An arch worth revisiting: a study on the feline humeral supracondylar foramen and its evolutionary significance.

The supracondylar foramen with a (seemingly) osseous peripheral arch noticed on the medio-distal feline humeri had remained disputed among anatomists. Some scholars have argued in favor of homology between this foramen and the supracondyloid foramen formed in presence of the ligament of Struthers in humans. Other theories include its presence as a retinaculum holding the median nerve and brachial artery to their anatomical position in a flexed elbow. Unfortunately, these theories lack investigative rigor. The emergence of non-invasive imaging modalities, such as micro-computed tomography, has enabled researchers to inspect the internal anatomy of bones without dismantling them. Thus, a micro-computed tomographic investigation was conducted on three feline (Felis catus) humeri specimens while the internal anatomy of the supracondylar foramina was examined. Unlike the humerus, the thin peripheral arch of the feline supracondylar foramen failed to elicit any osseous trabeculae or foci of calcification. While adhering to the humeral periosteum at its origin, the non-osseous arch, typical of a muscular tendon, attaches into the bony saddle related to the medial humeral epicondyle suggestive of a tendon or aponeurotic extension of a (vestigial) brachial muscle, with the coracobrachialis longus emerging to be the most likely candidate.

Straggler- and Adversary-Tolerant Secure Distributed Matrix Multiplication Using Polynomial Codes.

Large matrix multiplications commonly take place in large-scale machine-learning applications. Often, the sheer size of these matrices prevent carrying out the multiplication at a single server. Therefore, these operations are typically offloaded to a distributed computing platform with a master server and a large amount of workers in the cloud, operating in parallel. For such distributed platforms, it has been recently shown that coding over the input data matrices can reduce the computational delay by introducing a tolerance against straggling workers, i.e., workers for which execution time significantly lags with respect to the average. In addition to exact recovery, we impose a security constraint on both matrices to be multiplied. Specifically, we assume that workers can collude and eavesdrop on the content of these matrices. For this problem, we introduce a new class of polynomial codes with fewer non-zero coefficients than the degree +1. We provide closed-form expressions for the recovery threshold and show that our construction improves the recovery threshold of existing schemes in the literature, in particular for larger matrix dimensions and a moderate to large number of colluding workers. In the absence of any security constraints, we show that our construction is optimal in terms of recovery threshold.

Minocycline Inhibits Microglial Activation and Improves Visual Function in a Chronic Model of Age-Related Retinal Degeneration.

Age-related macular degeneration (AMD) is a chronic disease, which progresses slowly from early to late stages over many years. Inflammation critically contributes to the pathogenesis of AMD. Here, we investigated the therapeutic potential of minocycline in a chronic model of AMD (i.e., the LysMCre-Socs3fl/flCx3cr1gfp/gfp double knockout [DKO] mice). Five-month-old DKO and wild type (WT) (Socs3fl/fl) mice were gavage fed with minocycline (25 mg/kg daily) or vehicle (distilled water) for 3 months. At the end of the treatment, visual function and retinal changes were examined clinically (using electroretinography, fundus photograph and optic coherence tomography) and immunohistologically. Three months of minocycline treatment did not affect the body weight, behaviour and general health of WT and DKO mice. Minocycline treatment enhanced the a-/b-wave aptitudes and increased retinal thickness in both WT and DKO. DKO mouse retina expressed higher levels of Il1b, CD68 and CD86 and had mild microglial activation, and decreased numbers of arrestin+ photoreceptors, PKCα+ and secretagogin+ bipolar cells compared to WT mouse retina. Minocycline treatment reduced microglial activation and rescued retinal neuronal loss in DKO mice. Our results suggest that long-term minocycline treatment is safe and effective in controlling microglial activation and preserving visual function in chronic models of AMD.

Complement activation contributes to subretinal fibrosis through the induction of epithelial-to-mesenchymal transition (EMT) in retinal pigment epithelial cells.

