia in Healthy Individuals and Patients with Sickle Cell Anemia.

Background and Objectives: To compare autonomic and vascular responses during reactive hyperemia (RH) between healthy individuals and patients with sickle cell anemia (SCA). Materials and Methods: Eighteen healthy subjects and 24 SCA patients were subjected to arterial occlusion for 3 min at the lower right limb level. The pulse rate variability (PRV) and pulse wave amplitude were measured through photoplethysmography using the Angiodin® PD 3000 device, which was placed on the first finger of the lower right limb 2 min before (Basal) and 2 min after the occlusion. Pulse peak intervals were analyzed using time-frequency (wavelet transform) methods for high-frequency (HF: 0.15-0.4) and low-frequency (LF: 0.04-0.15) bands, and the LF/HF ratio was calculated. Results: The pulse wave amplitude was higher in healthy subjects compared to SCA patients, at both baseline and post-occlusion (p < 0.05). Time-frequency analysis showed that the LF/HF peak in response to the post-occlusion RH test was reached earlier in healthy subjects compared to SCA patients. Conclusions: Vasodilatory function, as measured by PPG, was lower in SCA patients compared to healthy subjects. Moreover, a cardiovascular autonomic imbalance was present in SCA patients with high sympathetic and low parasympathetic activity in the basal state and a poor response of the sympathetic nervous system to RH. Early cardiovascular sympathetic activation (10 s) and vasodilatory function in response to RH were impaired in SCA patients.

Vernakalant for Cardioversion of Recent-Onset Atrial Fibrillation in the Emergency Department: The SPECTRUM Study.

INTRODUCTION: Intravenous vernakalant is a therapeutic option for symptomatic, recent-onset atrial fibrillation (AF). This secondary analysis from the large SPECTRUM study assessed the safety and effectiveness of vernakalant when used in the emergency department setting (ED group) or in an inpatient hospital setting (non-ED group). METHODS: This post hoc analysis of the international, observational, post-authorization SPECTRUM study included 1,289 and 720 recent-onset AF episodes in adults in the ED and non-ED groups, respectively. Safety endpoints included the evaluation of pre-defined health outcomes of interest (HOIs) and other serious adverse events (SAEs) during vernakalant treatment and during the first 24 h after the last infusion. Effectiveness endpoints comprised the rate of successful vernakalant cardioversion, the time from the start of the vernakalant infusion to cardioversion, and the length of hospital stay. Data were analysed using descriptive statistics. RESULTS: The safety profile of vernakalant was similar in the ED and non-ED groups. In the ED group, 12 pre-defined HOIs were reported in 11 patients (0.9%); all but one occurred within 2 h after start of the first infusion. These events comprised nine significant bradycardia cases, of which one was associated with transient hypotension and three with sinus arrest, and 2 cases of atrial flutter with 1:1 conduction. Five other SAEs were reported. All patients with vernakalant-related events recovered without sequelae. No Torsade de Pointes, ventricular fibrillation, or deaths occurred. Successful cardioversion was reported in 67.8% (95% confidence interval: 65.2-70.4) and 66.4% (62.5-70.1) of episodes, with a median time to conversion of 11.0 and 10.0 min in the ED and non-ED groups, respectively. Patients had a median length of hospital stay of 7.4 h and 17.1 h in the ED and non-ED groups, respectively. CONCLUSION: Intravenous vernakalant was well tolerated with similar cardioversion rates in patients treated in the ED or non-ED setting and does not require admission to a coronary care unit or intensive care unit. First-line treatment with vernakalant could allow an early discharge in patients with recent-onset AF treated in the ED.

LPS Induces Opposing Memory-like Inflammatory Responses in Mouse Bone Marrow Neutrophils.

