American Journal of Pathology

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SQSTM1/p62 (hereafter referred to as p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 (LC3) protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease-related cellular inclusion bodies, such as Mallory-Denk Bodies (MDB), intracytoplasmic hyaline bodies (IHBs), α1 antitrypsin aggregates, as well as p62 bodies/condensates...

Antibiotic administration during early life has been shown to have lasting effects on the gut microbiota, which have been linked to sustained alterations in liver metabolism and adiposity. Recent investigations have discerned that the gut microbiota continues to develop towards an adult-like profile during adolescence. However, the impact of antibiotic exposure during adolescence on metabolism and adiposity is unclear. We performed a retrospective analysis of Medicaid claims data, which revealed tetracycline class antibiotics are commonly prescribed for the systemic treatment of adolescent acne...

Clinical evidence of vascular dysfunction and hypercoagulability as well as pulmonary vascular damage and microthrombosis are frequently reported in severe cases of human COVID-19 disease. Syrian golden hamsters recapitulate histopathologic pulmonary vascular lesions reported in COVID-19 patients. Here, special staining techniques and transmission electron microscopy further define vascular pathologies in a Syrian golden hamster model of human COVID-19 disease. The results show that regions of active pulmonary inflammation in SARS-CoV-2 infection are characterized by ultrastructural evidence of endothelial damage with platelet marginalization and both perivascular and subendothelial macrophage infiltration...

The principal mechanism underlying the reduced rate of protein synthesis in atrophied skeletal muscle is largely unknown. eEF2k impairs the ability of eEF2 to bind to the ribosome via T56 phosphorylation. Perturbations in the eEF2k/eEF2 pathway during various stages of disuse muscle atrophy have been investigated utilizing a rat hindlimb suspension (HS) model. Two distinct components of eEF2k/eEF2 pathway misregulation were demonstrated, observing a significant (P<0.01) increase in eEF2k mRNA expression as early as 1-day HS and in eEF2k protein level after 3-day HS...

In the liver, biliary epithelial cells (BECs) line intrahepatic bile ducts (IHBDs) and are primarily responsible for modifying and transporting hepatocyte-produced bile to the digestive tract. BECs comprise only 3-5% of the liver by cell number but are critical for maintaining choleresis through homeostasis and disease. To this end, BECs drive an extensive morphological remodeling of the IHBD network termed ductular reaction (DR) in response to direct injury or injury to the hepatic parenchyma. BECs are also the target of a broad and heterogenous class of diseases termed cholangiopathies, which can present with phenotypes ranging from defective IHBD development in pediatric patients to progressive periductal fibrosis and cancer...

Growth hormone (GH) is a key mediator of skeletal growth. In humans, excess GH secretion due to pituitary adenoma, seen in patients with acromegaly, results in severe arthropathies. This study investigated the effects of long-term excess GH on the knee joint tissues. One year-old wild-type and bovine GH (bGH) transgenic mice were used as a model for excess GH. bGH mice showed increased sensitivity to mechanical and thermal stimuli, as compared to WT mice. Micro-CT analyses of the distal femur subchondral bone (SCB) revealed significant reductions in trabecular thickness, significantly reduced bone mineral density of the tibial SCB-plate, that were associated with increased osteoclast activity in both male and female bGH as compared to WT mice...

Respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger chronic lung disease that persists and even progresses after expected clearance of infectious virus. To gain an understanding of this process, we examined a series of consecutive fatal cases of coronavirus disease 2019 (COVID-19) that came to autopsy at 27 to 51 days after hospital admission. In each patient, we identify a stereotyped bronchiolar-alveolar pattern of lung remodeling with basal epithelial cell hyperplasia, immune activation, and mucinous differentiation...

ΜiR-194 is abundantly expressed in hepatocytes, and its depletion induces hepatic resistance to acetaminophen-induced acute injuries. In this study, the biological role of miR-194 in cholestatic liver injury was investigated by using miR-194/192 cluster liver-specific knockout (LKO) mice, in which no liver injuries or metabolic disorders were predisposed. Bile duct ligation (BDL) and 1-naphthyl isothiocyanate (ANIT) were applied to LKO and matched control wild-type (WT) mice to induce hepatic cholestasis...

HIVAN is a severe complication of HIV-1 infection. To gain insight into the pathogenesis of kidney disease in the setting of HIV, we used a transgenic (Tg) mouse model (CD4C/HIV-Nef) in which HIV-1 nef expression is under control of regulatory sequences (CD4C) of the human CD4 gene, thus allowing expression in target cells of the virus. These Tg mice develop a collapsing focal segmental glomerulosclerosis (FSGS) associated with microcystic dilatation, similar to human HIVAN. Proliferation of tubular and glomerular Tg cells is enhanced...

Neurofibromas (NF), Bowen's disease (BD), and Seborrheic Keratosis (SK) are common skin tumors. Pathological examination is the golden standard for diagnosis of these tumors. Current pathological diagnosis is mainly based on the observation of naked eyes under microscope, which is laborious and time-consuming. Digitization of pathology brings the opportunity for AI technology to improve the efficiency of diagnosis. This research aims to develop an end-to-end extendable framework for the diagnosis of skin tumor based on pathological slide image...

