Primary varicella-zoster virus (VZV) infection causes varicella (chickenpox) and the establishment of a lifelong latent infection in ganglionic neurons. VZV reactivates in about one-third of infected ...individuals to cause herpes zoster, often accompanied by neurological complications. The restricted host range of VZV and, until recently, a lack of suitable in vitro models have seriously hampered molecular studies of VZV latency. Nevertheless, recent technological advances facilitated a series of exciting studies that resulted in the discovery of a VZV latency-associated transcript (VLT) and provide novel insights into our understanding of VZV latency and factors that may initiate reactivation. Deducing the function(s) of VLT and the molecular mechanisms involved should now be considered a priority to improve our understanding of factors that govern VZV latency and reactivation. In this review, we summarize the implications of recent discoveries in the VZV latency field from both a virus and host perspective and provide a roadmap for future studies.
To determine whether human epidermal growth factor receptor 2 (HER2) status is an independent prognostic factor in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma.
...Formalin-fixed paraffin-embedded tumor samples from 381 metastatic gastric/GEJ cancer patients enrolled at Krankenhaus Nordwest and Memorial Sloan–Kettering Cancer Centers on six first-line trials of chemotherapy without trastuzumab were examined for HER2 by immunohistochemistry (IHC) and in situ hybridization (ISH). IHC 3+ or ISH-positive tumors were considered HER2 positive.
Seventy-eight of 381 patients (20%) had HER2-positive disease. In the multivariate logistic model, there were significantly higher rates of HER2 positivity in patients with liver metastasis (liver metastasis 31%; no liver metastasis 11%; P = 0.025) and intestinal histology (intestinal 33%; diffuse/mixed 8%; P = 0.001). No significant differences in HER2 positivity were found between resections and biopsies or primaries and metastases. Patients with HER2-positive gastric cancer had longer median overall survival compared with HER2-negative gastric cancer patients (13.9 versus 11.4 months, P = 0.047), but multivariate analysis indicated that HER2 status was not an independent prognostic factor (hazard ratio 0.79; 0.44–1.14; P = 0.194).
Approximately 20% of Western patients with metastatic gastric cancer are HER2 positive. Unlike breast cancer, HER2 positivity is not independently prognostic of patient outcome in metastatic gastric or GEJ.
The Three‐Georges Dam holds many records in the history of engineering. While the dam has produced benefits in terms of flood control, hydropower generation and increased navigation capacity of the ...Yangtze River, serious questions have been raised concerning its impact on both upstream and downstream ecosystems. It has been suggested that the dam operation intensifies the extremes of wet and dry conditions in the downstream Poyang Lake, and affects adversely important local wetlands. A floodgate has been proposed to maintain the lake water level by controlling the flow between the Poyang Lake and Yangtze River. Using extensive hydrological data and generalized linear statistical models, we demonstrated that the dam operation induces major changes in the downstream river discharge near the dam, including an average “water loss”. The analysis also revealed considerable effects on the Poyang Lake water level, particularly a reduced level over the dry period from late summer to autumn. However, the dam impact needs to be further assessed based on long‐term monitoring of the lake ecosystem, covering a wide range of parameters related to hydrological and hydraulic characteristics of the lake, water quality, geomorphological characteristics, aquatic biota and their habitat, wetland vegetation and associated fauna.
Key Points
The 3GD induces major changes in the downstream river discharge near the dam
The 3GD causes considerable effects on the Poyang Lake water level
The lake behavior is controlled by local factors modulated by the dam
Varicella-zoster virus (VZV), an alphaherpesvirus, establishes lifelong latent infection in the neurons of >90% humans worldwide, reactivating in one-third to cause shingles, debilitating pain and ...stroke. How VZV maintains latency remains unclear. Here, using ultra-deep virus-enriched RNA sequencing of latently infected human trigeminal ganglia (TG), we demonstrate the consistent expression of a spliced VZV mRNA, antisense to VZV open reading frame 61 (ORF61). The spliced VZV latency-associated transcript (VLT) is expressed in human TG neurons and encodes a protein with late kinetics in productively infected cells in vitro and in shingles skin lesions. Whereas multiple alternatively spliced VLT isoforms (VLT
) are expressed during lytic infection, a single unique VLT isoform, which specifically suppresses ORF61 gene expression in co-transfected cells, predominates in latently VZV-infected human TG. The discovery of VLT links VZV with the other better characterized human and animal neurotropic alphaherpesviruses and provides insights into VZV latency.
Anxiety disorders are one of the most common and debilitating mental illnesses worldwide. Growing evidence indicates an age-dependent rise in the incidence of anxiety disorders from adolescence ...through adulthood, suggestive of underlying neurodevelopmental mechanisms. Kappa opioid receptors (KORs) are known to contribute to the development and expression of anxiety; however, the functional role of KORs in the basolateral amygdala (BLA), a brain structure critical in mediating anxiety, particularly across ontogeny, are unknown. Using whole-cell patch-clamp electrophysiology in acute brain slices from adolescent (postnatal day (P) 30–45) and adult (P60+) male Sprague-Dawley rats, we found that the KOR agonist, U69593, increased the frequency of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in the adolescent BLA, without an effect in the adult BLA or on sIPSC amplitude at either age. The KOR effect was blocked by the KOR antagonist, nor-BNI, which alone did not alter GABA transmission at either age, and the effect of the KOR agonist was TTX-sensitive. Additionally, KOR activation did not alter glutamatergic transmission in the BLA at either age. In contrast, U69593 inhibited sIPSC frequency in the central amygdala (CeA) at both ages, without altering sIPSC amplitude. Western blot analysis of KOR expression indicated that KOR levels were not different between the two ages in either the BLA or CeA. This is the first study to provide compelling evidence for a novel and unique neuromodulatory switch in one of the primary brain regions involved in initiating and mediating anxiety that may contribute to the ontogenic rise in anxiety disorders.
