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The ectopic expression of the transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. However, little is known about the barriers that impair reprogramming in an in vivo context. We report that natural killer (NK) cells significantly limit reprogramming, both in vitro and in vivo. Cells and tissues in the intermediate states of reprogramming upregulate the expression of NK-activating ligands, such as MULT1 and ICAM1. NK cells recognize and kill partially reprogrammed cells in a degranulation-dependent manner. Importantly, in vivo partial reprogramming is strongly reduced by adoptive transfer of NK cells, whereas it is significantly increased by their depletion. Notably, in the absence of NK cells, the pancreatic organoids derived from OSKM-expressing mice are remarkably large, suggesting that ablating NK surveillance favours the acquisition of progenitor-like properties. We conclude that NK cells pose an important barrier for in vivo reprogramming, and speculate that this concept may apply to other contexts of transient cellular plasticity. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether HCWs return to work (RTW) after COVID-19 was associated with time to a negative viral detection test. Methods: To evaluate the association of RTW with an undetectable RT-PCR adjusting for different factors. Results: Three hundred seventy-five HCWs who required medical leave for COVID-19 at a hospital in Madrid. Multivariable analyses confirmed the association of delayed RTW with interval to negative PCR (ORadj 1.12, 95% CI 1.08, 1.17) as well as age, sex, and nursing staff and clinical support services compared to physicians. A predictive model based on those variables is proposed, which had an area under the receiver operating curve of 0.82. Conclusions: Delayed RTW was associated with longer interval to a negative RT-PCR after symptom onset, adjusting for occupational category, age, and sex. [ABSTRACT FROM AUTHOR]

This article exposes allegations of sexual violence from 2015 to 2016 by United Nations peacekeepers during the peace operation of the Central African Republic. The main objective is to highlight accusations of sexual exploitation and abuse and condemn the measures implemented by the United Nations. An attempt is made to answer whether international humanitarian law should judge acts of sexual violence perpetrated by peacekeepers towards civilians in post-conflict zones. The analysis, carried out through bibliographic-documentary research, intends to oppose impunity and reinforce the credibility of peace operations, as well as their personnel as instruments of conflict resolution in the international scenario. [ABSTRACT FROM AUTHOR]

Background: The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of unwanted and/or misfolded soluble proteins. This includes proteins regulating cellular survival, synaptic plasticity and neurotransmitter signaling; processes controlling excitability thresholds that are altered by epileptogenic insults. Dysfunction of the UPS has been reported to occur in a brain region- and cell-specific manner and contribute to disease progression in acute and chronic brain diseases. Prolonged seizures, status epilepticus, may alter UPS function but there has been no systematic attempt to map when and where this occurs in vivo or to determine the consequences of proteasome inhibition on seizure-induced brain injury. Method: To determine whether seizures lead to an impairment of the UPS, we used a mouse model of status epilepticus whereby seizures are triggered by an intra-amygdala injection of kainic acid. Status ilepticus in this model causes cell death in selected brain areas, in particular the ipsilateral CA3 subfield of the hippocampus, and the development of epilepsy after a short latent period. To monitor seizure-induced sfunction of the UPS we used a UPS inhibition reporter mouse expressing the ubiquitin fusion degradation substrate ubiquitinG76V-green fluorescent protein. Treatment with the specific proteasome inhibitorepoxomicin was used to establish the impact of proteasome inhibition on seizure-induced pathology. Results and conclusions: Our studies show that status epilepticus induced by intra-amygdala kainic acid causes select spatio-temporal UPS inhibition which is most evident in damage-resistant regions of the hippocampus, including CA1 pyramidal and dentate granule neurons then appears later in astrocytes. In support of this exerting a beneficial effect, injection of mice with the proteasome inhibitor epoxomicin protected the normally vulnerable hippocampal CA3 subfield from seizure-induced neuronal death in the model. These studies reveal brain region- and cell-specific UPS impairment occurs after seizures and suggest UPS inhibition can protect against seizure-induced brain damage. Identifying networks or pathways regulated through the proteasome after seizures may yield novel target genes for the treatment of seizure-induced cell death and possibly epilepsy. [ABSTRACT FROM AUTHOR]

The article reports on research which was conducted to assess the three dimensional anatomy of the Lisfranc ligament and its attachment sites. Researchers evaluated 37 cadaver feet that were dissected to expose the ligament attachments at the Lisfranc joint.They found that the Lisfranc ligament is variable in anatomy and can have a single or double-bundle arrangement and that its area of attachment is larger than that of the plantar ligament.

