Aberrant Control Research Articles

Tunable fluidic lens with a dynamic high-order aberration control.

Fluidic lenses based on electrowetting actuation are attractive for their wide focal tuning range, yet are limited by optical aberrations, either intrinsic to the lenses themselves or due to the optical imaging systems in which they are employed. However, the ability to control the meniscus shape that forms the lens refractive surface with a high degree of spatial accuracy will allow correction of and compensation for a wide range of these aberrations. We demonstrate here for what we believe, to the best of our knowledge, is the first time a tunable optofluidic lens controlled by 32 azimuthally placed electrodes for which most aberrations up to the fourth radial Zernike order may be corrected. Using both wavefront sensing and sensorless wavefront estimation techniques, it is shown that focal length tunability with a significant reduction in imaging aberrations and the ability to compensate for externally induced aberrations may be achieved using a single component.

Aberrant dynamics of cognitive control and motor circuits predict distinct restricted and repetitive behaviors in children with autism

Restricted and repetitive behaviors (RRBs) are a defining clinical feature of autism spectrum disorders (ASD). RRBs are highly heterogeneous with variable expression of circumscribed interests (CI), insistence of sameness (IS) and repetitive motor actions (RM), which are major impediments to effective functioning in individuals with ASD; yet, the neurobiological basis of CI, IS and RM is unknown. Here we evaluate a unified functional brain circuit model of RRBs and test the hypothesis that CI and IS are associated with aberrant cognitive control circuit dynamics, whereas RM is associated with aberrant motor circuit dynamics. Using task-free fMRI data from 96 children, we first demonstrate that time-varying cross-network interactions in cognitive control circuit are significantly reduced and inflexible in children with ASD, and predict CI and IS symptoms, but not RM symptoms. Furthermore, we show that time-varying cross-network interactions in motor circuit are significantly greater in children with ASD, and predict RM symptoms, but not CI or IS symptoms. We confirmed these results using cross-validation analyses. Moreover, we show that brain-clinical symptom relations are not detected with time-averaged functional connectivity analysis. Our findings provide neurobiological support for the validity of RRB subtypes and identify dissociable brain circuit dynamics as a candidate biomarker for a key clinical feature of ASD.

1140-P: Immune Dysregulation as a Consequence of Aberrant Glycemic Control in Diabetes Mellitus

People with diabetes mellitus are more vulnerable to viral infections including influenza and the ongoing COVID-19 pandemic. Fatal pneumonia and cytokine storm is a contributor to the mortality. We hypothesized that aberrant glycemic control induces an immune dysregulation, which compromises the anti-viral immunity and promotes inflammation by altering the balance of the protective T-regulatory cells (Tregs) and IL-17 responses. Indeed, comparison of the peripheral blood lymphocytes in a limited cohort of healthy controls (HC; n=4) and people with diabetes (n=9) showed profound immune dysregulation. As compared to HC (66±21 x10^3/ml), the number of circulating Tregs were significantly (p<0.0001) reduced in diabetes group (15±2 x10^3/ml). Compared to HC, the proportion of IL-17 producing CD4 and CD8 T-cells was remarkably increased in the diabetes group at baseline as well as upon ex-vivo stimulation. A comparison of the ratio of IFNγ to IL-17 producing CD8 T-cells showed a significant bias towards reduced IFNγ and enhanced IL-17 production in the diabetes group (4.7±1.7) as compared to the HC (35±4). Similarly, comparison of the ratio of Tregs and Th1 to Th17 cells was also significantly biased towards reduced Treg and Th1 cells, and an exacerbated Th17 response in diabetes group as compared to the HC. Meta-analysis confirmed a significant positive correlation between HbA1c levels and the exacerbated IL-17 to IFNg ratios in CD4 (R2=0.7, p=0.0008) as well as CD8 (R2=0.6, p=0.002) cells. In summary, altered glycemic control, as indicated by higher HbA1c levels, significantly correlates with compromised IFNg production in the CD8 and Th1 cells, which is important for anti-viral immunity, as well as a marked proinflammatory shift shown as reduced Tregs levels and enhanced IL-17 production by both CD4 and CD8 cells. This immune-dysregulation in diabetes may thus contribute to a greater susceptibility to viral infections and infection-induced pathology. Disclosure V. Sabapathy: Stock/Shareholder; Self; 10x Genomics, Apple, AstraZeneca, Bayer U. S., Gilead Sciences, Inc. M. Dogan: None. R. Venkatadri: None. R. Arbab: None. J. Z. Ma: None. A. Basu: None. R. Basu: None. R. Sharma: Other Relationship; Self; SlateBio Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104963); University of Virginia

Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection.