BACKGROUND: We previously reported higher plasma levels of complement fragments C3a and C5a in neovascular Age-related Macular Degeneration (nAMD) patients with macular fibrosis. This study aimed to understand whether complement activation contributes to the development of macular fibrosis and the underlying mechanisms involved. METHODS: Complement activation was blocked using a C5 neutralizing antibody (BB5.1) in C57BL/6J mice after induction of subretinal fibrosis using the two-stage laser protocol. Fibrotic lesions were examined 10 days after the 2nd laser through fundus examination and immunohistochemistry. The expression of C5aR in fibrotic lesions and retinal pigment epithelial (RPE) cultures were examined by confocal microscopy. Primary murine RPE cells were treated with C3a or C5a (10-100 ng/mL) or TGF-ß2 (10 ng/mL). Epithelial-to-mesenchymal transition (EMT) was assessed through various readouts. The expression of E-cadherin, vimentin, fibronectin, α-SMA, Slug, ERK/AKT and pSMAD2/3 were determined by Western blot and immunocytochemistry. Collagen contraction and wound-healing assays were used as functional readouts of EMT. The production of IL-6, TGF-ß1, TGF-ß2 and VEGF by RPE cells were determined by ELISA. PMX53 was used to block C5aR in RPE cultures and in vivo in mice with subretinal fibrosis. RESULTS: Extensive C5b-9 deposition was detected at the site of subretinal fibrosis. BB5.1 treatment completely abrogated complement activation and significantly reduced subretinal fibrosis. C5aR was detected in RPE and infiltrating MHC-II+ cells in subretinal fibrosis. In vitro, RPE cells constitutively express C5/C5a and C5aR, and their expression was increased by TGF-ß2 treatment. C5a but not C3a increased fibronectin, α-SMA, vimentin and Slug expression, and decreased E-cadherin expression in RPE cells. C5a treatment also increased the contractility and migration of RPE cells and enhanced the production of VEGF and TGF-ß1/2. C5a treatment induced pSmad2/3 and pERK1/2 expression in RPE cells and this was blocked by PMX53. PMX53 treatment significantly reduced sodium fluorescein leakage in the subretinal fibrosis model, while collagen-I+ lesions only mildly reduced. CONCLUSIONS: Complement activation is critically involved in the development of subretinal fibrosis, partially through C5a-C5aR-mediated EMT in RPE cells. Targeting complement activation rather than C5a may be a novel approach for the management of macular fibrosis.

Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes.

We have previously reported that inhibition of the Janus kinase 1 (JAK1) signaling ameliorates IL-17A-mediated blood-retinal barrier (BRB) dysfunction. Higher levels of IL-17A have been observed in the blood and intraocular fluids in patients with diabetic retinopathy (DR), in particular those with diabetic macular oedema. This study aimed to understand whether JAK1 inhibition could prevent BRB dysfunction in db/db mice, a model of type 2 diabetes (T2D). An in vitro study showed that high glucose treatment disrupted the junctional distribution of claudin-5 in bEnd3 cells and ZO-1 in ARPE19 cells and that tofacitinib citrate treatment prevented high glucose-mediated tight junction disruption. Albumin leakage, accompanied by increased levels of the phosphorylated form of JAK1 (pJAK1), was observed in three-month-old db/db mice. Treatment of two-and-a-half-month-old db/db mice with tofacitinib citrate for two weeks significantly reduced retinal albumin leakage and reduced pJAK1 expression. pJAK1 expression was also detected in human DR retina. Our results suggest that JAK1 inhibition can ameliorate BRB dysfunction in T2D, and JAK1 inhibitors such as tofacitinib citrate may be re-purposed for the management of diabetic macular oedema.

IL-17A Damages the Blood-Retinal Barrier through Activating the Janus Kinase 1 Pathway.

Blood-retinal barrier (BRB) dysfunction underlies macular oedema in many sight-threatening conditions, including diabetic macular oedema, neovascular age-related macular degeneration and uveoretinitis. Inflammation plays an important role in BRB dysfunction. This study aimed to understand the role of the inflammatory cytokine IL-17A in BRB dysfunction and the mechanism involved. Human retinal pigment epithelial (RPE) cell line ARPE19 and murine brain endothelial line bEnd.3 were cultured on transwell membranes to model the outer BRB and inner BRB, respectively. IL-17A treatment (3 days in bEnd.3 cells and 6 days in ARPE19 cells) disrupted the distribution of claudin-5 in bEnd.3 cells and ZO-1 in ARPE19 cells, reduced the transepithelial/transendothelial electrical resistance (TEER) and increased permeability to FITC-tracers in vitro. Intravitreal (20 ng/1 µL/eye) or intravenous (20 ng/g) injection of recombinant IL-17A induced retinal albumin leakage within 48 h in C57BL/6J mice. Mechanistically, IL-17A induced Janus kinase 1 (JAK1) phosphorylation in bEnd.3 but not ARPE19 cells. Blocking JAK1 with Tofacitinib prevented IL-17A-mediated claudin-5 dysmorphia in bEnd.3 cells and reduced albumin leakage in IL-17A-treated mice. Our results suggest that IL-17A can damage the BRB through the activating the JAK1 signaling pathway, and targeting this pathway may be a novel approach to treat inflammation-induced macular oedema.

Recent Progress on Polysaccharide-Based Hydrogels for Controlled Delivery of Therapeutic Biomolecules.

