Miracle-dz/UniFAR-FTUs huggingface dataset:
Amyloid-Associated Neuron Loss and Gliogenesis in the Neocortex of Amyloid Precursor Protein Transgenic Mice

APP23 transgenic mice express mutant human amyloid precursor protein and develop amyloid plaques predominantly in neocortex and hippocampus progressively with age, similar to Alzheimer's disease. We have previously reported neuron loss in the hippocampal CA1 region of 14- to 18-month-old APP23 mice. In contrast, no neuron loss was found in neocortex. In the present study we have reinvestigated neocortical neuron numbers in adult and aged APP23 mice. Surprisingly, results revealed that 8-month-old APP23 mice have 13 and 14% more neocortical neurons compared with 8-month-old wild-type and 27-month-old APP23 mice, respectively. In 27-month-old APP23 mice we found an inverse correlation between amyloid load and neuron number. These results suggest that APP23 mice have more neurons until they develop amyloid plaques but then lose neurons in the process of cerebral amyloidogenesis. Supporting this notion, we found more neurons with a necrotic–apoptotic phenotype in the neocortex of 24-month-old APP23 mice compared with age-matched wild-type mice. Stimulated by recent reports that demonstrated neurogenesis after targeted neuron death in the mouse neocortex, we have also examined neurogenesis in APP23 mice. Strikingly, we found a fourfold to sixfold increase in newly produced cells in 24-month-old APP23 mice compared with both age-matched wild-type mice and young APP23 transgenic mice. However, subsequent cellular phenotyping revealed that none of the newly generated cells in neocortex had a neuronal phenotype. The majority were microglial and to a lesser extent astroglial cells. We conclude that cerebral amyloidosis in APP23 mice causes a modest neuron loss in neocortex and induces marked gliogenesis.
A Fast Optimization Transfer Algorithm for Image Inpainting in Wavelet Domains

A wavelet inpainting problem refers to the problem of filling in missing wavelet coefficients in an image. A variational approach was used by Chan et al. The resulting functional was minimized by the gradient descent method. In this paper, we use an optimization transfer technique which involves replacing their univariate functional by a bivariate functional by adding an auxiliary variable. Our bivariate functional can be minimized easily by alternating minimization: for the auxiliary variable, the minimum has a closed form solution, and for the original variable, the minimization problem can be formulated as a classical total variation (TV) denoising problem and, hence, can be solved efficiently using a dual formulation. We show that our bivariate functional is equivalent to the original univariate functional. We also show that our alternating minimization is convergent. Numerical results show that the proposed algorithm is very efficient and outperforms that of Chan et al.
MicroRNA-202 maintains spermatogonial stem cells by inhibiting cell cycle regulators and RNA binding proteins

Abstract miRNAs play important roles during mammalian spermatogenesis. However, the function of most miRNAs in spermatogenesis and the underlying mechanisms remain unknown. Here, we report that miR-202 is highly expressed in mouse spermatogonial stem cells (SSCs), and is oppositely regulated by Glial cell-Derived Neurotrophic Factor (GDNF) and retinoic acid (RA), two key factors for SSC self-renewal and differentiation. We used inducible CRISPR-Cas9 to knockout miR-202 in cultured SSCs, and found that the knockout SSCs initiated premature differentiation accompanied by reduced stem cell activity and increased mitosis and apoptosis. Target genes were identified with iTRAQ-based proteomic analysis and RNA sequencing, and are enriched with cell cycle regulators and RNA-binding proteins. Rbfox2 and Cpeb1 were found to be direct targets of miR-202 and Rbfox2 but not Cpeb1, is essential for the differentiation of SSCs into meiotic cells. Accordingly, an SSC fate-regulatory network composed of signaling molecules of GDNF and RA, miR-202 and diverse downstream effectors has been identified.
Actin filaments, stereocilia, and hair cells of the bird cochlea. II. Packing of actin filaments in the stereocilia and in the cuticular plate and what happens to the organization when the stereocilia are bent