A growing body of evidence suggests that innate immune cells can respond in a memory-like (adaptive) fashion, which is referred to as trained immunity. Only few in vivo studies have shown training effects in neutrophils; however, no in vitro setup has been established to study the induction of trained immunity or tolerance in neutrophils by microbial agents. In light of their short lifespan (up to 48 h), we suggest to use the term trained sensitivity for neutrophils in an in vitro setting. Here, we firstly describe a feasible two-hit model, using different doses of lipopolysaccharide (LPS) in bone marrow neutrophils. We found that low doses (10 pg/mL) induce pro-inflammatory activation (trained sensitivity), whereas priming with high doses (100 ng/mL) leads to suppression of pro-inflammatory mediators such as TNF-α or IL-6 (tolerance) (p < 0.05). On a functional level, trained neutrophils displayed increased phagocytic activity and LFA-1 expression as well as migrational capacity and CD11a expression, whereas tolerant neutrophils show contrasting effects in vitro. Mechanistically, TLR4/MyD88/PI3Ks regulate the activation of p65, which controls memory-like responses in mouse bone marrow neutrophils (p < 0.05). Our results open a new window for further in vitro studies on memory-like inflammatory responses of short-lived innate immune cells such as neutrophils.

Simplified method to quantify valve back-leak uncovers severe mesenteric lymphatic valve dysfunction in mice deficient in connexins 43 and 37.

KEY POINTS: Lymphatic valve defects are one of the major causes of lymph transport dysfunction; however, there are no accessible methods for quantitatively assessing valve function. This report describes a novel technique for quantifying lymphatic valve back-leak. Postnatal endothelial-specific deletion of connexin 43 (Cx43) in connexin 37 null (Cx37-/- ) mice results in rapid regression of valve leaflets and severe valve dysfunction. This method can also be used for assessing the function of venous and lymphatic valves from various species, including humans. ABSTRACT: The lymphatic system relies on robust, spontaneous contractions of collecting lymphatic vessels and one-way secondary lymphatic valves to efficiently move lymph forward. Secondary valves prevent reflux and allow for the generation of propulsive pressure during each contraction cycle. Lymphatic valve defects are one of the major causes of lymph transport dysfunction. Genetic mutations in multiple genes have been associated with the development of primary lymphoedema in humans; and many of the same mutations in mice result in valve defects that subsequently lead to chylous ascites or chylothorax. At present the only experimental technique for the quantitative assessment of lymphatic valve function utilizes the servo-null micropressure system, which is highly accurate and precise, but relatively inaccessible and difficult to use. We developed a novel, simplified alternative method for quantifying valve function and determining the degree of pressure back-leak through an intact valve in pressurized, single-valve segments of isolated lymphatic vessels. With this diameter-based method, the competence of each lymphatic valve is challenged over a physiological range of pressures (e.g. 0.5-10cmH2 O) and pressure back-leak is extrapolated from calibrated, pressure-driven changes in diameter upstream from the valve. Using mesenteric lymphatic vessels from C57BL/6J, Ub-CreERT2 ;Rasa1fx/fx , Foxc2Cre/+ , Lyve1-Cre;Cx43fx/fx , and Prox1-CreERT2 ;Cx43fx/fx ;Cx37-/- mice, we tested our method on lymphatic valves displaying a wide range of dysfunction, from fully competent to completely incompetent. Our results were validated by simultaneous direct measurement of pressure back-leak using a servo-null micropressure system. Our diameter-based technique can be used to quantify valve function in isolated lymphatic valves from a variety of species. This method also revealed that haplodeficiency in Foxc2 (Foxc2Cre/+ ) is not sufficient to cause significant valve dysfunction; however, postnatal endothelial-specific deletion of Cx43 in Cx37-/- mice results in rapid regression of valve leaflets and severe valve dysfunction.

Melatonin's antioxidant properties protect plants under salt stress.

This article comments on: "Melatonin improves rice salinity stress tolerance by NADPH oxidase-dependent control of the plasma membrane K+ transporters and K+ homeostasis". This article is protected by copyright. All rights reserved.

Mechanisms of Connexin-Related Lymphedema.

