Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis

1. Download high-res image (356KB)
2. Download full-size image

     

Visual orientation in the rat: A dissociation of deficits following cortical and collicular lesions

Summary Rats with either bilateral ablations of superior colliculus, bilateral ablations of visual cortex, or sham operations were trained to run across a large arena towards a small illuminated target which varied in location from trial to trial. An impairment in this visually-guided running was apparent in the cortical group, but not in the collicular group. When, in a second experiment, the spatial relationships within the apparatus were changed by extending the entry-tunnel some distance into the arena, the running of the cortical group became even more impaired, while the collicular animals continued to run towards the targets under efficient visual control. In a third experiment, the effect of introducing a novel flashing light in various locations around the perimeter of the arena was investigated. It was found that unlike the other two groups, the collicular animals showed no orienting reflex to the novel stimulus when it was presented outside a broad central area of the visual field.The authors acknowledge the financial support of the Science Research Council (grant no B/RG/61112)     

Adaptation to destabilizing dynamics by means of muscle cocontraction

Adaptive control of wrist mechanics was investigated by means of destabilizing dynamics created by a torque motor. Subjects performed a 20 degrees movement to a 3 degrees target under the constraint that no motion should occur outside of the target zone once 800 ms had elapsed from movement onset. This constraint served as the minimum acceptable level of postural stability. The ability of subjects to modify their muscle activation patterns in order to successfully achieve this stability was investigated by creating three types of destabilizing dynamics with markedly different features: negative stiffness, negative damping, and square-wave vibration. Subjects performed sets of trials with the first type of destabilizing dynamics and were then required to adapt to the second and third. The adaptive response was quantified in terms of the rms electromyographic (EMG) activity recorded during various phases of the task. Surface EMG activity was recorded from three muscles contributing to wrist flexion and three muscles contributing to wrist extension. With negative stiffness, a significant compensatory increase in cocontraction of wrist flexor and extensor muscles was observed for slow movements, but there was little change in the muscle activity for rapid movements. With negative damping, muscle cocontraction was elevated to stabilize rapid movements, declining only gradually after the target was reached. For slow movements, cocontraction occurred only when negative damping was high. The response to square-wave vibration (10 Hz, +/-0.5 Nm), beginning at movement onset, was similar to that of negative damping, in that it resulted in elevated cocontraction. However, because the vibration persisted after the target was reached, there was no subsequent decrease in muscle activity. When the frequency was reduced to 5.5 Hz, but with the same torque impulse, cocontraction increased. This is consistent with greater mechanical instability. In summary, agonist-antagonist cocontraction was adapted to the stability of the task. This generally resulted in less of a change in muscle activity during the movement phase, when the task was performed quickly compared with slowly. On the other hand, the change in muscle activity during stabilization depended more on the nature of the instability than the movement speed.     

Continuous Glucose Monitoring Use in Clinical Trials for On-Market Diabetes Drugs

To the best of our knowledge, there are no published data on the historical and recent use of CGM in clinical trials of pharmacological agents used in the treatment of diabetes. We analyzed 2,032 clinical trials of 40 antihyperglycemic therapies currently on the market with a study start date between 1 January 2000 and 31 December 2019. According to ClinicalTrials.gov, 119 (5.9%) of these trials used CGM. CGM usage in clinical trials has increased over time, rising from <5% before 2005 to 12.5% in 2019. However, it is still low given its inclusion in the American Diabetes Association’s latest guidelines and known limitations of A1C for assessing ongoing diabetes care.