A plethora of applications using polysaccharides have been developed in recent years due to their availability as well as their frequent nontoxicity and biodegradability. These polymers are usually obtained from renewable sources or are byproducts of industrial processes, thus, their use is collaborative in waste management and shows promise for an enhanced sustainable circular economy. Regarding the development of novel delivery systems for biotherapeutics, the potential of polysaccharides is attractive for the previously mentioned properties and also for the possibility of chemical modification of their structures, their ability to form matrixes of diverse architectures and mechanical properties, as well as for their ability to maintain bioactivity following incorporation of the biomolecules into the matrix. Biotherapeutics, such as proteins, growth factors, gene vectors, enzymes, hormones, DNA/RNA, and antibodies are currently in use as major therapeutics in a wide range of pathologies. In the present review, we summarize recent progress in the development of polysaccharide-based hydrogels of diverse nature, alone or in combination with other polymers or drug delivery systems, which have been implemented in the delivery of biotherapeutics in the pharmaceutical and biomedical fields.

Hyaloid Vasculature as a Major Source of STAT3+ (Signal Transducer and Activator of Transcription 3) Myeloid Cells for Pathogenic Retinal Neovascularization in Oxygen-Induced Retinopathy.

OBJECTIVE: Myeloid cells are critically involved in inflammation-induced angiogenesis, although their pathogenic role in the ischemic retina remains controversial. We hypothesize that myeloid cells contribute to pathogenic neovascularization in retinopathy of prematurity through STAT3 (signal transducer and activator of transcription 3) activation. Approach and Results: Using the mouse model of oxygen-induced retinopathy, we show that myeloid cells (CD45+IsolectinB4 [IB4]+) and particularly M2-type macrophages (CD45+ Arg1+), comprise a major source of STAT3 activation (pSTAT3) in the immature ischemic retina. Most of the pSTAT3-expressing myeloid cells concentrated at the hyaloid vasculature and their numbers were strongly correlated with the severity of pathogenic neovascular tuft formation. Pharmacological inhibition of STAT3 reduced the load of IB4+ cells in the hyaloid vasculature and significantly reduced the formation of pathogenic neovascular tufts during oxygen-induced retinopathy, leading to improved long-term visual outcomes (ie, increased retinal thickness and scotopic b-wave electroretinogram responses). Genetic deletion of SOCS3 (suppressor of cytokine signaling 3), an endogenous inhibitor of STAT3, in myeloid cells, enhanced pathological and physiological neovascularization in oxygen-induced retinopathy, indicating that myeloid-STAT3 signaling is crucial for retinal angiogenesis. CONCLUSIONS: Circulating myeloid cells may migrate to the immature ischemic retina through the hyaloid vasculature and contribute to retinal neovascularization via activation of STAT3. Understanding how STAT3 modulates myeloid cells for vascular repair/pathology may provide novel therapeutic options in pathogenic angiogenesis.

VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions.

Purpose: Müller glia are important in retinal health and disease and are a major source of retinal VEGF-A. Of the different VEGF family members, the role of VEGF-A in retinal health and disease has been studied extensively. The potential contribution of other VEGF family members to retinal pathophysiology, however, remains poorly defined. This study aimed to understand the role of VEGF-B in Müller cell pathophysiology. Methods: The expression of different VEGFs and their receptors in human MIO-M1 and mouse QMMuC-1 Müller cell lines and primary murine Müller cells was examined by RT-PCR, ELISA, and Western blot. The effect of recombinant VEGF-B or VEGF-B neutralization on Müller cell viability and survival under normal, hypoxic, and oxidative (4-hydroxynonenal [4-HNE]) conditions was evaluated by Alamar Blue, Yo-Pro uptake, and immunocytochemistry. The expression of glial fibrillary acidic protein, aquaporin-4, inward rectifying K+ channel subtype 4.1, glutamine synthetase, and transient receptor potential vanilloid 4 under different treatment conditions was examined by RT-PCR, immunocytochemistry, and Western blot. Transient receptor potential vanilloid 4 channel activity was assessed using a Fura-2-based calcium assay. Results: VEGF-B was expressed in Müller cells at the highest levels compared with other members of the VEGF family. VEGF-B neutralization did not affect Müller cell viability or functionality under normal conditions, but enhanced hypoxia- or 4-HNE-induced Müller cell death and decreased inward rectifying K+ channel subtype 4.1 and aquaporin-4 expression. Recombinant VEGF-B restored Müller cell glutamine synthetase expression under hypoxic conditions and protected Müller cells from 4-HNE-induced damage by normalizing transient receptor potential vanilloid 4 channel expression and activity. Conclusions: Autocrine production of VEGF-B protects Müller cells under pathologic conditions.

NMR with excitation modulated by Frank sequences.

Miniaturized NMR is of growing importance in bio-, chemical, and -material sciences. Other than the magnet, bulky components are the radio-frequency power amplifier and the power supply or battery pack. We show that constant flip-angle excitation with phase modulation following a particular type of polyphase perfect sequences results in low peak excitation power at high response peak power. It has ideal power distribution in both the time domain and the frequency domain. A savings in peak excitation power of six orders of magnitude has been realized compared to conventionally pulsed excitation. Among others, the excitation promises to be of use for button-cell operated miniature NMR devices as well as for complying with specific-absorption-rate regulations in high-field medical imaging.