The glycine transporter GLYT1 regulates both glycinergic and glutamatergic neurotransmission by controlling the reuptake of glycine at synapses. Trafficking of GLYT1 to and from the cell surface is critical for its function. Activation of PKC down-regulates the activity of GLYT1 through a mechanism that has so far remained uncharacterized. Here we show that GLYT1b undergoes fast constitutive endocytosis that is accelerated by phorbol esters. Both constitutive and regulated endocytosis occur through a dynamin 2and clathrin-dependent pathway, accumulating in the transporter in transferrin-containing endosomes. A chimera with the extracellular and transmembrane domains of the nerve growth factor receptor and the COOH-terminal tail of GLYT1 was efficiently internalized through this clathrin pathway, suggesting the presence of molecular determinants for GLYT1b endocytosis in its COOH-terminal tail. Extensive site-directed mutagenesis in this region of the chimera highlighted the involvement of lysine residues in its internalization. In the context of the full-length transporter, lysine 619 played a prominent role in both the constitutive and phorbol 12-myristate 13-acetate-induced endocytosis of GLYT1b, suggesting the involvement of ubiquitin modification of GLYT1b during the internalization process. Indeed, we show that GLYT1b undergoes ubiquitination and that this process is stimulated by phorbol 12-myristate 13-acetate. In addition, this endocytosis is impaired in an ubiquitination-deficient cell line, further evidence that constitutive and regulated endocytosis of GLYT1b is ubiquitin-dependent. It remains to be determined whether GLYT1b recycling might be affected in pathologies involving alterations to the ubiquitin system, thereby interfering with its influence on inhibitory and excitatory neurotransmission. [ABSTRACT FROM AUTHOR]

Understanding urothelial stem cell biology and differentiation has been limited by the lack of methods for their unlimited propagation. Here, we establish mouse urothelial organoids that can be maintained uninterruptedly for >1 year. Organoid growth is dependent on EGF and Wnt activators. High CD49f/ITGA6 expression features a subpopulation of organoid-forming cells expressing basal markers. Upon differentiation, multilayered organoids undergo reduced proliferation, decreased cell layer number, urothelial program activation, and acquisition of barrier function. Pharmacological modulation of PPARγ and EGFR promotes differentiation. RNA sequencing highlighted genesets enriched in proliferative organoids (i.e. ribosome) and transcriptional networks involved in differentiation, including expression of Wnt ligands and Notch components. Single-cell RNA sequencing (scRNA-Seq) analysis of the organoids revealed five clusters with distinct gene expression profiles. Together with the use of γ-secretase inhibitors, scRNA-Seq confirms that Notch signaling is required for differentiation. Urothelial organoids provide a powerful tool to study cell regeneration and differentiation. The biology of the urothelium has been difficult to study given the lack of methods to propagate these cells. Here, the authors generate mouse urothelial organoids derived from bladder urothelial cells with high CD49f/ITGA6 and define what regulates urothelium differentiation, which is PPARγ, EGFR and Notch signalling. [ABSTRACT FROM AUTHOR]

Hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, producing hypertonia and apnea episodes. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Dominant and recessive mutations in the human glycine receptor (GlyR) α1 gene (GLRA1) are the major cause of this disorder. However, recessive mutations in the presynaptic Na+/Cl--dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease. In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation: pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom. Curiously, individuals harboring this mutation show significant variation in clinical presentation. In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. We functionally characterized this mutation using molecular modeling, electrophysiology, [3H]glycine transport, cell surface expression, and cysteine labeling assays. We found that the introduced cysteine interacts with the cysteine pair Cys-311- Cys-320 in the second external loop of GlyT2. This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function. Additionally, Y705C presents altered H+ and Zn2+ dependence of glycine transport that may affect the function of glycinergic neurotransmission in vivo. [ABSTRACT FROM AUTHOR]

Glutamate transporter-1 (GLT-1) is the main glutamate transporter in the central nervous system, and its concentration severely decreases in neurodegenerative diseases. The number of transporters in the plasma membrane reflects the balance between their insertion and removal, and it has been reported that the regulated endocytosis of GLT-1 depends on its ubiquitination triggered by protein kinase C (PKC) activation. Here, we identified serine 520 of GLT-1 as the primary target for PKC-dependent phosphorylation, although elimination of this serine did not impair either GLT-1 ubiquitination or endocytosis in response to phorbol esters. In fact, we present evidence indicating that the ubiquitin ligase Nedd4-2 mediates the PKC-dependent ubiquitination and down-regulation of GLT-1. Overexpression of Nedd4-2 increased the ubiquitination of the transporter and promoted its degradation. Moreover, phorbol myristate acetate enhanced Nedd4-2 phosphorylation and the formation of GLT-1_Nedd4-2 complexes, whereas siRNA knockdown of Nedd4-2 prevented ubiquitination, endocytosis, and the concomitant decrease in GLT-1 activity triggered by PKCactivation. These results indicate that GLT-1 endocytosis is independent of its phosphorylation and that Nedd4-2 mediates PKC-dependent down-regulation of the transporter. [ABSTRACT FROM AUTHOR]