The availability of reliable continuous glucose monitoring (CGM) systems has proven to be a major innovation in diabetes management and research. Most current CGM systems are approved for 7- to 14-day use and use a wire-tipped glucose oxidase sensor inserted in subcutaneous tissue to monitor glucose concentrations in interstitial fluid. One implanted CGM system is approved for longer-term use (90–180 days); it operates with fluorescence-based technology. CGM sensors record a glucose data point every 1–15 minutes (depending on the system), collecting far more granular data and information on glycemic patterns than self-monitoring of blood glucose (SMBG) alone. Real-time CGM or intermittently scanned CGM systems send data continuously or intermittently to dedicated receivers or smartphones, whereas professional CGM systems provide retrospective data, either blinded or unblinded, for analysis and can be used to identify patterns of hypo- and hyperglycemia. Professional CGM can be helpful to evaluate patients when other CGM systems are not available to the patient or the patient prefers a blinded analysis or a shorter experience with unblinded data.In the 20 years since CGM systems first became available to people with diabetes, technological improvements, particularly pertaining to accuracy and form factor, have made CGM increasingly viable for both patient use and clinical investigation (1,2). Average sensor MARD (mean absolute relative difference; a summary accuracy statistic) has decreased from >20 to <10% (3–10), including two systems that do not require fingerstick calibrations and three that are approved to be used for insulin dosing (11). Concurrently, size, weight, and cost of CGM systems have all decreased, while user-friendliness and convenience have increased (12).To encourage use of CGM-derived data, researchers and clinicians have worked to develop a standard set of glycemic metrics beyond A1C. In 2017, two international groups of leading diabetes clinical and research organizations published consensus definitions for key metrics, including clinically relevant glycemic cut points for hypoglycemia (<70 and <54 mg/dL), hyperglycemia (>180 and >250 mg/dL), and time in range (TIR; 70–180 mg/dL) (13,14).CGM-derived metrics provide far greater precision and granularity than is possible with SMBG or A1C data alone (Table 1), enabling clinicians and investigators to better represent inter- and intraday glycemic differences with metrics such as TIR, glycemic variability, and time in hypoglycemia and hyperglycemia (15). Crucially, CGM also allows for the accurate measurement and detection of nocturnal glycemia (16). The use of these metrics enables a more comprehensive understanding of glycemic management that can facilitate individualized treatment for people with diabetes or prediabetes. Although A1C is a useful estimate of mean glucose over the previous 2–3 months, especially when evaluating population health, it is important to include other glycemic outcomes in clinical trials. Furthermore, there is emerging evidence suggesting that TIR predicts the development of microvascular complications at least as well as A1C (17,18).TABLE 1Benefits of CGM Compared With A1C Alone in Assessing Glycemia

Automatic avoidance of obstacles is a dorsal stream function: evidence from optic ataxia

When we reach out to pick something up, our arm is directed to the target by visuomotor networks in the cortical dorsal stream. However, our reach trajectories are influenced also by nontarget objects, which might be construed as potential obstacles. We tested two patients with bilateral dorsal-stream (parietal lesions, both of whom were impaired at pointing to visual stimuli (optic ataxia). We asked them to reach between two cylinders, which varied in location from trial to trial. We found that the patients' reaches remained invariant with changes in obstacle location. In a control task when they were asked to point midway between the two objects, however, their responses shifted in an orderly fashion. We conclude that the dorsal stream provides the visual guidance we automatically build into our movements to avoid potential obstacles, as well as that required to ensure arrival at the target.     

1141610241Altered expression of HuR, an mRNA stabilizing protein, mediates aberrant Placenta Growth Factor (PlGF) expression in preeclampsia

Background:  Control of mRNA stability is an essential regulatory process in eukaryotic gene expression. HuR, a 3'UTR mRNA binding protein, can protect AU-rich mRNA from degradation in response to stresses. PlGF, an angiogenic growth factor, contains two consensus AU-rich sites suggesting that under normal conditions HuR may protect PlGF mRNA from degradation. Trophoblast expression of PlGF is significantly decreased in preeclampsia and by hypoxia in vitro . We hypothesize that decreased levels of cytoplasmic HuR may contribute to decreased PlGF expression in hypoxic and preeclamptic trophoblast.
Methods:  Western blots were used to determine relative effects of in vitro hypoxia on HuR protein expression and subcellular localization in trophoblast. Immunohistochemistry was used to compare HuR expression patterns in trophoblast of preeclamptic and normal placentae.
Results:  Cytoplasmic expression of HuR was decreased 1.4 fold in the cytoplasm and 1.2 fold in the nucleus of JEG3 cells. A shift in HuR was more apparent in primary trophoblast with a greater than 2-fold decrease in the cytoplasm and a 1.4 fold decrease in the nucleus following 24 hr of hypoxia. Immunohistochemical analyses detected HuR expression in near term trophoblast in situ . However, this technical approach did not detect a significant change in HuR expression between normal and preeclamptic trophoblast.
Conclusions:  HuR expression is decreased in hypoxic trophoblast, at least in vitro , which may provide a causal link to decreased PlGF mRNA expression. Down regulation of trophoblast PlGF expression is thought to contribute to the pathophysiology associated with preeclampsia including the relative lack of perfusion of the placenta and systemic renal effects.     