Patients with coronavirus disease 2019 (COVID-19) are reported to have a greater prevalence of hyperglycaemia. Cytokine release as a consequence of severe acute respiratory syndrome coronavirus 2 infection may precipitate the onset of metabolic alterations by affecting glucose homeostasis. Here we describe abnormalities in glycometabolic control, insulin resistance and beta cell function in patients with COVID-19 without any pre-existing history or diagnosis of diabetes, and document glycaemic abnormalities in recovered patients 2 months after onset of disease. In a cohort of 551 patients hospitalized for COVID-19 in Italy, we found that 46% of patients were hyperglycaemic, whereas 27% were normoglycaemic. Using clinical assays and continuous glucose monitoring in a subset of patients, we detected altered glycometabolic control, with insulin resistance and an abnormal cytokine profile, even in normoglycaemic patients. Glycaemic abnormalities can be detected for at least 2 months in patients who recovered from COVID-19. Our data demonstrate that COVID-19 is associated with aberrant glycometabolic control, which can persist even after recovery, suggesting that further investigation of metabolic abnormalities in the context of long COVID is warranted.

Aberrant Salient and Corticolimbic Connectivity in Hypersexual Parkinson's Disease.

Introduction: Impulse control disorders (ICDs) represent a side effect of dopaminergic medication in Parkinson's disease (PD). Patients experience an excessive desire toward natural rewards paired with uncontrolled actions. Yet, the precise neural and behavioral mechanisms associated with ICDs and, importantly, each specific subdomain remain unclear. We aim to decipher resting-state and corticolimbic functional connectivity in PD patients with and without hypersexual ICD. Materials and Methods: Seventeen PD patients with hypersexuality (PD+HS) and 15 PD patients without hypersexuality (PD-HS) underwent two sessions (with and without medication) of resting-state functional magnetic resonance imaging and were compared with 17 healthy controls. Dual-regression independent component analyses extracted salience, sensorimotor, default-mode, and central executive networks. Seed-based functional connectivity with three striatal subdivisions (motor, associative, and limbic) was obtained and significant changes were correlated with key impulsivity and inhibitory measures. Results: Enhanced salience network (SN) activity represented by a significant rise in the right inferior frontal gyrus was found in PD+HS compared with PD-HS. Connectivity analyses revealed a functional disconnection between associative and limbic striatum with precuneus and superior parietal lobe in PD+HS, some connections explained by abnormal sexual behavior and inhibition in PD+HS. Conclusions: Hypersexual ICD is associated with enhanced SN signaling and corticolimbic disconnections, including striatal associative and limbic loops that contribute to altered control of sexually driven behavior and overall severity in PD and ICD. Impact statement We enlarge the neurobiological basis to one specific Parkinson's disease (PD) and impulse control disorder (ICD) (PD+ICD) subtype-that is, hypersexuality-and reveal its associated resting-state functional connectivity linked to altered behavior. We report enhanced salience network and right inferior frontal gyrus as part of the underlying resting-state functional networks in PD patients with hypersexuality (PD+HS). Corticolimbic changes were associated with sexual severity in PD+HS to hypoactive connectivity between associative-limbic striatum with precuneus and superior parietal lobe. The connectivity changes seen in PD+HS could explain baseline differences that engender aberrant control over sexual behavior in ICD.

