Bone abnormalities in latent TGF-β binding protein (Ltbp)-3–null mice indicate a role for Ltbp-3 in modulating TGF-β bioavailability

The TGF-βs are multifunctional proteins whose activities are believed to be controlled by interaction with the latent TGF-β binding proteins (LTBPs). In spite of substantial effort, the precise in vivo significance of this interaction remains unknown. To examine the role of the Ltbp-3, we made an Ltbp-3–null mutation in the mouse by gene targeting. Homozygous mutant animals develop cranio-facial malformations by day 10. At 2 mo, there is a pronounced rounding of the cranial vault, extension of the mandible beyond the maxilla, and kyphosis. Histological examination of the skulls from null animals revealed ossification of the synchondroses within 2 wk of birth, in contrast to the wild-type synchondroses, which never ossify. Between 6 and 9 mo of age, mutant animals also develop osteosclerosis and osteoarthritis. The pathological changes of the Ltbp-3–null mice are consistent with perturbed TGF-β signaling in the skull and long bones. These observations give support to the notion that LTBP-3 is important for the control of TGF-β action. Moreover, the results provide the first in vivo indication for a role of LTBP in modulating TGF-β bioavailability

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Peopling of Western Japan, Focusing on Kyushu, Shikoku, and Ryukyu Archipelago

The discovery of the Iwajuku site in Japan is the beginning of the study of the first Paleolithic cultures in the region. In this paper we examine the timing of the earliest colonization of southern Japan, especially focusing on the areas of Kyushu, Shikoku, and the Ryukyu archipelago. Osteological studies have proposed the ultimate origin of these western Japanese Paleolithic populations in Southeast Asia. If this hypothesis is correct, Native Americans may be remotely related to the populations of this region. Greater attention to data from areas such as Japan is necessary to understand the timing and nature of New World colonization.The Radiocarbon archives are made available by Radiocarbon and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform February 202

Cytomegalovirus Uveitis with Hypopyon Mimicking Bacterial Endophthalmitis

We report an 83-year-old immune-competent female with unilateral endophthalmitis extraordinarily caused by cytomegalovirus (CMV). Since she was suspected of suffering possible bacterial endophthalmitis, she was referred to our hospital. At the first visit, hypopyon in the anterior chamber and the opacity of vitreous body were observed in the left eye. The best-corrected visual acuity (BCVA) of the left eye was counting fingers and the intraocular pressure (IOP) was 20 mmHg. Bacterial and fungus culture of the aqueous humor revealed no infection. However, the density of corneal endothelial cell was less than the measurable range and CMV was detected by PCR of the aqueous humor. She was immune-competent and the data indicated neither systemic infections nor diseases. Systemic valganciclovir and corticosteroid were administered. After that, hypopyon in the anterior chamber and the opacity of vitreous body of the left eye were improved, and the BCVA of the left eye was 20/200 one year after the first visit. However, the inflammation of the anterior chamber recurred accompanied by elevated IOP after the discontinuance of administering valganciclovir. CMV-induced uveitis accompanied with hypopyon is quite rare. Therefore, it can be easily misdiagnosed as bacterial endophthalmitis

Ganglioside composition of the human cranial nerves, with special reference to pathophysiology of Miller Fisher syndrome

Total ganglioside fractions from the human cranial nerves purified on a Phenyl Sepharose column, were given mild alkaline treatment, after which their composition and amounts of lipid-bound sialic acid were determined by HPTLC-densitometry with resorcinol as the coloring reagent. The total amounts of lipid-bound sialic acid were 156.5 ng/mg of wet tissue in the Ist cranial nerve (olfactory tract) and 131.9 ng/mg in the IInd nerve, greater than the amounts in the other nerves (99.1–120.0 ng/mg). The Ist, IInd, and VIIIth nerves had GM4, but not LM1. It may reflect their histological feature of the central nervous system. The IIIrd, IVth, and VIth nerves, as well as the IInd, had significantly higher percentages of GQ1b (11.6–13.2%) than the other nerves (5.2–8.4%). The high proportion of GQ1b specific to these three cranial nerves involved in the ocular movement lends support to the role of serum anti-GQ1b antibody in the pathogenetic mechanisms of ophthalmoplegia in Miller Fisher syndrome and Guillain-Barré syndrome

The International Workshop on Meibomian Gland Dysfunction: Report of the Subcommittee on Anatomy, Physiology, and Pathophysiology of the Meibomian Gland

The tarsal glands of Meibom (glandulae tarsales) are large sebaceous glands located in the eyelids and, unlike those of the skin, are unassociated with hairs. According to Duke-Elder and Wyler,1 they were first mentioned by Galenus in 200 AD and later, in 1666, they were described in more detail by the German physician and anatomist Heinrich Meibom, after whom they are named. Lipids produced by the meibomian glands are the main component of the superficial lipid layer of the tear film that protects it against evaporation of the aqueous phase and is believed also to stabilize the tear film by lowering surface tension.2 Hence, meibomian lipids are essential for the maintenance of ocular surface health and integrity. Although they share certain principal characteristics with ordinary sebaceous glands, they have several distinct differences in anatomy, location, secretory regulation, composition of their secretory product, and function. Functional disorders of the meibomian glands, referred to today as meibomian gland dysfunction (MGD),3 are increasingly recognized as a discrete disease entity.4–8 In patients with dry eye disease, alterations in the lipid phase that point to MGD are reportedly more frequent than isolated alterations in the aqueous phase. In a study by Heiligenhaus et al.,9 a lipid deficiency occurred in 76.7% of dry eye patients compared with only 11.1% of those with isolated alterations of the aqueous phase. This result is in line with the observations by Shimazaki et al.10 of a prevalence of MGD in the absolute majority of eyes with ocular discomfort defined as dry eye symptoms. These observations noted that 64.6% of all such eyes and 74.5% of those excluding a deficiency of aqueous tear secretion were found to have obstructive MGD, or a loss of glandular tissue, or both.10 Horwath-Winter et al.11 reported MGD in 78% of dry eye patients or, if only non-Sjögren patients are considered, in 87% compared with 13% with isolated aqueous tear deficiency. It may thus be accepted that MGD is important, conceivably underestimated, and possibly the most frequent cause of dry eye disease due to increased evaporation of the aqueous tears.5,9–12 After some excellent reviews of MGD4,7,8,13,14 in the past, many new findings have been reported in recent years, and other questions remain to be identified and resolved. A sound understanding of meibomian gland structure and function and its role in the functional anatomy of the ocular surface15 is needed, to understand the contribution of the meibomian glands to dysfunction and disease. Herein, we seek to provide a comprehensive review of physiological and pathophysiological aspects of the meibomian glands