Known allosteric proteins have central roles in genetic disease

Allostery is a form of protein regulation, where ligands that bind sites located apart from the active site can modify the activity of the protein. The molecular mechanisms of allostery have been extensively studied, because allosteric sites are less conserved than active sites, and drugs targeting them are more specific than drugs binding the active sites. Here we quantify the importance of allostery in genetic disease. We show that 1) known allosteric proteins are central in disease networks, and contribute to genetic disease and comorbidities much more than non-allosteric proteins, in many major disease types like hematopoietic diseases, cardiovascular diseases, cancers, diabetes, or diseases of the central nervous system. 2) variants from cancer genome-wide association studies are enriched near allosteric proteins, indicating their importance to polygenic traits; and 3) the importance of allosteric proteins in disease is due, at least partly, to their central positions in protein-protein interaction networks, and probably not due to their dynamical properties

Treatment outcome of supraglottoplasty vs. wait-and-see policy in patients with laryngomalacia

In most cases, laryngomalacia presents as a mild disease, and the symptoms resolve after wait-and-see policy. Up to 20 % of patients present with severe laryngomalacia and may require surgery (i.e. supraglottoplasty); however, the indication for surgery is not firmly established yet. The goal of this study is to determine whether supraglottoplasty results in a better outcome than wait-and-see and to investigate how different comorbidities influence outcome. A retrospective study of pediatric cases of in a tertiary referral center was performed. Photo and video documentation was available and revised in all cases. Electronic and paper charts were reviewed for the following variables: gender, sex, gestational age, birth weight, symptoms, comorbidity, date of endoscopy, severity and type of laryngomalacia, treatment modality and technique and follow-up data and a total 89 patients were included. Supraglottoplasty was found to lead to significantly faster complete improvement of laryngomalacia than wait-and-see policy (5 weeks vs. 29, p = 0.026). Synchronous airway lesions (SALs) were present in 40.4 % of patients and were associated with prolonged symptoms of laryngomalacia (38.5 weeks vs. 14.5, p = 0.043). Supraglottoplasty is safe and effective in treatment of severe laryngomalacia. SALs and comorbidities are frequently found in patients with laryngomalacia and are responsible for longer onset of complaints

Label-free optical monitoring of surface adhesion of extracellular vesicles by grating coupled interferometry

In this proof-of-principle study a label-free optical sensor is demonstrated to monitor the surface adhesion of extracellular vesicles secreted by live cells on to various extracellular matrix proteins

Assessment of sample preparation bias in mass spectrometry-based proteomics

For mass spectrometry-based proteomics, the selected sample preparation strategy is a key determinant for information that will be obtained. However, the corresponding selection is often not based on a fit-for-purpose evaluation. Here we report a comparison of in-gel (IGD), in-solution (ISD), on-filter (OFD), and on-pellet digestion (OPD) workflows on the basis of targeted (QconCAT-multiple reaction monitoring (MRM) method for mitochondrial proteins) and discovery proteomics (data dependent acquisition, DDA) analyses using three different human head and neck tissues (i.e. nasal polyps, parotid gland, and palatine tonsils). Our study reveals differences between the sample preparation methods, for example with respect to protein and peptide losses, quantification variability, protocol-induced methionine oxidation and asparagine/glutamine deamidation as well as identification of cysteine containing peptides. However, none of the methods performed best for all types of tissues, which argues against the existence of a universal sample preparation method for proteome analysis

Shooter localization and weapon classification with soldier-wearable networked sensors

The paper presents a wireless sensor network-based mobile countersniper system. A sensor node consists of a helmetmounted microphone array, a COTS MICAz mote for internode communication and a custom sensorboard that implements the acoustic detection and Time of Arrival (ToA) estimation algorithms on an FPGA. A 3-axis compass provides self orientation and Bluetooth is used for communication with the soldier’s PDA running the data fusion and the user interface. The heterogeneous sensor fusion algorithm can work with data from a single sensor or it can fuse ToA or Angle of Arrival (AoA) observations of muzzle blasts and ballistic shockwaves from multiple sensors. The system estimates the trajectory, the range, the caliber and the weapon type. The paper presents the system design and the results from an independent evaluation at the US Army Aberdeen Test Center. The system performance is characterized by 1-degree trajectory precision and over 95 % caliber estimation accuracy for all shots, and close to 100 % weapon estimation accuracy for 4 out of 6 guns tested

