Explore the vast range of titles available.

What individual differences in neural activity predict the future escalation of alcohol drinking from casual to compulsive? The neurobiological mechanisms that gate the transition from moderate to compulsive drinking remain poorly understood. We longitudinally tracked the development of compulsive drinking across a binge-drinking experience in male mice. Binge drinking unmasked individual differences, revealing latent traits in alcohol consumption and compulsive drinking despite equal prior exposure to alcohol. Distinct neural activity signatures of cortical neurons projecting to the brainstem before binge drinking predicted the ultimate emergence of compulsivity. Mimicry of activity patterns that predicted drinking phenotypes was sufficient to bidirectionally modulate drinking. Our results provide a mechanistic explanation for individual variance in vulnerability to compulsive alcohol drinking.

An engineered patch of retinal pigment epithelium generated from human embryonic stem cells is transplanted into the eyes of two patients. Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)–derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more. We report successful delivery and survival of the RPE patch by biomicroscopy and optical coherence tomography, and a visual acuity gain of 29 and 21 letters in the two patients, respectively, over 12 months. Only local immunosuppression was used long-term. We also present the preclinical surgical, cell safety and tumorigenicity studies leading to trial approval. This work supports the feasibility and safety of hESC-RPE patch transplantation as a regenerative strategy for AMD.

Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. The mechanisms regulating CSF clearance during the postnatal critical period are unclear. Here, we show that CSF K + , accompanied by water, is cleared through the choroid plexus (ChP) during mouse early postnatal development. We report that, at this developmental stage, the ChP showed increased ATP production and increased expression of ATP-dependent K + transporters, particularly the Na + , K + , Cl − , and water cotransporter NKCC1. Overexpression of NKCC1 in the ChP resulted in increased CSF K + clearance, increased cerebral compliance, and reduced circulating CSF in the brain without changes in intracranial pressure in mice. Moreover, ChP-specific NKCC1 overexpression in an obstructive hydrocephalus mouse model resulted in reduced ventriculomegaly. Collectively, our results implicate NKCC1 in regulating CSF K + clearance through the ChP in the critical period during postnatal neurodevelopment in mice. Abnormal CSF accumulation in the brain can lead to hydrocephalus. The mechanisms regulating CSF clearance during early development are unclear. Here, the authors show that NKCC1 regulates the clearance of both CSF K + and fluid volume through the choroid plexus during postnatal development in mice.

Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF -mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf ⱽ⁶⁰⁰ᴱ mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.

Critical work on nineteenth-century religious and poetic form has, by and large, focused its attention upon a horizontal plane, tending to discuss the ways in which prayer and poetry functioned as modes of expression or unification for poets and readers. It has, however, rarely ventured into an exploration of what Victorian writers and readers understood to be happening vertically. In the main, Christians understand prayer to be a communication with God—a vertical activity that moves both up (in human expression) and down (in divine action or communication). Given the close connection between nineteenth-century religion and poetic form, the question arises as to what Victorians might have understood to be happening vertically, not only in the act of prayer but also in the writing or reading of poetry. This essay takes the novelist and literary scholar George MacDonald as a case study for thinking about how a vertical conception of prayer can open up new ways of thinking about the relation between nineteenth-century literary and religious forms—in particular, the theological work that nineteenth-century writers understood poetic form to be capable of doing. To this end, it examines MacDonald's notion of poetic \"word-music\" and its role in the communication of spiritual knowledge. It begins by exploring MacDonald's understanding of the relationship between feeling and spiritual knowledge before moving on to demonstrate how, for him, poetry's capacity to convey meaning through its prosody makes it particularly suited to the communication of spiritual knowledge. Through its vertical reading of MacDonald, this essay illuminates nineteenth-century attitudes toward literary form and prayer more generally and invites us to reimagine what a vertical conception of spiritual knowledge offers to the way we understand the relation between religious and literary form in the Victorian period.

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake Ttr mNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF. The choroid plexus (ChP) modulates cerebrospinal fluid (CSF) composition and the blood-CSF barrier. Here the authors show that the ChP is a critical circadian component with time-of-day variations in translation, barrier, and metabolism to alter CSF composition.

This paper reports on the design and testing of a tool for assessing the degree of stem cell failure on the surface of the eye. This tool monitors treatment response with transplanted engineered cell sheets containing allogeneic human corneal epithelial stem cells and was used to demonstrate that this cell therapy is effective in reversing the signs of corneal stem cell deficiency in the short term (less than 3 years). Limbal stem cell deficiency (LSCD) is an eye disorder in which the stem cells responsible for forming the surface skin of the cornea are destroyed by disease. This results in pain, loss of vision, and a cosmetically unpleasant appearance. Many new treatments, including stem cell therapies, are emerging for the treatment of this condition, but assessment of these new technologies is severely hampered by the lack of biomarkers for this disease or validated tools for assessing its severity. The aims of this study were to design and test the reliability of a tool for grading LSCD, to define a set of core outcome measures for use in evaluating treatments for this condition, and to demonstrate their utility. This was achieved by using our defined outcome set (which included the Clinical Outcome Assessment in Surgical Trials of Limbal stem cell deficiency [COASTL] tool) to evaluate the 3‐year outcomes for allogeneic ex vivo cultivated limbal epithelial transplantation (allo‐CLET) in patients who had bilateral total LSCD secondary to aniridia or Stevens‐Johnson syndrome. The results demonstrate that our new grading tool for LSCD, the COASTL tool, is reliable and repeatable, and that improvements in the biomarkers used in this tool correlate positively with improvements in visual acuity. The COASTL tool showed that following allo‐CLET there was a decrease in LSCD severity and an increase in visual acuity up to 12 months post‐treatment, but thereafter LSCD severity and visual acuity progressively deteriorated.

We present here updates to the known species of ferns and lycophytes in the Hawaiian Islands since the publication of Palmer (2003) and the overview and updates of Vernon and Ranker (2013).

The Hawaiian Islands are well known for having one of the highest documented percentages of endemic plants in the world. Hawaiian ferns and lycophytes represent a relatively large percentage of the endemic flora with approximately 74% of the native fern and lycophyte species considered endemic. In addition, at least 40 taxa are naturalized aliens. We present a new synopsis of the Hawaiian fern and lycophyte flora that includes new state and island records, recent taxonomic updates and problems, and a summary of known and hypothesized geographical origins of fern and lycophyte lineages. We also provide a checklist and access to an interactive key to the native and naturalized ferns and lycophytes of the Hawaiian Islands (http://www.herbarium.hawaii.edu/lucid/ferns/introduction.html).