Compensatory and orienting eye movements induced by off-vertical axis rotation (OVAR) in monkeys

Nystagmus induced by off-vertical axis rotation (OVAR) about a head yaw axis is composed of a yaw bias velocity and modulations in eye position and velocity as the head changes orientation relative to gravity. The bias velocity is dependent on the tilt of the rotational axis relative to gravity and angular head velocity. For axis tilts <15 degrees, bias velocities increased monotonically with increases in the magnitude of the projected gravity vector onto the horizontal plane of the head. For tilts of 15-90 degrees, bias velocity was independent of tilt angle, increasing linearly as a function of head velocity with gains of 0.7-0.8, up to the saturation level of velocity storage. Asymmetries in OVAR bias velocity and asymmetries in the dominant time constant of the angular vestibuloocular reflex (aVOR) covaried and both were reduced by administration of baclofen, a GABA(B) agonist. Modulations in pitch and roll eye positions were in phase with nose-down and side-down head positions, respectively. Changes in roll eye position were produced mainly by slow movements, whereas vertical eye position changes were characterized by slow eye movements and saccades. Oscillations in vertical and roll eye velocities led their respective position changes by approximately 90 degrees, close to an ideal differentiation, suggesting that these modulations were due to activation of the orienting component of the linear vestibuloocular reflex (lVOR). The beating field of the horizontal nystagmus shifted the eyes 6.3 degrees /g toward gravity in side down position, similar to the deviations observed during static roll tilt (7.0 degrees /g). This demonstrates that the eyes also orient to gravity in yaw. Phases of horizontal eye velocity clustered ~180 degrees relative to the modulation in beating field and were not simply differentiations of changes in eye position. Contributions of orientating and compensatory components of the lVOR to the modulation of eye position and velocity were modeled using three components: a novel direct otolith-oculomotor orientation, orientation-based velocity modulation, and changes in velocity storage time constants with head position re gravity. Time constants were obtained from optokinetic after-nystagmus, a direct representation of velocity storage. When the orienting lVOR was combined with models of the compensatory lVOR and velocity estimator from sequential otolith activation to generate the bias component, the model accurately predicted eye position and velocity in three dimensions. These data support the postulates that OVAR generates compensatory eye velocity through activation of velocity storage and that oscillatory components arise predominantly through lVOR orientation mechanisms.     

Comparative Study of Distribution of Active Sites According to Their Stereospecificity in Propylene Polymerization over the Traditional TiCl3 and Supported Titanium–Magnesium Catalysts with Different Composition

The preparative‐temperature rising elution fractionation method is used to obtain comparative data on contents of fractions with different microtacticities for polypropylene (PP) samples prepared using three catalytic systems: the traditional Ziegler–Natta (Z–N) catalyst δ‐TiCl₃ and two types of supported titanium–magnesium catalysts: the “donor‐free” TiCl₄/MgCl₂ catalyst and TiCl₄/MgCl₂·nDBP catalyst (DBP – dibutylphthalate used as an internal donor) at polymerization with the same cocatalyst (AlEt₃) in the absence and presence of an external donor (propyltrimetoxy silane). The separated individual PP fractions are also studied by gel permeation chromatography (molecular weight and molecular weight distribution) and differential scanning calorimetry. The results demonstrate general regularities and differences in the formation of active sites having different isospecificities for the traditional TiCl₃‐based Z–N catalyst and highly active supported titanium–magnesium catalysts.     

Treatment Satisfaction with Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency: a Pooled Analysis of Six Hizentra® Studies

Purpose

Primary immunodeficiency diseases (PIDDs) are a heterogenous group of disorders characterized by intrinsic impairment in the immune system. Most patients with PIDD require life-long immunoglobulin G replacement therapy, which has been shown to reduce the rate of infections and, related hospitalizations and reduce health-related quality of life (HRQOL). Here, treatment satisfaction and HRQOL in patients with PIDD was evaluated upon switching from intravenous (IVIG) or subcutaneous immunoglobulins (SCIGs) to 20% SCIG (Hizentra®), and during long-term steady-state Hizentra® treatment.

Methods

Analyses were based on two pivotal (switch) and four extension/follow-up (maintenance) Phase III studies of Hizentra® conducted in Europe (EU), Japan (JP), and the United States (US). Two validated questionnaires were used: Life Quality Index (LQI) for assessment of IgG-specific perceptions of HRQOL and Short Form 36 version 2 (SF-36v2).