A comparison of hair cells from different parts of the cochlea reveals the same organization of actin filaments; the elements that vary are the length and number of the filaments. Thin sections of stereocilia reveal that the actin filaments are hexagonally packed and from diffraction patterns of these sections we found that the actin filaments are aligned such that the crossover points of adjacent actin filaments are in register. As a result, the cross-bridges that connect adjacent actin filaments are easily seen in longitudinal sections. The cross-bridges appear as regularly spaced bands that are perpendicular to the axis of the stereocilium. Particularly interesting is that, unlike what one might predict, when a stereocilium is bent or displaced, as might occur during stimulation by sound, the actin filaments are not compressed or stretched but slide past one another so that the bridges become tilted relative to the long axis of the actin filament bundle. In the images of bent bundles, the bands of cross- bridges are then tilted off perpendicular to the stereocilium axis. When the stereocilium is bent at its base, all cross-bridges in the stereocilium are affected. Thus, resistance to bending or displacement must be property of the number of bridges present, which in turn is a function of the number of actin filaments present and their respective lengths. Since hair cells in different parts of the cochlea have stereocilia of different, yet predictable lengths and widths, this means that the force needed to displace the stereocilia of hair cells located at different regions of the cochlea will not be the same. This suggests that fine tuning of the hair cells must be a built-in property of the stereocilia. Perhaps its physiological vulnerability may result from changes of stereociliary structure.
Fatty Acid Synthesis Is Essential for Survival of Cryptococcus neoformans and a Potential Fungicidal Target

ABSTRACT Fatty acid synthase in the yeast Cryptococcus neoformans is composed of two subunits encoded by FAS1 and FAS2 genes. We inserted a copper-regulated promoter (PCTR4-2) to regulate FAS1 and FAS2 expression in Cryptococcus neoformans (strains PCTR4-2/FAS1 and PCTR4-2/FAS2, respectively). Both mutants showed growth rates similar to those of the wild type in a low-copper medium in which FAS1 and FAS2 were expressed, but even in the presence of exogenous fatty acids, strains were suppressed in growth under high-copper conditions. The treatment of C. neoformans with fluconazole was shown to have an increased inhibitory activity and even became fungicidal when either FAS1 or FAS2 expression was suppressed. Furthermore, a subinhibitory dose of fluconazole showed anticryptococcal activity in vitro in the presence of cerulenin, a fatty acid synthase inhibitor. In a murine model of pulmonary cryptococcosis, a tissue census of yeast cells in PCTR4-2/FAS2 strain at day 7 of infection was significantly lower than that in mice treated with tetrathiomolybdate, a copper chelator (P < 0.05), and a yeast census of PCTR4-2/FAS1 strain at day 14 of infection in the brain was lower in the presence of more copper. In fact, no positive cultures from the brain were detected in mice (with or without tetrathiomolybdate treatment) infected with the PCTR4-2/FAS2 strain, which implies that this mutant did not reach the brain in mice. We conclude that both FAS1 and FAS2 in C. neoformans are essential for in vitro and in vivo growth in conditions with and without exogenous fatty acids and that FAS1 and FAS2 can potentially be fungicidal targets for C. neoformans with a potential for synergistic behavior with azoles.
Differential Expression of KCNQ4 in Inner Hair Cells and Sensory Neurons Is the Basis of Progressive High-Frequency Hearing Loss

Human KCNQ4 mutations known as DFNA2 cause non-syndromic, autosomal-dominant, progressive high-frequency hearing loss in which the cellular and molecular basis is unclear. We provide immunofluorescence data showing that Kcnq4 expression in the adult cochlea has both longitudinal (base to apex) and radial (inner to outer hair cells) gradients. The most intense labeling is in outer hair cells at the apex and in inner hair cells as well as spiral ganglion neurons at the base. Spatiotemporal expression studies show increasing intensity of KCNQ4 protein labeling from postnatal day 21 (P21) to P120 mice that is most apparent in inner hair cells of the middle turn. We have identified four alternative splice variants of Kcnq4 in mice. The alternative use of exons 9-11 produces three transcript variants (v1-v3), whereas the fourth variant (v4) skips all three exons; all variants have the same amino acid sequence at the C termini. Both reverse transcription-PCR and quantitative PCR analyses demonstrate that these variants have differential expression patterns along the length of the mouse organ of Corti and spiral ganglion neurons. Our expression data suggest that the primary defect leading to high-frequency loss in DFNA2 patients may be attributable to high levels of the dysfunctional Kcnq4_v3 variant in the spiral ganglion and inner hair cells in the basal hook region. Progressive hearing loss associated with aging may result from an increasing mutational load expansion toward the apex in inner hair cells and spiral ganglion neurons.
Roles for p 21 waf 1 / cip 1 and p 27 kip 1 during the adaptation response to massive intestinal resection