Suppression of breathing by Gram‐positive bacterial proteins in neonatal Sprague Dawley rat pups

Preterm infants regularly present with immature and unstable respiratory control networks at birth leading to oxygen dysregulation in the newborn (Hofstetter et al., 2007). Sequentially, the requirement for prolonged medical support and hospital stays increases the risk of late-onset infection. Hypoxic stress during early life can alter central networks that control the cardiorespiratory system with profound autonomic dysregulation. We hypothesised that chronic neonatal exposure to intermittent hypoxia and hyperoxia (cIHH) with subsequent Gram-positive bacterial infection alters respiratory control. On postnatal day (PND) three, Sprague Dawley litters were exposed for 10 days to either cIHH or room air gas exposure. On PND13, pups were studied using whole body plethysmography at 30◦C. After an initial acclimatisation period, a baseline normoxic measurement was taken. Following intraperitoneal administration of lipoteichoic acid and peptidoglycan (LTA+PGN) or pyro-free saline (n=10 per group), animals were monitored for 3 hours under normoxic conditions. Oxygen dysregulation in early life in and of itself, did not alter breathing frequency (P=0.37) or minute ventilation (P=0.07). Administration of LTA+PGN suppressed breathing as shown by a decrease in frequency and minute ventilation (both P<0.05). Furthermore, administration of LTA+PGN on PND13 increased cytokine expression in both sexes as well as corticosterone concentration in male pups compared to relevant controls. Administration of LTA+PGN did not significantly alter rectal temperature compared to controls. Neonatal infection remains a significant challenge, with a paucity of studies investigating the response to Gram-positive bacterial proteins despite its clinical relevance. We report that Gram-positive bacterial proteins can quickly suppress breathing frequency and elicit both an inflammatory and stress response. Further studies are necessary to elucidate the mechanisms underlying aberrant respiratory control. References Hofstetter AO, Legnevall L & Ericherleniuskise EH (2007). Cardiorespiratory development in extremely preterm infants: vulnerability to infection and persistence of events beyond term-equivalent age. 285–292.

Control of Linear Astigmatism Aberration in a Perturbed Axially Symmetric Optical System and Tolerancing

Linear astigmatism aberration is undesirable because it rapidly degrades image quality. We discuss some techniques to control and mitigate this aberration, and provide a comparison of lens systems that have been desensitized for linear astigmatism aberration.

A central role for cAMP/EPAC/RAP/PI3K/AKT/CREB signaling in LH-induced follicular Pgr expression at medaka ovulation†.

Nuclear progestin receptor (PGR) is a ligand-activated transcription factor that has been identified as a pivotal mediator of many processes associated with ovarian and uterine function, and aberrant control of PGR activity causes infertility and disease including cancer. The essential role of PGR in vertebrate ovulation is well recognized, but the mechanisms by which PGR is rapidly and transiently induced in preovulatory follicles after the ovulatory LH surge are not known in lower vertebrates. To address this issue, we utilized the small freshwater teleost medaka Oryzias latipes, which serves as a good model system for studying vertebrate ovulation. In the in vitro ovulation system using preovulatory follicles dissected from the fish ovaries, we found that inhibitors of EPAC (brefeldin A), RAP (GGTI298), PI3K (Wortmannin), AKT (AKT inhibitor IV), and CREB (KG-501) inhibited LH-induced follicle ovulation, while the PKA inhibitor H-89 had no effect on follicle ovulation. The inhibitors capable of inhibiting follicle ovulation also inhibited follicular expression of Pgr and matrix metalloproteinase-15 (Mmp15), the latter of which was previously shown to not only be a downstream effector of Pgr but also a proteolytic enzyme indispensable for follicle rupture in medaka ovulation. Further detailed analysis revealed for the first time that the cAMP/EPAC/RAP/PI3K/AKT/CREB signaling pathway mediates the LH signal to induce Pgr expression in preovulatory follicles. Our data also showed that phosphorylated Creb1 is a transcription factor essential for pgr expression and that Creb1 phosphorylated by Akt1, rather than PKA, may be preferably used to induce pgr expression.