Results

In the EU and JP switch studies, there was significant and meaningful improvement from Screening in LQI domain scores at all time points, largely driven by patients switching from IVIG to SCIG. In the EU switch study, there were also significant increases in mean SF-36v2 domain scores for Physical Function and General Health from Screening to Week 12. These improvements were observed also at Week 24. Overall, LQI and SF-36v2 domain scores were generally sustained in the maintenance studies.

Conclusions

These results showed that switching patients from IVIG to SCIG improves patient self-reported health status and IgG-specific HRQOL perception. The maintenance studies generally showed no deterioration of this improved health status over a long follow-up period.

     

Rapamycin Extends Maximal Lifespan in Cancer-Prone Mice

Aging is associated with obesity and cancer. Calorie restriction both slows down aging and delays cancer. Evidence has emerged that the nutrient-sensing mammalian target of rapamycin (mTOR) pathway is involved in cellular and organismal aging. Here we show that the mTOR inhibitor rapamycin prevents age-related weight gain, decreases rate of aging, increases lifespan, and suppresses carcinogenesis in transgenic HER-2/neu cancer-prone mice. Rapamycin dramatically delayed tumor onset as well as decreased the number of tumors per animal and tumor size. We suggest that, by slowing down organismal aging, rapamycin delays cancer.Astonishing discoveries in model organisms indicate that lifespan is genetically controlled.¹ In particular, the nutrient-sensing target of rapamycin (TOR) pathway is involved in both mammalian cell senescence² and aging in diverse organisms from worms to mammals.^3,4,5,6 In mammals, TOR (mTOR) controls cell growth and metabolism in response to nutrients (eg, amino acids), insulin, and growth factors such as IGF-1.⁷ Calorie restriction (CR) deactivates mTOR in mice.⁸ Not surprisingly, CR extends lifespan in most species including rodents and primates.^9,10 Furthermore, the TOR inhibitor rapamycin decelerates senescence in both yeast¹¹ and mammalian cells.¹² Based on these findings it was suggested that rapamycin, a clinically approved drug, is an antiaging drug.¹³ Recently it has been demonstrated that rapamycin in fact extends lifespan in mice.¹⁴ However, its effect on longevity of cancer-prone mice has not been addressed. There are several lines of evidence that suggest that suppression of organismal aging may delay carcinogenesis. Thus, cancer is an age-related disease, and the incidence of cancer increases with age in both humans and animals.^15,16 Consistently, carcinogenesis is delayed in slowly aging Ames dwarf mice.^17,18 Cancer is often associated with age-related obesity and metabolic syndrome,¹⁹ and calorie restriction affects both the process of aging (by slowing it down) and carcinogenesis (by delaying the tumor onset in normal and cancer-prone mice^20,21). Interestingly, centenarians, people who age slowly, are endowed with a peculiar resistance to cancer.²² Therefore it is reasonable to hypothesize that by slowing down aging rapamycin could delay cancer. Our data demonstrate that rapamycin not only extends lifespan but also significantly delays the onset of spontaneous carcinogenesis in cancer-prone HER-2/neu transgenic mice.     

VEGFR1/CXCR4-positive progenitor cells modulate local inflammation and augment tissue perfusion by a SDF-1-dependent mechanism

Recruitment and retention of circulating progenitor cells at the site of injured or ischemic tissues facilitates adult neo-vascularization. We hypothesized that cell therapy could modulate local neo-vascularization through the vascular endothelial growth factor (VEGF)/stromal cell-derived factor-1 (SDF-1) axis and by paracrine effects on local endothelial cells. We isolated from rat bone marrow a subset of multipotent adult progenitor cell-derived progenitor cells (MDPC). In vitro, MDPCs secreted multiple cytokines related to inflammation and angiogenesis, including monocyte chemotactic protein-1, SDF-1, basic fibroblast growth factor, and VEGF, and expressed the chemokine receptors CXCR4 and VEGFR1. To investigate in vivo properties, we transplanted MDPCs into the ischemic hind limbs of rats. Elevated levels of the chemokine SDF-1 and colocalization of CD11b⁺ cells marked the initial phase of tissue remodeling after cell transplantation. Prolonged engraftment was observed in the adventitial–medial border region of arterioles of ischemic muscles. However, engrafted cells did not differentiate into endothelial or smooth muscle cells. Limb perfusion normalized 4 weeks after cell injection. Inhibition of SDF-1 reduced the engraftment of transplanted cells and decreased endothelial cell proliferation. These findings suggest a two-stage model whereby transplanted MDPCs modulate wound repair through recruitment of inflammatory cells to ischemic tissue. This is an important potential mechanism for cell transplantation, in addition to the direct modulation of local vascular cells through paracrine mechanisms.     