RATIONALE: Mutations in GJC2 and GJA1, encoding Cxs (connexins) 47 and 43, respectively, are linked to lymphedema, but the underlying mechanisms are unknown. Because efficient lymph transport relies on the coordinated contractions of lymphatic muscle cells (LMCs) and their electrical coupling through Cxs, Cx-related lymphedema is proposed to result from dyssynchronous contractions of lymphatic vessels. OBJECTIVE: To determine which Cx isoforms in LMCs and lymphatic endothelial cells are required for the entrainment of lymphatic contraction waves and efficient lymph transport. METHODS AND RESULTS: We developed novel methods to quantify the spatiotemporal entrainment of lymphatic contraction waves and used optogenetic techniques to analyze calcium signaling within and between the LMC and the lymphatic endothelial cell layers. Genetic deletion of the major lymphatic endothelial cell Cxs (Cx43, Cx47, or Cx37) revealed that none were necessary for the synchronization of the global calcium events that triggered propagating contraction waves. We identified Cx45 in human and mouse LMCs as the critical Cx mediating the conduction of pacemaking signals and entrained contractions. Smooth muscle-specific Cx45 deficiency resulted in 10- to 18-fold reduction in conduction speed, partial-to-severe loss of contractile coordination, and impaired lymph pump function ex vivo and in vivo. Cx45 deficiency resulted in profound inhibition of lymph transport in vivo, but only under an imposed gravitational load. CONCLUSIONS: Our results (1) identify Cx45 as the Cx isoform mediating the entrainment of the contraction waves in LMCs; (2) show that major endothelial Cxs are dispensable for the entrainment of contractions; (3) reveal a lack of coupling between lymphatic endothelial cells and LMCs, in contrast to arterioles; (4) point to lymphatic valve defects, rather than contraction dyssynchrony, as the mechanism underlying GJC2- or GJA1-related lymphedema; and (5) show that a gravitational load exacerbates lymphatic contractile defects in the intact mouse hindlimb, which is likely critical for the development of lymphedema in the adult mouse.

Biaxial Stress Relaxation of Vaginal Tissue in Pubertal Gilts.

Pelvic organ prolapse (POP) is a condition characterized by displacement of the vagina from its normal anatomical position leading to symptoms such as incontinence, physical discomfort, and poor self-image. Conservative treatment has shown limited success and surgical procedures, including the use of mesh, often lead to severe complications. To improve the current treatment methods for prolapse, the viscoelastic properties of vaginal tissue need to be characterized. We determined the biaxial stress relaxation response of vaginal tissue isolated from healthy pubertal gilts. Square specimens (n = 20) with sides aligned along the longitudinal directions (LD) and circumferential direction (CD) of the vagina were biaxially displaced up to 5 N. The specimens were then kept at the displacements corresponding to 5 N for 20 min in both the LD and CD, and the corresponding strains were measured using digital image correlation (DIC). The stresses in the LD and CD were found to decrease by 49.91 ± 5.81% and 46.22 ± 5.54% after 20 min, respectively. The strain in the LD and CD increased slightly from 0.080 ± 0.054 to 0.091 ± 0.064 and 0.050 ± 0.039 to 0.058 ± 0.047, respectively, but these changes were not significant (p > 0.01). By using the Peleg model, the initial decay rate and the asymptotic stress during stress relaxation were found to be significantly higher in the LD than in the CD (p≪0.001), suggesting higher stress relaxation in the LD. These findings may have implications for improving current surgical mesh, mechanical devices, and physical therapy used for prolapse treatment.

Disentangling expectation from selective attention during perceptual decision making.

A large body of work has investigated the effects of attention and expectation on early sensory processing to support decision making. In a recent paper published in The Journal of Neuroscience, Rungratsameetaweemana et al. (Rungratsameetaweemana N, Itthipuripat S, Salazar A, Serences JT. J Neurosci 38: 5632-5648, 2018) found that expectations driven by implicitly learned task regularities do not modulate neural markers of early visual processing. Here, we discuss these findings and propose several lines of follow-up analyses and experiments that could expand on these findings in the broader perceptual decision making literature.