Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis,which is characterized by increased bone resorption and inadequate bone formation.As novel antiosteoporotic therapeutics are needed,understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets.This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation.Osteoclasts were differentiated from CD14+monocytes from eight female donors.RNA sequencing during differentiation revealed 8980 differentially expressed genes grouped into eight temporal patterns conserved across donors.These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs.Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks.The donor-specific expression patterns revealed genes at the monocyte stage,such as filamin B(FLNB)and oxidized low-density lipoprotein receptor 1(OLR1,encoding LOX-1),that are predictive of the resorptive activity of mature osteoclasts.The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation,and these receptors are associated with bone mineral density SNPs,suggesting that they play a pivotal role in osteoclast differentiation and activity.The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1(C5AR1),somatostatin receptor 2(SSTR2),and free fatty acid receptor 4(FFAR4/GPR120).Activating C5AR1 enhanced osteoclast formation,while activating SSTR2 decreased the resorptive activity of mature osteoclasts,and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts.In conclusion,we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity.These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

COVID-19 and liver injury in individuals with obesity

Coronavirus disease 2019 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 that manifests as a variety of clinical manifestations,including liver damage commonly detected by a hepatocellular pattern from liver function tests.Liver injury is associated with a worse prognosis overall.Conditions associated with the severity of the disease include obesity and cardiometabolic comorbidities,which are also associated with nonalcoholic fatty liver disease(NAFLD).The presence of NAFLD,similarly to obesity,is associated with an unfavourable impact on the coronavirus disease 2019 outcome.Individuals with these conditions could present with liver damage and elevated liver function tests due to direct viral cytotoxicity,systemic inflammation,ischemic or hypoxic liver damage or drug side effects.However,liver damage in the setting of NAFLD could also be attributed to a pre-existing chronic low-grade inflammation associated with surplus and dysfunctional adipose tissue in these individuals.Here we investigate the hypothesis that a pre-existing inflammatory status is exacerbated after severe acute respiratory syndrome coronavirus 2 infection,which embodies a second hit to the underestimated liver damage.

The interplay of aging,genetics and environmental factors in the pathogenesis of Parkinson’s disease

Background:Parkinson’s disease(PD)is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies(LB).During the course of disease,misfoldedα-synuclein,the major constituent of LB,spreads to different regions of the brain in a prion-like fashion,giving rise to successive non-motor and motor symptoms.Etiology is likely multifactorial,and involves interplay among aging,genetic susceptibility and environmental factors.Main body:The prevalence of PD rises exponentially with age,and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death.However,the majority of those over the age of 80 do not have PD,thus other factors in addition to aging are needed to cause disease.Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk.Nevertheless,the causality of most environmental factors is not conclusively established,and alternative explanations such as reverse causality and recall bias cannot be excluded.The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD.Rare mutations as well as common variants in genes such as SNCA,LRRK2 and GBA are associated with risk of PD,but Mendelian causes collectively only account for 5%of PD and common polymorphisms are associated with small increase in PD risk.Heritability of PD has been estimated to be around 30%.Thus,aging,genetics and environmental factors each alone is rarely sufficient to cause PD for most patients.Conclusion:PD is a multifactorial disorder involving interplay of aging,genetics and environmental factors.This has implications on the development of appropriate animal models of PD which take all these factors into account.Common converging pathways likely include mitochondrial dysfunction,impaired autophagy,oxidative stress and neuroinflammation,which are associated with the accumulation and spread of misfoldedα-synuclein and neurodegeneration.Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.

LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson’s disease

Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.

Depth perception on fundus images using a single-channel stereomicroscopy

Typical fundus photography produces a two-dimensional image.This makes it difficult to observe the microvascular and neural abnormalities,because the depth of the image is missing.To provide depth appreciation,we develop a single-channel stereoscopic fundus video imaging sys-tem based on a rotating refractor.With respect to the pupil center,the rotating refractor laterally displaces the optical path and the illumination.This allows standard monocular fundus cameras to generate stereo-parallax and image disparity through sequential image acquisition.We opti-mize our imaging system,characterize the stereo-base,and image an eyeball model and a rabbit eye.When virtual realities are considered,our imaging system can be a simple yet efficient technique to provide depth perception in a virtual space that allows users to perceive abnor-malities in the eye fundus.