Integrated 3D motion analysis with functional magnetic resonance neuroimaging to identify neural correlates of lower extremity movement

BackgroundTo better understand the neural drivers of aberrant motor control, methods are needed to identify whole brain neural correlates of isolated joints during multi-joint lower-extremity coordinated movements. This investigation aimed to identify the neural correlates of knee kinematics during a unilateral leg press task. New MethodThe current study utilized an MRI-compatible motion capture system in conjunction with a lower extremity unilateral leg press task during fMRI. Knee joint kinematics and brain activity were collected concurrently and averaged range of motion were modeled as covariates to determine the neural substrates of knee out-of-plane (frontal) and in-plane (sagittal) range of motion. ResultsIncreased out-of-plane (frontal) range of motion was associated with altered brain activity in regions important for attention, sensorimotor control, and sensorimotor integration (z >3.1, p < .05), but no such correlates were found with in-plane (sagittal) range of motion (z >3.1, p > .05).Comparison with Existing Method(s): Previous studies have either presented overall brain activation only, or utilized biomechanical data collected outside MRI in a standard biomechanics lab for identifying single-joint neural correlates. ConclusionsThe study shows promise for the MRI-compatible system to capture lower-extremity biomechanical data collected concurrently during fMRI, and the present data identified potentially unique neural drivers of aberrant biomechanics.Future research can adopt these methods for patient populations with CNS-related movement disorders to identify single-joint kinematic neural correlates that may adjunctively supplement brain-body therapeutic approaches.

Subanesthetic ketamine with an AMPAkine attenuates motor impulsivity in rats.

The concept of 'impulse control' has its roots in early psychiatry and today has progressed into a well-described, although poorly understood, multidimensional endophenotype underlying many neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder, schizophrenia, substance use disorders). There is mounting evidence suggesting that the cognitive and/or behavioral dimensions underlying impulsivity are driven by dysfunctional glutamate (Glu) neurotransmission via targeted ionotropic Glu receptor (GluR) [e.g., N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)] mechanisms and associated synaptic alterations within key brain nodes. Ketamine, a noncompetitive NMDAR antagonist and FDA-approved for treatment-resistant depression, induces a 'glutamate burst' that drives resculpting of the synaptic milieu, which lasts for several days to a week. Thus, we hypothesized that single and repeated treatment with a subanesthetic ketamine dose would normalize motor impulsivity. Next, we hypothesized that AMPAR positive allosteric modulation, alone or in combination with ketamine, would attenuate impulsivity and provide insight into the mechanisms underlying GluR dysfunction relevant to motor impulsivity. To measure motor impulsivity, outbred male Sprague-Dawley rats were trained on the one-choice serial reaction time task. Rats pretreated with single or repeated (3 days) administration of ketamine (10 mg/kg; i.p.; 24-h pretreatment) or with the AMPAkine HJC0122 (1 or 10 mg/kg; i.p.; 30-min pretreatment) exhibited lower levels of motor impulsivity vs. control. Combination of single or repeated ketamine plus HJC0122 also attenuated motor impulsivity vs. control. We conclude that ligands designed to promote GluR signaling represent an effective pharmacological approach to normalize impulsivity and subsequently, neuropsychiatric disorders marked by aberrant impulse control.

Aberrant gene expression induced by a high fat diet is linked to H3K9 acetylation in the promoter-proximal region

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with an estimated global prevalence of 1 in 4 individuals. Aberrant transcriptional control of gene expression is central to the pathophysiology of metabolic diseases. However, the molecular mechanisms leading to gene dysregulation are not well understood. Histone modifications play important roles in the control of transcription. Acetylation of histone 3 at lysine 9 (H3K9ac) is associated with transcriptional activity and is implicated in transcript elongation by controlling RNA polymerase II (RNAPII) pause-release. Hence, changes in this histone modification may shed information on novel pathways linking transcription control and metabolic dysfunction. Here, we carried out genome-wide analysis of H3K9ac in the liver of mice fed a control or a high-fat diet (an animal model of NAFLD), and asked whether this histone mark associates with changes in gene expression. We found that over 70% of RNAPII peaks in promoter-proximal regions overlapped with H3K9ac, consistent with a role of H3K9ac in the regulation of transcription. When comparing high-fat with control diet, approximately 17% of the differentially expressed genes were associated with changes in H3K9ac in their promoters, showing a strong correlation between changes in H3K9ac signal and gene expression. Overall, our data indicate that in response to a high-fat diet, dysregulated gene expression of a subset of genes may be attributable to changes in transcription elongation driven by H3K9ac. Our results point at an added mechanism of gene regulation that may be important in the development of metabolic diseases.