Stress and Traumatic Brain Injury: A Behavioral, Proteomics, and Histological Study

Psychological stress and traumatic brain injury (TBI) can both result in lasting neurobehavioral abnormalities. Post-traumatic stress disorder and blast induced TBI (bTBI) have become the most significant health issues in current military conflicts. Importantly, military bTBI virtually never occurs without stress. In this experiment, we assessed anxiety and spatial memory of rats at different time points after repeated exposure to stress alone or in combination with a single mild blast. At 2 months after injury or sham we analyzed the serum, prefrontal cortex (PFC), and hippocampus (HC) of all animals by proteomics and immunohistochemistry. Stressed sham animals showed an early increase in anxiety but no memory impairment at any measured time point. They had elevated levels of serum corticosterone (CORT) and hippocampal IL-6 but no other cellular or protein changes. Stressed injured animals had increased anxiety that returned to normal at 2 months and significant spatial memory impairment that lasted up to 2 months. They had elevated serum levels of CORT, CK-BB, NF-H, NSE, GFAP, and VEGF. Moreover, all of the measured protein markers were elevated in the HC and the PFC; rats had an increased number of TUNEL-positive cells in the HC and elevated GFAP and Iba1 immunoreactivity in the HC and the PFC. Our findings suggest that exposure to repeated stress alone causes a transient increase in anxiety and no significant memory impairment or cellular and molecular changes. In contrast, repeated stress and blast results in lasting behavioral, molecular, and cellular abnormalities characterized by memory impairment, neuronal and glial cell loss, inflammation, and gliosis. These findings may have implications in the development of diagnostic and therapeutic measures for conditions caused by stress or a combination of stress and bTBI

The Effect of Enriched Environment on the Outcome of Traumatic Brain Injury; A Behavioral, Proteomics, and Histological Study

De novo hippocampal neurogenesis contributes to functional recovery following traumatic brain injury (TBI). Enriched environment (EEN) can improve the outcome of TBI by positively affecting neurogenesis. Blast induced traumatic brain injury (bTBI) characterized by memory impairment and increased anxiety levels, is a leading cause of chronic disability among soldiers. Using a rodent model of bTBI we asked: (a) whether long-term exposure to EEN after injury can ameliorate behavioral abnormalities and (b) what the effects of EEN are at the molecular and cellular levels and on de novo neurogenesis. We found that housing injured animals in EEN resulted in significantly improved spatial memory while animals in normal housing (NH) showed persistent memory impairment. VEGF and Tau protein but not Interleukin-6 (IL-6) levels were normalized in the dorsal hippocampus (DHC) of EEN rats while all three markers remained elevated in NH rats. Interestingly, after peaking at 6 weeks post-injury, anxiety returned to normal levels at 2 months independent of housing conditions. Housing animals in EEN had no significant effect on VEGF and Tau protein levels in the ventral hippocampus (VHC) and the amygdala (AD). We also found that EEN reduced IL-6 and IFNγ levels in the VHC; these markers remained elevated following NH. We observed an increase in GFAP and DCX immunoreactivities in the VHC of NH animals at 2 months post-injury. Conversely, injured animals housed in EEN showed no increase in GFAP or DCX immunoreactivity in their VHC. In summary, long-term exposure of injured animals to EEN appears to play a positive role in the restoration of memory functions but not on anxiety, which returned to normal levels after a significant period of time. Cellular and molecular changes in response to EEN appear to be a part of neurogenesis-independent as well as dependent recovery processes triggered by bTBI

Rare occult macular dystrophy with a pathogenic variant in the RP1L1 gene in a patient of Swiss descent