•Incidence of anxiety disorders increases from adolescence into adulthood.•Kappa opioid receptors (KORs) are involved in anxiety.•KORs increase GABA transmission in the BLA of adolescent, but not adults.•KORs decrease GABA transmission in the adolescent and adult CeA.•Age-dependent switch in BLA KOR function may contribute to anxiety disorders.
Cooperative interactions among species, termed mutualisms, have played a crucial role in the evolution of life on Earth. However, despite key potential benefits to partners, there are many cases in ...which two species cease to cooperate and mutualisms break down. What factors drive the evolutionary breakdown of mutualism? We examined the pathways toward breakdowns of the mutualism between plants and arbuscular mycorrhizal fungi. By using a comparative approach, we identify ∼25 independent cases of complete mutualism breakdown across global seed plants. We found that breakdown of cooperation was only stable when host plants (i) partner with other root symbionts or (ii) evolve alternative resource acquisition strategies. Our results suggest that key mutualistic services are only permanently lost if hosts evolve alternative symbioses or adaptations.
Varicella-zoster virus (VZV) establishes lifelong neuronal latency in most humans world-wide, reactivating in one-third to cause herpes zoster and occasionally chronic pain. How VZV establishes, ...maintains and reactivates from latency is largely unknown. VZV transcription during latency is restricted to the latency-associated transcript (VLT) and RNA 63 (encoding ORF63) in naturally VZV-infected human trigeminal ganglia (TG). While significantly more abundant, VLT levels positively correlated with RNA 63 suggesting co-regulated transcription during latency. Here, we identify VLT-ORF63 fusion transcripts and confirm VLT-ORF63, but not RNA 63, expression in human TG neurons. During in vitro latency, VLT is transcribed, whereas VLT-ORF63 expression is induced by reactivation stimuli. One isoform of VLT-ORF63, encoding a fusion protein combining VLT and ORF63 proteins, induces broad viral gene transcription. Collectively, our findings show that VZV expresses a unique set of VLT-ORF63 transcripts, potentially involved in the transition from latency to lytic VZV infection.
•Seawater intrusion vulnerability indicator equations developed for strip islands.•Equations derived for flux-controlled and head-controlled conditions.•Vulnerability to sea-level rise, land ...inundation and recharge change quantified.•Ranking of lenses according to vulnerability illustrated.
Freshwater lenses on small islands are some of the most vulnerable aquifer systems in the world. However, there is currently little guidance on methods for rapidly assessing the vulnerability of freshwater lenses to the potential effects of climate change. We address this gap using a simple steady-state analytic modelling approach to develop seawater intrusion (SWI) vulnerability indicator equations, which quantify the propensity for SWI to occur in strip islands due to recharge change and sea-level rise (SLR) (incorporating the effect of land surface inundation (LSI)). The following inferences about SWI vulnerability in freshwater lenses can be made from the analysis: (1) SWI vulnerability indicators for SLR (under flux-controlled conditions) are proportional to lens thickness (or volume) and the rate of LSI and inversely proportional to island width; (2) SWI vulnerability indicators for recharge change (under flux-controlled conditions) are proportional to lens thickness (or volume) and inversely proportional to recharge; and (3) SLR has greater impact under head-controlled conditions rather than flux-controlled conditions, whereas the opposite is the case for LSI and recharge change. Example applications to several case studies illustrate use of the method for rapidly ranking lenses according to vulnerability, thereby allowing for prioritisation of areas where further and more detailed SWI investigations may be required.
Herpes simplex virus (HSV) encephalitis (HSE) is a serious and potentially life-threatening disease, affecting both adults and newborns. Progress in understanding the virus and host factors involved ...in neonatal HSE has been hampered by the limitations of current brain models that do not fully recapitulate the tissue structure and cell composition of the developing human brain in health and disease. Here, we developed a human fetal organotypic brain slice culture (hfOBSC) model and determined its value in mimicking the HSE neuropathology in vitro.
Cell viability and tissues integrity were determined by lactate dehydrogenase release in supernatant and immunohistological (IHC) analyses. Brain slices were infected with green fluorescent protein (GFP-) expressing HSV-1 and HSV-2. Virus replication and spread were determined by confocal microscopy, PCR and virus culture. Expression of pro-inflammatory cytokines and chemokines were detected by PCR. Cell tropism and HSV-induced neuropathology were determined by IHC analysis. Finally, the in situ data of HSV-infected hfOBSC were compared to the neuropathology detected in human HSE brain sections.
Slicing and serum-free culture conditions were optimized to maintain the viability and tissue architecture of ex vivo human fetal brain slices for at least 14 days at 37 °C in a CO
incubator. The hfOBSC supported productive HSV-1 and HSV-2 infection, involving predominantly infection of neurons and astrocytes, leading to expression of pro-inflammatory cytokines and chemokines. Both viruses induced programmed cell death-especially necroptosis-in infected brain slices at later time points after infection. The virus spread, cell tropism and role of programmed cell death in HSV-induced cell death resembled the neuropathology of HSE.
We developed a novel human brain culture model in which the viability of the major brain-resident cells-including neurons, microglia, astrocytes and oligodendrocytes-and the tissue architecture is maintained for at least 2 weeks in vitro under serum-free culture conditions. The close resemblance of cell tropism, spread and neurovirulence of HSV-1 and HSV-2 in the hfOBSC model with the neuropathological features of human HSE cases underscores its potential to detail the pathophysiology of other neurotropic viruses and as preclinical model to test novel therapeutic interventions.
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