Impedance control and internal model use during the initial stage of adaptation to novel dynamics in humans

This study investigated the neuromuscular mechanisms underlying the initial stage of adaptation to novel dynamics. A destabilizing velocity-dependent force field (VF) was introduced for sets of three consecutive trials. Between sets a random number of 4–8 null field trials were interposed, where the VF was inactivated. This prevented subjects from learning the novel dynamics, making it possible to repeatedly recreate the initial adaptive response. We were able to investigate detailed changes in neural control between the first, second and third VF trials. We identified two feedforward control mechanisms, which were initiated on the second VF trial and resulted in a 50% reduction in the hand path error. Responses to disturbances encountered on the first VF trial were feedback in nature, i.e. reflexes and voluntary correction of errors. However, on the second VF trial, muscle activation patterns were modified in anticipation of the effects of the force field. Feedforward cocontraction of all muscles was used to increase the viscoelastic impedance of the arm. While stiffening the arm, subjects also exerted a lateral force to counteract the perturbing effect of the force field. These anticipatory actions indicate that the central nervous system responds rapidly to counteract hitherto unfamiliar disturbances by a combination of increased viscoelastic impedance and formation of a crude internal dynamics model.     

Plasticity of the medial prefrontal cortex: Facilitated acquisition of intracranial self-stimulation by pretraining stimulation

Prior electrical stimulation of the medial prefrontal cortex MFC facilitated the subsequent acquisition of intracranial self-stimulation (ICSS) from the same MFC electrode site. Stimulations that were spaced over a period of six days were more effective in producing this facilitation than the same number of stimulations delivered over a two day period. These data suggest that the rewarding effects of MFC stimulation may involve some process akin to the kindling phenomenon and as such may provide insights in the neuronal modifications thought to underlie learning and memory.     

Influence of interaction force levels on degree of motor adaptation in a stable dynamic force field

Studies have shown that the point-to-point reaching movements of subjects seated in a dark, rotating room demonstrate errors in movement trajectories and endpoints, consistent with the direction of the Coriolis force perturbations created by room rotation. Adaptation of successive reaches and the presence of postrotation aftereffects have indicated that subjects form internal models of the Coriolis field dynamics in order to make appropriate movement corrections. It has been argued that these findings are inconsistent with predictions of peripheral stabilization assumed in equilibrium-point models of motor control. A possibility that has been raised, however, is that the Coriolis field findings may in fact stem from changes in control commands elicited due to the magnitude and destabilizing nature of the Coriolis perturbations. That is, it has been suggested that a perturbation threshold exists, below which central reactions are not necessary in order to maintain movement stability. We tested the existence of a perturbation threshold in normal-speed reaching movements. Twelve normal human subjects performed non-visually guided reaching movements while grasping a robotic manipulandum. The endpoints and trajectory deviations of their movements were measured before, during, and after a position-dependent force field (similar to a Coriolis field in terms of the time history of applied forces) was applied to their movements. We examined the responses to a range of perturbation field strengths from small to considerable. Our experimental results demonstrated a substantial adaptation response over the entire range of perturbation field magnitudes examined. Neither the amount of adaptation after 5 trials nor after 25 trials was found to change as disturbance magnitudes decreased. These findings indicate that there is an adaptive response even for small perturbations; i.e., threshold behavior was not found. This result contradicts the assertion that peripheral stabilization mechanisms enable the central controller to ignore small details of peripheral or environmental dynamics. Our findings instead point to a central dynamic modeler that is both highly sensitive and continually active. The results of our study also showed that subjects were able to maintain baseline pointing accuracies despite exposure to perturbation forces of sizeable magnitude (more than 7 N).