Studies of systemic autoimmune diseases point to characteristic microbial patterns in various diseases, including inflammatory bowel disease (IBD). Autoimmune diseases, and IBD in particular, show a predisposition to vitamin D deficiency leading to alterations in the microbiome and disruption of intestinal epithelial barrier integrity. In this review, we examine the role of the gut microbiome in IBD and discuss how vitamin D-vitamin D receptor (VDR)-associated molecular signaling pathways contribute to the development and progression of IBD through their effects on gut barrier function, the microbial community, and immune system function...

Keratoconus (KC) affects corneal structure, resulting in thinning and bulging outward into a cone shape. Irregular astigmatism and decreased visual acuity appear during puberty and progress into the mid-30s, with unpredictable disease severity. The cause of KC is recognized as multifactorial, but remains poorly understood. Hormonal imbalances are a significant modulator for the onset of KC. This study sought to investigate the role of gonadotropins; follicular stimulating hormone (FSH) and luteinizing hormone (LH) in KC using a 3D self-assembled matrix in-vitro model...

Retinopathy of prematurity (ROP), a blinding condition affecting preterm infants, is an interruption of retinal vascular maturation that is incomplete when born preterm. Although ROP demonstrates delayed onset following preterm birth, representing a window for therapeutic intervention, we cannot cure or prevent this disease. The in utero environment, including placental function, is increasingly recognized for contributions to preterm infant disease risk. Herein, we identify a protective association between acute placental inflammation and preterm infant ROP development using logistic regression, with the most significant association found for infants without gestational exposure to maternal preeclampsia and those with earlier preterm birth...

Breast cancer is a common indication for ovarian cryopreservation. However, whether the grafting ovarian tissue meets functional requirements, as well as the need for additional interventions remains unclear. The current study demonstrates abnormal serum hormones in breast cancer in humans and breast cancer cell line-derived tumor-bearing mice, and for the first time show tumor induced loss of primordial and growing follicles and the number of follicles being lost to either growth or atresia. A gene signature of tumor-bearing mice demonstrates the disturbed regulatory network of steroidogenesis which links to mitochondria dysfunction in oocytes and granulosa cells via the PI3K signaling pathway...

Chordoma is a rare malignant tumor demonstrating notochordal differentiation. It is dependent on Brachyury (TBXT), a hallmark notochordal gene and transcription factor, and shares histological features and the same anatomical location as the notochord. In this study, we perform a molecular comparison of chordoma and notochord to identify dysregulated cellular pathways. The lack of a molecular reference from appropriate control tissue limits our understanding of chordoma and its relationship to notochord. Accordingly, we conducted an unbiased comparison of chordoma, human notochord, and an atlas of normal and cancerous tissue using gene expression profiling to clarify the chordoma/notochord relationship and potentially identify novel drug targets...

Retinopathy of prematurity (ROP), a leading cause of childhood blindness worldwide, is strongly associated with gestational age and weight at birth. Yet, many extremely preterm infants never develop ROP or develop only mild ROP with spontaneous regression. In addition, a myriad of other factors play a role in the retinal pathology, one of which may include the early gut microbiome. Among the complications associated with early gestational age include dysbiosis of the dynamic neonatal gut microbiome, as evidenced by the development of often concomitant conditions such as necrotizing enterocolitis (NEC)...

Human retinal diseases are frequently characterized by pathology that is restricted to specific cell types and to specific regions of the eye. Several disease entities either selectively affect or spare the macula, the retinal region at the center of the posterior pole. Photoreceptor cells of the macula are responsible for high acuity vision and require metabolic support from non-neuronal cell types. Macular diseases often involve an epithelial cell layer known as the retinal pigment epithelium (RPE) that has several essential metabolic support functions for the overlying photoreceptors...

Hepatic zonation is critical for most metabolic functions in liver. Wnt signaling plays an important role in establishing and maintaining liver zonation. Yet, the anatomic expression of Wnt signaling components, especially all 10 Frizzled receptors (Fzds), has not been characterized in adult liver. To address this, we quantitatively mapped the spatial expression of Fzd receptors in adult mouse liver via multiplex fluorescent in situ hybridization. While all 10 Fzds are expressed within a metabolic unit, Fzds 1, 4, and 6 are the highest expressed...

Abnormal aggregation of α-synuclein (αS) is thought to initiate neuronal dysfunction and death in Parkinson's disease (PD). In addition to higher molecular weight, oligomeric and polymeric forms of αS associated with neurotoxicity and disease, recent findings indicate the occurrence of physiological tetrameric assemblies in healthy neurons in culture and in brain. Here, we found that the PD-associated neurotoxin paraquat (PQ) reduced physiological tetramers and led to calpain-truncated monomers and an ∼70 kDa apparent oligomer different in size from physiological αS multimers...