Targeting autophagy drug discovery: Targets, indications and development trends.

Autophagy plays a vital role in sustaining cellular homeostasis and its alterations have been implicated in the etiology of many diseases. Drugs development targeting autophagy began decades ago and hundreds of agents were developed, some of which are licensed for the clinical usage. However, no existing intervention specifically aimed at modulating autophagy is available. The obstacles that prevent drug developments come from the complexity of the actual impact of autophagy regulators in disease scenarios. With the development and application of new technologies, several promising categories of compounds for autophagy-based therapy have emerged in recent years. In this paper, the autophagy-targeted drugs based on their targets at various hierarchical sites of the autophagic signaling network, e.g., the upstream and downstream of the autophagosome and the autophagic components with enzyme activities are reviewed and analyzed respectively, with special attention paid to those at preclinical or clinical trials. The drugs tailored to specific autophagy alone and combination with drugs/adjuvant therapies widely used in clinical for various diseases treatments are also emphasized. The emerging drug design and development targeting selective autophagy receptors (SARs) and their related proteins, which would be expected to arrest or reverse the progression of disease in various cancers, inflammation, neurodegeneration, and metabolic disorders, are critically reviewed. And the challenges and perspective in clinically developing autophagy-targeted drugs and possible combinations with other medicine are considered in the review.

We know what attention is!

Attention is one of the most thoroughly investigated psychological phenomena, yet skepticism about attention is widespread: we do not know what it is, it is too many things, there is no such thing. The deficiencies highlighted are not about experimental work but the adequacy of the scientific theory of attention. Combining common scientific claims about attention into a single theory leads to internal inconsistency. This paper demonstrates that a specific functional conception of attention is incorporated into the tasks used in standard experimental paradigms. In accepting these paradigms as valid probes of attention, we commit to this common conception. The conception unifies work at multiple levels of analysis into a coherent scientific explanation of attention. Thus, we all know what attention is.

Production of high protein yeast using enzymatically liquefied almond hulls.

Animal feed ingredients, especially those abundant in high quality protein, are the most expensive component of livestock production. Sustainable alternative feedstocks may be sourced from abundant, low value agricultural byproducts. California almond production generates nearly 3 Mtons of biomass per year with about 50% in the form of hulls. Almond hulls are a low-value byproduct currently used primarily for animal feed for dairy cattle. However, the protein and essential amino acid content are low, at ~30% d.b.. The purpose of this study was to improve the protein content and quality using yeast. To achieve this, the almond hulls were liquefied to liberate soluble and structural sugars. A multi-phase screening approach was used to identify yeasts that can consume a large proportion of the sugars in almond hulls while accumulating high concentrations of amino acids essential for livestock feed. Compositional analysis showed that almond hulls are rich in polygalacturonic acid (pectin) and soluble sucrose. A pectinase-assisted process was optimized to liquefy and release soluble sugars from almond hulls. The resulting almond hull slurry containing solubilized sugars was subsequently used to grow high-protein yeasts that could consume nutrients in almond hulls while accumulating high concentrations of high-quality protein rich in essential amino acids needed for livestock feed, yielding a process that would produce 72 mg protein/g almond hull. Further work is needed to achieve conversion of galacturonic acid to yeast cell biomass.

Addressing Discrepancies between Experimental and Computational Procedures.

Imaging subject-specific heart valve, a crucial step to its design, has experimental variables that if unaccounted for, may lead to erroneous computational analysis and geometric errors of the resulting model. Preparation methods are developed to mitigate some sources of the geometric error. However, the resulting 3D geometry often does not retain the original dimensions before excision. Inverse fluid-structure interaction analysis is used to analyze the resulting geometry and to assess the valve's closure. Based on the resulting closure, it is determined if the geometry used can yield realistic results. If full closure is not reached, the geometry is adjusted adequately until closure is observed.

Disseminated cysticercosis in China with complex and variable clinical manifestations: a case series.

BACKGROUND: Cysticercosis is an emerging and neglected tropical disease (NTD) that poses a serious public health concern worldwide. Disseminated cysticercosis (DCC) is an uncommon manifestation of cysticercosis, also found in China. CASE PRESENTATION: We report three cases of DCC in patients living in China, with different clinical and radiological presentations. All three patients had DCC with active ocular cysticercosis, including one patient with widespread DCC caused by direct ingestion of Taenia solium eggs. The intravitreal cysticercus cyst in this patient was completely extracted entirely by 23-gauge pars plana vitrectomy, and the cyst was oval in shape on the flat mount preparation. CONCLUSION: The clinical presentation of DCC is highly sophisticated. The diagnosis depended on the typical radiological presentations, biopsy and flat mount preparations of the cyst.

Mechanisms of auditory verbal hallucination in schizophrenia.

Recent work on the mechanisms underlying auditory verbal hallucination (AVH) has been heavily informed by self-monitoring accounts that postulate defects in an internal monitoring mechanism as the basis of AVH. A more neglected alternative is an account focusing on defects in auditory processing, namely a spontaneous activation account of auditory activity underlying AVH. Science is often aided by putting theories in competition. Accordingly, a discussion that systematically contrasts the two models of AVH can generate sharper questions that will lead to new avenues of investigation. In this paper, we provide such a theoretical discussion of the two models, drawing strong contrasts between them. We identify a set of challenges for the self-monitoring account and argue that the spontaneous activation account has much in favor of it and should be the default account. Our theoretical overview leads to new questions and issues regarding the explanation of AVH as a subjective phenomenon and its neural basis. Accordingly, we suggest a set of experimental strategies to dissect the underlying mechanisms of AVH in light of the two competing models.