Purpose: We report a first case of bilateral occult macular dystrophy (OMD) with a c.133C>T (p.Arg45Trp) pathogenic variant in the retinitis pigmentosa 1-like 1 (RP1L1) gene in a patient of Caucasian Swiss decent. Observations: A 34-year-old man presented with decreased visual acuity known since childhood. Fundus examination of both eyes revealed no pathology other than mildly increased granularity of the foveal retinal pigment epithelium. The full-field electroretinogram (ffERG) presented with normal findings while the multifocal electroretinogram (mfERG) showed severely reduced amplitudes of the foveal response. Optical coherence tomography (OCT) showed foveal outer retinal atrophy. Fundus autofluorescence (FAF) imaging demonstrated near-normal findings with minimal mottling at the posterior pole. The genetic analysis revealed a heterozygous pathogenic variant (c.133C>T, p.Arg45Trp) in the RP1L1 gene. Conclusion and importance: Our present case suggests that OMD shows a wide range of clinical presentations with a variety of ophthalmological findings, age of disease onset, visual acuity, and genetic diversity

Narrow-Band Imaging in Transoral Laser Surgery for Early Glottic Cancer:A Randomized Controlled Trial

Objective: Assessing whether the additional use of narrow-band imaging (NBI) in transoral laser surgery (TOLS) for early laryngeal cancer improves clinical outcomes. Study Design: Randomized controlled trial, performed between September 2015 and November 2022. Setting: A tertiary referral hospital in The Netherlands. Methods: TOLS was carried out in 113 patients. The procedure was performed with white light imaging (WLI, n = 56) alone, or combined with NBI (n = 57). Patients received frequent follow-up laryngoscopy. Resection margin status, recurrence rate, and recurrence-free survival at 12 months, 18 months, and after study termination (maximum 86 months) were analyzed. Results: Thirty-one cases in the WLI group had a positive resection margin, versus 16 in the NBI group (p =.002). After 12 months, the recurrence-free survival was 92%: 87% for WLI versus 96% for NBI, p =.07. The recurrence rate was 7/56 (13%) for WLI, versus 2/57 (4%) for NBI, p =.09. After 18 months, the recurrence-free survival was 84% for WLI versus 96% for NBI, p =.02. The recurrence rate was 9/56 (16%) for WLI, versus 2/57 (4%) for NBI, p =.02. After study termination, the recurrence-free survival was 71% for WLI versus 83% for the NBI group (p =.08). The recurrence rate was 16/56 for WLI, versus 10/57 for NBI (p =.16). Conclusion: The additional use of NBI during TOLS significantly decreased the number of positive resection margins. Although not statistically significant at all time points, patients treated with NBI-supported TOLS showed a lower recurrence rate and better recurrence-free survival. Further studies in larger patient groups are needed to confirm these results.</p

Narrow-Band Imaging in Transoral Laser Surgery for Early Glottic Cancer:A Randomized Controlled Trial

Objective: Assessing whether the additional use of narrow-band imaging (NBI) in transoral laser surgery (TOLS) for early laryngeal cancer improves clinical outcomes. Study Design: Randomized controlled trial, performed between September 2015 and November 2022. Setting: A tertiary referral hospital in The Netherlands. Methods: TOLS was carried out in 113 patients. The procedure was performed with white light imaging (WLI, n = 56) alone, or combined with NBI (n = 57). Patients received frequent follow-up laryngoscopy. Resection margin status, recurrence rate, and recurrence-free survival at 12 months, 18 months, and after study termination (maximum 86 months) were analyzed. Results: Thirty-one cases in the WLI group had a positive resection margin, versus 16 in the NBI group (p =.002). After 12 months, the recurrence-free survival was 92%: 87% for WLI versus 96% for NBI, p =.07. The recurrence rate was 7/56 (13%) for WLI, versus 2/57 (4%) for NBI, p =.09. After 18 months, the recurrence-free survival was 84% for WLI versus 96% for NBI, p =.02. The recurrence rate was 9/56 (16%) for WLI, versus 2/57 (4%) for NBI, p =.02. After study termination, the recurrence-free survival was 71% for WLI versus 83% for the NBI group (p =.08). The recurrence rate was 16/56 for WLI, versus 10/57 for NBI (p =.16). Conclusion: The additional use of NBI during TOLS significantly decreased the number of positive resection margins. Although not statistically significant at all time points, patients treated with NBI-supported TOLS showed a lower recurrence rate and better recurrence-free survival. Further studies in larger patient groups are needed to confirm these results.</p