Neural mechanisms of reward processing in adolescent irritability.

Irritability is impairing and prevalent across pediatric psychiatric disorders and typical development, yet its neural mechanisms are largely unknown. This study evaluated the relation between adolescent irritability and reward-related brain function as a candidate neural mechanism. Adolescents from intervention-seeking families in the community (N=52; mean age=13.80, SD=1.94) completed a monetary incentive delay task to assess reward anticipation and feedback (reward receipt and omission) during fMRI acquisition. Whole-brain analyses, controlling for age, examined brain activation and striatal and amygdala connectivity in relation to irritability. Irritability was measured using the parent- and youth-reported Affective Reactivity Index. Irritability was associated with altered reward processing-related activation and connectivity in multiple networks during reward anticipation and feedback, including increased striatal activation and altered ventral striatum connectivity with prefrontal areas. Our findings suggest that irritability is associated with altered neural patterns during reward processing and that aberrant prefrontal cortex-mediated top-down control may be related to irritability. These findings inform our understanding of the etiology of youth irritability and the development of mechanism-based interventions.

Characteristics and control of linear astigmatism aberration in a nonaxially symmetric optical system

We examine the characteristics of linear astigmatism in a nonaxially symmetric optical system. The conventional view of interpreting linear astigmatism aberration using P and N focal surfaces is revisited. A perspective to explain and visualize the behavior of linear astigmatism is provided using the concept of field curves. Methods of controlling linear astigmatism are discussed, including a ray-tracing method using pupil imaging. Confocal mirror designs free from linear astigmatism are also discussed.

Maintenance of Endoplasmic Reticulum Protein Homeostasis in Cancer: Friend or Foe.

The endoplasmic reticulum, as the site of synthesis for proteins in the secretory pathway has evolved select machineries to ensure the correct folding and modification of proteins. However, sometimes these quality control mechanisms fail and proteins are misfolded. Other factors, such as nutrient deprivation, hypoxia or an increased demand on protein synthesis can also cause the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. There are mechanisms that recognise and deal with this accumulation of protein through degradation and/or export. Many diseases are associated with aberrant quality control mechanisms, and among these, cancer has emerged as a group of diseases that rely on endoplasmic reticulum homeostasis to sustain development and growth. The knowledge of how protein quality control operates in cancer has identified opportunities for these pathways to be pharmacologically targeted, which could lead to newer or more effective treatments in the future.

Resting-state functional network connectivity underlying eating disorder symptoms in healthy young adults

Previous neuroimaging research of eating disorders such as anorexia nervosa and bulimia nervosa has mainly focused on clinical patients, indicating the crucial role of intrinsic connectivity networks involved in aberrant behavioral control (i.e., executive control network), reward reactivity (i.e., basal ganglia network), and excessive self-focused and body-focused ruminations (i.e., default mode network) in the onset and maintenance of eating disturbances. However, examinations of large-scale resting-state networks that support the role of cognitive control, reward sensitivity, and self-directed thinking in disordered eating have rarely involved non-clinical samples from the general population. This study, involving a total of 693 healthy young adults (68.69% females; mean age, 18.37 years), investigated these issues by using pre-defined functional regions of interest from the executive control network, basal ganglia network, default mode network, and a seed-based region of interest-to-region of interest approach. After statistically controlling for differences in age, sex, body mass index, and head motion, we observed significant associations of higher levels of eating disorder symptoms, especially bulimia-type eating (i.e., binge eating and a combination of binge eating and compensatory behaviors, such as purging via self-induced vomiting or laxative use, and compulsive exercise), with weaker intra-network and inter-network functional synchrony. These results remained significant after excluding underweight, overweight, and obese participants. These findings suggest that these neural circuits may play a key role in the symptoms of disordered eating in healthy adults. They further reveal that the less efficient information exchange within and between intrinsic networks associated with self-referential thinking, inhibitory control, and reward sensitivity are strongly related to eating disorder symptoms.

