A new human embryonic cell type associated with activity of young transposable elements allows definition of the inner cell mass.

There remains much that we do not understand about the earliest stages of human development. On a gross level, there is evidence for apoptosis, but the nature of the affected cell types is unknown. Perhaps most importantly, the inner cell mass (ICM), from which the foetus is derived and hence of interest in reproductive health and regenerative medicine, has proven hard to define. Here, we provide a multi-method analysis of the early human embryo to resolve these issues. Single-cell analysis (on multiple independent datasets), supported by embryo visualisation, uncovers a common previously uncharacterised class of cells lacking commitment markers that segregates after embryonic gene activation (EGA) and shortly after undergo apoptosis. The discovery of this cell type allows us to clearly define their viable ontogenetic sisters, these being the cells of the ICM. While ICM is characterised by the activity of an Old non-transposing endogenous retrovirus (HERVH) that acts to suppress Young transposable elements, the new cell type, by contrast, expresses transpositionally competent Young elements and DNA-damage response genes. As the Young elements are RetroElements and the cells are excluded from the developmental process, we dub these REject cells. With these and ICM being characterised by differential mobile element activities, the human embryo may be a "selection arena" in which one group of cells selectively die, while other less damaged cells persist.

Novel targets, treatments, and advanced models for intracerebral haemorrhage.

Intracerebral haemorrhage (ICH) is the second most common type of stroke and a major cause of mortality and disability worldwide. Despite advances in surgical interventions and acute ICH management, there is currently no effective therapy to improve functional outcomes in patients. Recently, there has been tremendous progress uncovering new pathophysiological mechanisms underlying ICH that may pave the way for the development of therapeutic interventions. Here, we highlight emerging targets, but also existing gaps in preclinical animal modelling that prevent their exploitation. We particularly focus on (1) ICH aetiology, (2) the haematoma, (3) inflammation, and (4) post-ICH pathology. It is important to recognize that beyond neurons and the brain, other cell types and organs are crucially involved in ICH pathophysiology and successful interventions likely will need to address the entire organism. This review will spur the development of successful therapeutic interventions for ICH and advanced animal models that better reflect its aetiology and pathophysiology.

Viruses and Endogenous Retroviruses as Roots for Neuroinflammation and Neurodegenerative Diseases.

Many neurodegenerative diseases are associated with chronic inflammation in the brain and periphery giving rise to a continuous imbalance of immune processes. Next to inflammation markers, activation of transposable elements, including long intrespersed nuclear elements (LINE) elements and endogenous retroviruses (ERVs), has been identified during neurodegenerative disease progression and even correlated with the clinical severity of the disease. ERVs are remnants of viral infections in the human genome acquired during evolution. Upon activation, they produce transcripts and the phylogenetically youngest ones are still able to produce viral-like particles. In addition, ERVs can bind transcription factors and modulate immune response. Being between own and foreign, ERVs are reviewed in the context of viral infections of the central nervous system, in aging and neurodegenerative diseases. Moreover, this review tests the hypothesis that viral infection may be a trigger at the onset of neuroinflammation and that ERVs sustain the inflammatory imbalance by summarizing existing data of neurodegenerative diseases associated with viruses and/or ERVs.

How to tame an endogenous retrovirus: HERVH and the evolution of human pluripotency.

HERVH is one of the most successful endogenous retrovirus in the human genome. Relative to other endogenous retroviruses, slower degradation of HERVH internal sequences indicates their potential relevance for the host. HERVH is transcriptionally active during human preimplantation embryogenesis. In this review, we focus on the role of HERVH in regulating human pluripotency. The HERVH-mediated pluripotency network has been evolved recently in primates. Nevertheless, it became an essential feature of human pluripotency. We discuss how HERVH modulates the human pluripotency network by providing alternative transcription factor binding sites, functioning as a long-range enhancer, and as being a major source for pluripotency specific long non-coding RNAs and chimeric transcripts.

Blocking stroke-induced immunodeficiency increases CNS antigen-specific autoreactivity but does not worsen functional outcome after experimental stroke.

Stroke-induced immunodepression (SIDS) is an essential cause of poststroke infections. Pharmacological inhibition of SIDS appears promising in preventing life-threatening infections in stroke patients. However, SIDS might represent an adaptive mechanism preventing autoreactive immune responses after stroke. To address this, we used myelin oligodendrocyte glycoprotein (MOG) T-cell receptor transgenic (2D2) mice where >80% of peripheral CD4(+) T cells express a functional receptor for MOG. We investigated in a murine model of middle cerebral artery occlusion the effect of blocking SIDS by inhibiting body's main stress axes, the sympathetic nervous system (SNS) with propranolol and the hypothalamic-pituitary-adrenal axis (HPA) with mifepristone. Blockade of both stress axes robustly reduced infarct volumes, decreased infection rate, and increased long-term survival of 2D2 and C57BL/6J wild-type mice. Despite these protective effects, blockade of SIDS increased CNS antigen-specific Type1 T helper cell (Th1) responses in the brains of 2D2 mice 14 d after middle cerebral artery occlusion. One month after experimental stroke, 2D2 mice developed signs of polyradiculitis, which were diminished by SIDS blockade. Adoptive transfer of CD4(+) T cells, isolated from 2D2 mice, into lymphocyte-deficient Rag-1KO mice did not reveal differences between SIDS blockade and vehicle treatment in functional long-term outcome after stroke. In conclusion, inhibiting SIDS by pharmacological blockade of body's stress axes increases autoreactive CNS antigen-specific T-cell responses in the brain but does not worsen functional long-term outcome after experimental stroke, even in a mouse model where CNS antigen-specific autoreactive T-cell responses are boosted.