Vitamin D status and its influence on outcomes following major burn injury and critical illness

Vitamin D deficiency is common among the general population. It is also observed in up to 76% of critically ill patients.Despite the high prevalence of hypovitaminosis D in critical illness, vitamin D is often overlooked by medical staff as the clinical implications and consequences of vitamin D deficiency in acute contexts remain to be fully understood.Vitamin D has a broad range of pleotropic effects on various processes and systems including the immuneinflammatory response. 1α,25-dihydroxyvitamin D (1,25(OH)2D), has been shown to promote a tolerogenic immune response limiting deleterious inflammatory effects, modulation of the innate immune system, and enhancement of anti-microbial peptides. Vitamin D deficiency is frequently observed in critically ill patients and has been related to extrinsic causes (i.e., limited sunlight exposure), magnitude of injury/illness, or the treatment started by medical doctors including fluid resuscitation. Low levels of vitamin D in critically ill patients have been associated with sepsis, organ failure, and mortality. Despite this, there are subpopulations of critical illness, such as burn patients, where the literature regarding vitamin D status and its influence on outcomes remain insufficient. Thermal injury results in damage to both burned and non-burned tissues, as well as induces an exaggerated and persistent immune-inflammatory and hypermetabolic response. In this review, we propose potential mechanisms in which burn injury affects the vitamin D status and summarizes current literature investigating the influence of vitamin D status on outcomes. In addition, wereviewed the literature and trials investigating vitamin D supplementation in critically ill patients and discuss the therapeutic potential of vitamin D supplementation in burn and critically ill patients. We also highlight current limitations of studies that have investigated vitamin D status and supplementation in critical illness. Thermal injury influences vitamin D status. More studies investigating vitamin D depletion in burn patients and its influence on prognosis, via standardized methodology, are required to reach definitive conclusions and influence clinical practice.

表现为头痛的颅内高压

一名24岁女性,在经历了短暂的意识丧失之后来到急诊,被诊断为惊恐发作并出院。2天后,因头痛加剧和视觉障碍,她被再次送回医院进行进一步的检查。第3天行头颅计算机断层扫描及静脉造影成像采集,结果均正帯。在第7天,她进行了腰椎穿刺,脑脊液开放压力为70 cm CSFo第8天,眼底镜检查发现视乳头水肿。最佳矫正视力下降至双眼6/24,同时面对面检查双眼周边视野缺损。她被诊断为暴发性原发颅内高压症,并转到神经科学中心,第9天在那里急诊行了腰椎腹膜分流术。术后2周,双眼视力提高到6/9。

LRRK2 mutant knock-in mouse models: therapeutic relevance in Parkinson’s disease

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarities between LRRK2-associated PD (LRRK2-PD) and sporadic PD, suggesting that LRRK2 is a potential disease modulator and a thera-peutic target in PD. LRRK2 mutant knock-in (KI) mouse models display subtle alterations in pathological aspects that mirror early-stage PD, including increased susceptibility of nigrostriatal neurotransmission, development of motor and non-motor symptoms, mitochondrial and autophagy-lysosomal defects and synucleinopathies. This review provides a rationale for the use of LRRK2 KI mice to investigate the LRRK2-mediated pathogenesis of PD and implications from current findings from different LRRK2 KI mouse models, and ultimately discusses the therapeutic potentials against LRRK2-associated pathologies in PD.

早期流产的最佳处理方法是什么?

早期流产是指妊娠≤13周时发生的流产,是一种除了造成出血和疼痛等生理效应外,还可能对女性产生毁灭性心理影响的重大生活事件。在月经推迟、妊娠测试呈阳性的女性中,有四分之一最终会发生早期流产。在英国,每年约有12.5万例早期流产,其中有5万例需住院治疗。