Botulinum toxin as novel treatment for excess mucous membrane graft secretions.

Salivary gland secretion is an unusual complication of mucous membrane grafting. The authors report a case in which botulinum toxin was successfully used to treat graft secretions after buccal mucous membrane autograft for recurrent pterygium repair.

Light damage induced changes in mouse retinal gene expression.

Oxidative stress plays a role in the light damage model of retinal degeneration as well as in age-related macular degeneration. The purpose of this study is to identify retinal genes induced by acute photo-oxidative stress, which may function as mediators of apoptosis or as survival factors. To accomplish this, Balb/c mice were exposed to bright cool white fluorescent light for 7 hr. Retinas were then isolated for total RNA preparation followed by Affymetrix DNA microarray analysis to compare gene expression in light damaged mice to unexposed controls. Three independent light damage experiments were carried out and statistical filters were applied to detect genes with expression changes averaging at least two-fold. Quantitative PCR was carried out to confirm altered gene expression. Seventy genes were upregulated at least two-fold immediately following light damage. QPCR confirmed upregulation of all 10 genes tested. The upregulated genes fall into several categories including antioxidants: ceruloplasmin, metallothionein, and heme oxygenase; antiapoptotic gene: bag3, chloride channels: clic1 and clic4; transcription factors: c-fos, fra1, junB, stat1, krox-24 and c/ebp; secreted signaling molecules: chitinase 3-like protein 1 and osteopontin; inflammation related genes: MCP-1 and ICAM1 and others. Upregulation of five interferon-gamma responsive genes suggests elevated interferon levels after light damage. Upregulation of three components of the AP-1 transcription factor is consistent with previous evidence implicating AP-1 in light damage pathogenesis. Four copper or iron binding proteins were upregulated, suggesting that photo-oxidative stress may affect metal homeostasis. The genes found upregulated by light damage may affect the survival of photoreceptors subjected to photo-oxidative stress.

Increased metallothionein in light damaged mouse retinas.

Oxidative stress plays a role in human age-related macular degeneration and in the light damage model of retinal degeneration. Metallothionein (MT), an antioxidant, has been reported to protect retinal pigment epithelial cells against apoptosis and oxidative stress. The purpose of this study was to evaluate changes in MT expression level and retinal localization following light damage. To accomplish this, Balb/c mice were exposed to cool white fluorescent light (10,000 lx) for 7 hr. In three independent experiments, at several intervals after the light injury, retinal MTs were studied at the protein level by immunohistochemistry (IHC) and Western analysis, and at the mRNA level by quantitative PCR with isoform-specific primers. Western analysis and IHC indicated an increase in metallothionein protein following light damage. MT localized to the retinal pigment epithelium and several layers of neural retina. Quantitative PCR identified the expression of MT I-III isoforms, not the MT IV isoform in the mouse retina, and, following light damage, showed increased expression of retinal MT-I and MT-II mRNAs by 8- and 22-fold, respectively. Increased expression of the antioxidant MT in the light damaged mouse retina suggests that upregulation of MT is an important acute retinal response to photo-oxidative stress.

Cataract surgery in patients with nanophthalmos: results and complications.

PURPOSE: To evaluate the results and complications of cataract surgery in patients with nanophthalmos. SETTING: University hospital practice. METHODS: The records of consecutive patients with nanophthalmos who had cataract surgery from 1978 through 2002 were reviewed for ocular diagnoses, corneal diameter, keratometry, axial length, retinal-choroidal-scleral thickness determined by echography, ocular surgeries, visual acuity, and complications. RESULTS: Eight patients (6 women, 2 men) with a mean age of 59 years were reviewed. Four patients were not previously diagnosed with nanophthalmos; increased retinal-choroidal-scleral thickness (mean 2.41 mm) confirmed the diagnosis. Twelve eyes had cataract extraction with posterior chamber intraocular lens (IOL) implantation, 11 by phacoemulsification and 1 by extracapsular cataract extraction, and 4 eyes had lamellar scleral resections. Additional surgeries included glaucoma laser treatment (8 eyes), cyclocryotherapy (2 eyes), trabeculectomy with scleral resection (1 eye), trabeculectomy combined with phacoemulsification (1 eye), and neodymium:YAG laser capsulotomy (4 eyes). No eye lost vision; however, complications included severe iritis, broken IOL haptic with vitreous loss, posterior capsule opacity, choroidal hemorrhage, phthisis, and aqueous misdirection. CONCLUSIONS: Results indicate that echography should be used to assess retinal-choroidal-scleral thickness in eyes that are hyperopic and at risk for narrow-angle glaucoma. Thickening may confirm the diagnosis of nanophthalmos and allow careful preoperative assessment and appropriate operative procedures in these high-risk eyes. With advances in cataract, glaucoma, and uveal effusion treatments, surgical results in patients with nanophthalmos are improving.