Aim: The use of intravitreal antiangiogenic therapy has showed good results in angiogenesis-dependent intraocular diseases. In this small case series study, the biologic effects on physiological angiogenesis and pathological angiogenesis in the retina of patients with retinopathy of prematurity (ROP) after treatment of either bevacizumab or ranibizumab, is described. Methods: In this non-comparative, prospective, experimental and interventional case series study, we injected a single dose of either bevacizumab or ranibizumab into the vitreous of 20 eyes of 10 patients with ROP. Patients included in this study were prematures with stage 3, zone I, or posterior zone II with or without plus disease and patients with stage 4 a, any zone. Clinical response and any evidence of ocular toxicities were documented both pre- and post-injection by RetCam retinal images. Results: After one week of intavitreal injection of bevacizumab or ranibizumab, all eyes had significant inhibition of angiogenesis without affecting the development of normal retina vasculature. After six weeks, all eyes showed completed vasculature of the retina without any sign of pathological angiogenesis. We found no differences between bevacizumab and ranibizumab results. Neither local nor systemic adverse effects occurred in 18 eyes, two eyes with ROP stage 4 a, developed a central retinal fibrosis. Conclusions: Intravitreal therapy with bevacizumab or ranibizumab inhibits pathological angiogenesis and allows the developement of normal vasculature of the retina in ROP. This study proves that intravitreal antiangiogenic therapy does not cause inhibition of physiological angiogenesis in the retinal vessels and may suggest that the same could happen in the systemic vasculature process. [ABSTRACT FROM AUTHOR]

Aim: The use of intravitreal antiangiogenic therapy has showed good results in angiogenesis-dependent intraocular diseases. In this small case series study, the biologic effects on physiological angiogenesis and pathological angiogenesis in the retina of patients with retinopathy of prematurity (ROP) after treatment of either bevacizumab or ranibizumab, is described. Methods: In this non-comparative, prospective, experimental and interventional case series study, we injected a single dose of either bevacizumab or ranibizumab into the vitreous of 20 eyes of 10 patients with ROP. Patients included in this study were prematures with stage 3, zone I, or posterior zone II with or without plus disease and patients with stage 4 a, any zone. Clinical response and any evidence of ocular toxicities were documented both pre- and post-injection by RetCam retinal images. Results: After one week of intavitreal injection of bevacizumab or ranibizumab, all eyes had significant inhibition of angiogenesis without affecting the development of normal retina vasculature. After six weeks, all eyes showed completed vasculature of the retina without any sign of pathological angiogenesis. We found no differences between bevacizumab and ranibizumab results. Neither local nor systemic adverse effects occurred in 18 eyes, two eyes with ROP stage 4 a, developed a central retinal fibrosis. Conclusions: Intravitreal therapy with bevacizumab or ranibizumab inhibits pathological angiogenesis and allows the developement of normal vasculature of the retina in ROP. This study proves that intravitreal antiangiogenic therapy does not cause inhibition of physiological angiogenesis in the retinal vessels and may suggest that the same could happen in the systemic vasculature process. [ABSTRACT FROM AUTHOR]

Purpose: To determine the importance of fluorescein angiography in planning laser treatment for the clinically significant diabetic macular edema. Methods: Prospective study of 84 eyes of 54 diabetic patients with clinical significant macular edema, each case was documented with stereoscopic color photographs and a corresponding fluorescein angiogram The therapeutic plan was established after analyzing twice every case, the first time based only on the photographs and the second time based on both, the photographs and the angiograms. We compared the ability of the retina specialist to plan laser treatment with and without the use of fluorescein angiography. Results: In 85.7% of cases the ability of the specialist to decide laser treatment after the photograph analysis without the use of fluorescein angiographies was the same compared with the therapeutic plan based upon using the angiograms 14.3% showed small differences between both analyses. Conclusions: Fluorescein angiography improves the accuracy of laser treatment planning for clinically significant macular edema. [ABSTRACT FROM AUTHOR]