Loss of hippocampal interneurons and epileptogenesis: a comparison of two animal models of acquired epilepsy.

Reduced hippocampal GABAergic inhibition is acknowledged to be associated with epilepsy. However, there are no studies that had quantitatively compared the loss of various interneuron populations in different models of epilepsy. We tested a hypothesis that the more severe the loss of hippocampal interneurons, the more severe was the epilepsy. Epileptogenesis was triggered in adult rats by status epilepticus (SE) (56 SE, 24 controls) or by traumatic brain injury (TBI) (45 TBI, 23 controls). The total number of hippocampal parvalbumin (PARV), cholecystokinin (CCK), calretinin (CR), somatostatin (SOM), or neuropeptide Y (NPY) positive neurons was estimated using unbiased stereology at 1 or 6 months post-insult. The rats with TBI had no spontaneous seizures but showed increased seizure susceptibility. Eleven of the 28 rats (39 %) in the SE group had spontaneous seizures. The most affected hippocampal area after TBI was the ipsilateral dentate gyrus, where 62 % of PARV-immunoreactive (ir) (p < 0.001 compared to controls), 77 % of CR-ir (p < 0.05), 46 % of SOM-ir (p < 0.001), and 59 % of NPY-ir (p < 0.001) cells remained at 1 month after TBI. At 6 months post-TBI, only 35 % of PARV-ir (p < 0.001 compared to controls), 63 % of CCK-ir (p < 0.01), 74 % of CR-ir (p < 0.001), 55 % of SOM-ir (p < 0.001), and 51 % of NPY-ir (p < 0.001) cells were remaining. Moreover, the reduction in PARV-ir, CCK-ir, and CR-ir neurons was bilateral (all p < 0.05). Substantial reductions in different neuronal populations were also found in subfields of the CA3 and CA1. In rats with epilepsy after SE, the number of PARV-ir neurons was reduced in the ipsilateral CA1 (80 % remaining, p < 0.05) and the number of NPY-ir neurons bilaterally in the dentate gyrus (33-37 %, p < 0.01) and the CA3 (54-57 %, p < 0.05). Taken together, interneuron loss was substantially more severe, widespread, progressive, and included more interneuron subclasses after TBI than after SE. Interneurons responsible for perisomatic inhibition were more vulnerable to TBI than those providing dendritic inhibition. Unlike expected, we could not demonstrate any etiology-independent link between the severity of hippocampal interneuron loss and the overall risk of spontaneous seizures.

Superiority of preventive antibiotic treatment compared with standard treatment of poststroke pneumonia in experimental stroke: a bed to bench approach.

Stroke patients are prone to life-threatening bacterial pneumonia. Previous experimental stroke studies have demonstrated that preventive antibiotic treatment (PAT) improves outcome compared with placebo treatment, which however does not model the clinical setting properly. Here we investigate whether PAT is superior to the current clinical 'gold standard' for treating poststroke infections. Therefore, we modeled stroke care according to the current stroke guidelines recommending early antibiotic treatment after diagnosing infections. To reliably diagnose pneumonia in living mice, we established a general health score and a magnetic resonance imaging protocol for radiologic confirmation. Compared with standard treatment after diagnosis by these methods, PAT not only abolished pneumonia successfully but also improved general medical outcome. Both, preventive and standard antibiotic treatment using enrofloxacin improved survival in a similar way compared with placebo treatment. However, in contrast to standard treatment, only PAT improved functional outcome assessed by gait analysis. In conclusion, standard and preventive treatment approach reduced poststroke mortality, however at the cost of a worse neurologic outcome compared with preventive approach. These data support the concept of PAT for treating patients at risk for poststroke infections and warrant phase III trials to prove this concept in clinical setting.

Gait analysis as a method for assessing neurological outcome in a mouse model of stroke.

Ameliorating stroke induced neurological deficits is one of the most important goals of stroke therapy. In order to improve stroke outcome, novel treatment approaches as well as animal stroke models predictive for the clinical setting are of urgent need. One of the main obstacles in experimental stroke research is measuring long-term outcome, in particular in mouse models of stroke. On the other hand, assessing functional deficits in animal models of stroke is critical to improve the prediction of preclinical findings. Automated gait analysis provides a sensitive tool to examine locomotion and limb coordination in small rodents. Comparing mice before and 10 days after experimental stroke (60 min MCAo) we observed a significant decrease in maximum contact area, stride length and swing speed in the hind limbs, especially the contralateral one. Mice showed a disturbed interlimb coordination represented by changes in regularity index and phase dispersion. To assess whether gait analysis is applicable to assess improvements by neuroprotective compounds, we applied a model calculation and approached common statistical problems. In conclusion, gait analysis is a promising tool to assess mid- to long-term outcome in experimental stroke research.