The Photoinduced Birefringence in Thick Films of Chiral Azodye Copolymers

The photoinduced birefringence, Δn_ind, in 19–35 μm thick films has been studied for two series of chiral photochromic liquid crystalline side chain copolymers. The birefringence measured is induced by excitation of the n‐π* band only. The Δn_ind value induced in 10 min is linear upon concentration of dye moieties but achieves saturation with increase of illumination intensity. Evolution of the birefringence can be described by double exponent growth; the faster exponent is the same for both copolymer series and should relate to the photoselection process, while the slower one should relate mainly to photo‐orientation and differs strongly dependent on chemical structure of photochromic groups. The different behaviour of two copolymer series during the growth governed by the second exponent is interpreted in terms of the “frictional model”. Due to elevated thickness of the films, rather moderate Δn_ind values result in huge phase retardation up to 270° and more. The materials are promising therefore for holography applications.

Chemical structure of the synthesised chiral photochromic copolymers.     

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics

Rationale  

We evaluated locomotor hyperactivity induced in BALB/C mice by an N-methyl-d-aspartate receptor antagonist MK-801 as an assay for the detection of antipsychotic drugs.     

A design strategy to generate a SARS-CoV-2 RBD vaccine that abrogates ACE2 binding and improves neutralizing antibody responses

The structure-based design of antigens holds promise for developing vaccines with higher efficacy and improved safety profiles. We postulate that abrogation of host receptor interaction bears potential for the improvement of vaccines by preventing antigen-induced modification of receptor function as well as the displacement or masking of the immunogen. Antigen modifications may yet destroy epitopes crucial for antibody neutralization. Here, we present a methodology that integrates deep mutational scans to identify and score SARS-CoV-2 receptor binding domain variants that maintain immunogenicity, but lack interaction with the widely expressed host receptor. Single point mutations were scored in silico, validated in vitro, and applied in vivo. Our top-scoring variant receptor binding domain-G502E prevented spike-induced cell-to-cell fusion, receptor internalization, and improved neutralizing antibody responses by 3.3-fold in rabbit immunizations. We name our strategy BIBAX for body-inert, B-cell-activating vaccines, which in the future may be applied beyond SARS-CoV-2 for the improvement of vaccines by design.     

Electrophysiology of statistical learning: Exploring the online learning process and offline learning product

A continuous stream of syllables is segmented into discrete constituents based on the transitional probabilities (TPs) between adjacent syllables by means of statistical learning. However, we still do not know whether people attend to high TPs between frequently co‐occurring syllables and cluster them together as parts of the discrete constituents or attend to low TPs aligned with the edges between the constituents and extract them as whole units. Earlier studies on TP‐based segmentation also have not distinguished between the segmentation process (how people segment continuous speech) and the learning product (what is learnt by means of statistical learning mechanisms). In the current study, we explored the learning outcome separately from the learning process, focusing on three possible learning products: holistic constituents that are retrieved from memory during the recognition test, clusters of frequently co‐occurring syllables, or a set of statistical regularities which can be used to reconstruct legitimate candidates for discrete constituents during the recognition test. Our data suggest that people employ boundary‐finding mechanisms during online segmentation by attending to low inter‐syllabic TPs during familiarization and also identify potential candidates for discrete constituents based on their statistical congruency with rules extracted during the learning process. Memory representations of recurrent constituents embedded in the continuous speech stream during familiarization facilitate subsequent recognition of these discrete constituents.     

Novel case of neurodegeneration with brain iron accumulation 4 (NBIA4) caused by a pathogenic variant affecting splicing

Neurodegeneration with brain iron accumulation type 4 (NBIA4) also known as MPAN (mitochondria protein-associated neurodegeneration) is a rare neurological disorder which main feature is brain iron accumulation most frequently in the globus pallidus and substantia nigra. Whole exome sequencing (WES) in a 12-year-old patient revealed 2 variants in the C19orf12 gene, a previously reported common 11 bp deletion c.204_214del11, p.(Gly69Argfs*10) and a novel splicing variant c.193+5G>A. Functional analysis of novel variant showed skipping of the second exon, resulting in a formation of a truncated nonfunctional protein. This is the first functionally annotated pathogenic splicing variant in NBIA4.