Application of chromatic aberration control of metalens

The predecessor of China Optics was China Optics and Applied Optics Digest, which was founded in 1985. At that time, it was the only retrieval journal in the field of optics in China. At the end of 2008, China Optics and Applied Optics Digest was renamed

Atypical alert state control in adult patients with ADHD: A pupillometry study.

Although behavioral studies have repeatedly demonstrated that individuals with attention-deficit/hyperactivity disorder (ADHD) have deficits in alertness, little is known about its underlying neural basis. It is hypothesized that pupil diameter reflects the firing of norepinephrine (NE) neurons in the locus coeruleus (LC), and that the LC-NE neuromodulatory system for regulating alertness may be dysfunctional in ADHD. To clinically and non-invasively examine this hypothesis, we monitored the kinetics of pupil diameter in response to stimuli and compared them between adults with ADHD (n = 17) and typically developing (TD) adults (n = 23) during an auditory continuous performance task. Individuals in the ADHD group exhibited a significantly larger tonic pupil diameter, and a suppressed stimulus-evoked phasic pupil dilation, compared to those in the TD group. These findings provide support for the idea that the aberrant regulatory control of pupil diameter in adults with ADHD may be consistent with a compromised state of alertness resulting from a hyperactivated LC-NE system.

MicroRNAs in Several Cutaneous Autoimmune Diseases: Psoriasis, Cutaneous Lupus Erythematosus and Atopic Dermatitis.

MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that regulate the gene expression at a post-transcriptional level and participate in maintaining the correct cell homeostasis and functioning. Different specific profiles have been identified in lesional skin from autoimmune cutaneous diseases, and their deregulation cause aberrant control of biological pathways, contributing to pathogenic conditions. Detailed knowledge of microRNA-affected pathways is of crucial importance for understating their role in skin autoimmune diseases. They may be promising therapeutic targets with novel clinical implications. They are not only present in skin tissue, but they have also been found in other biological fluids, such as serum, plasma and urine from patients, and therefore, they are potential biomarkers for the diagnosis, prognosis and response to treatment. In this review, we discuss the current understanding of the role of described miRNAs in several cutaneous autoimmune diseases: psoriasis (Ps, 33 miRNAs), cutaneous lupus erythematosus (CLE, 2 miRNAs) and atopic dermatitis (AD, 8 miRNAs). We highlight their role as crucial elements implicated in disease pathogenesis and their applicability as biomarkers and as a novel therapeutic approach in the management of skin inflammatory diseases.

Development of a compact imaging spectrometer form for the solar reflective spectral region.

Current imaging spectrometer forms for terrestrial remote sensing in the visible, near-, and shortwave infrared (VNR/SWIR) spectral range have been implemented in hardware and achieve a high level of performance in terms of both aberration control and signal-to-noise level. These forms are compact, relative to prior art, but more size, weight, and power optimization, while maintaining performance, is desirable for usage on small satellite platforms. Pursuant to that goal, we have developed a compact breadboard prototype VNIR/SWIR imaging spectrometer that maintains the current aberration control and has a large number of spatial samples. The new form utilizes a catadioptric lens and a flat dual-blaze immersion grating yielding a compact design that is relatively easy to manufacture.

Pyruvate Kinase M2 Coordinates Metabolism Switch between Glycolysis and Glutaminolysis in Cancer Cells.

SummaryCancer cells alter their nutrition metabolism to cope the stressful environment. One important metabolism adjustment is that cancer cells activate glutaminolysis in response to the reduced carbon from glucose entering into the TCA cycle due to inactivation of several enzymes in glycolysis. An important question is how the cancer cells coordinate the changes of glycolysis and glutaminolysis. In this report, we demonstrate that the pyruvate kinase inactive dimer PKM2 facilitates activation of glutaminolysis. Our experiments show that growth stimulations promote PKM2 dimer. The dimer PKM2 plays a role in regulation of glutaminolysis by upregulation of mitochondrial glutaminase I (GLS-1). PKM2 dimer regulates the GLS-1 expression by controlling internal ribosome entry site (IRES)-dependent c-myc translation. Growth stimulations promote PKM2 interacting with c-myc IRES-RNA, thus facilitating c-myc IRES-dependent translation. Our study reveals an important linker that coordinates the metabolism adjustment in cancer cells.