Stehr, Wolfgang, Nicole P. Bernal, Christopher R. Erwin, Kathryn Q. Bernabe, Jun Guo, and Brad W. Warner. Roles for p21 and p27 during the adaptation response to massive intestinal resection. Am J Physiol Gastrointest Liver Physiol 290: G933–G941, 2006. First published December 8, 2005; doi:10.1152/ajpgi.00235. 2005. —The magnitude of gut adaptation is a decisive factor in determining whether patients are able to live independent of parenteral nutrition after massive small bowel loss. We previously established that the cyclindependent kinase inhibitor (CDKI) p21 is necessary for enterocyte proliferation and a normal adaptation response. In the present study, we have further elucidated the role of this CDKI in the context of p27, another member of the Cip/Kip CDKI family. Small bowel resections (SBRs) or sham operations were performed in control (C57/BL6), p21-null, p27-null, and p21/p27 double-null mice. Morphological (villus height/crypt depth) alterations in the mucosa, the kinetics of enterocyte turnover (rates of enterocyte proliferation and apoptosis), and the protein expression of various cell cycle-regulatory proteins were recorded at various postoperative times. Enterocyte compartment-specific mRNA expression was investigated using laser capture microdissection. Resection-induced adaptation in control mice coincided with increased protein expression of p21 and decreased p27 within 3 days postoperatively. Identical changes in mRNA expression were detected in crypt but not in villus enterocytes. Adaptation occurred normally in control and p27-null mice; however, mice deficient in both p21 and p27 failed to increase baseline rates of enterocyte proliferation and adaptation. The expression of p21 protein and mRNA in the proliferative crypt compartment is necessary for resection-induced enterocyte proliferation and adaptation. The finding that deficient expression of p27 does not affect adaptation suggests that these similar CDKI family members display distinctive cellular functions during the complex process of intestinal adaptation.
EFFECTS OF MITOTIC SPINDLE INHIBITORS ON NEUROTUBULES AND NEUROFILAMENTS IN ANTERIOR HORN CELLS

An understanding of the chemistry of the microtubule and of its in vivo response to colchicine administration has been facilitated by the recent work of Taylor and his coworkers (1, 2). Robbins and Gonatas (3) have shown that colchicine causes the breakdown of mitotic spindle tubules of HeLa cells and a simultaneous increase in the apparent number of 90-A microfilaments in the cytoplasm. Similar changes have been observed by Padawer in the mast cell. ' Finally, the homology between the spindle tubule and the neurotubule has been suggested (4). After subarachnoid injection of colchicine, there is an accumulation of filaments in the neurons of the spinal cord anterior horn (5). Similar proliferation of neurofilaments is seen after subarachnoid administration of the mitotic spindle inhibitors vinblastine and podophyllotoxin. The experiments reported here show the reversibility
The Characteristics of Antioxidant Activity after Liver Transplantation in Biliary Atresia Patients

Purpose. Cholestatic liver injury is associated with a high production of free radicals. The pathogenesis of liver injury in biliary atresia (BA) patients is largely undefined. The goal of the present study was to clarify the oxidative damage and the changes in antioxidant enzyme activities that occur during the development of BA and after liver transplantation (LT). Methods. We enrolled BA patients and control subjects and collected their clinical information. The activities of antioxidant enzymes in BA patients before LT (BA group) and after LT (LT group) were analyzed. Results. The number of mitochondrial DNA copies had increased in the LT group compared with the BA group. Similarly, the activity of glutathione peroxidase had increased in the LT group compared with the BA group. The level of glutathione was higher in the LT group than in the BA group. Malondialdehyde levels were decreased in the LT group compared with the BA group. Conclusions. These data indicate that LT is associated with increased antioxidant enzyme activities and decreased malondialdehyde levels in BA patients. The manipulation of mitochondria-associated antioxidative activity might be an important future management strategy for BA.
Pre-SCNAClonal: Efficient GC bias correction for SCNA based tumor subclonal populations inferring

Somatic copy number alternations (SCNAs) can be utilized to infer tumor subclonal populations in whole genome seuqncing studies, where usually their read count ratios between tumor-normal paired samples serve as the inferring proxy. We found that, in a GC study, the GC contents and read count ratios on SCNA segments present a Log linear biased pattern. However, currently no subclonal inferring tools take into account this information. We provide Pre-SCNAClonal, a comprehensive GC bias correction tool for inferring tumor subclonal populations based on SCNAs. Results show that Pre-SCNAClonal could effectively and robustly correct the GC bias and improve the performance of the SCNAs based tumor subclonal population inferring tools. Pre-SCNAClonal could be strung together with the SCNAs based subclonal population inferring tool as a pipeline or run individually as needed. Pre-SCNAClonal is publicly available as a Python package: https://github.com/dustincys/Pre-SCNAClonal
Minimal access aortic valve surgery.

OBJECTIVE We report our experience with minimal access aortic valve surgery and discuss the three approaches used. METHODS From June 1996 to October 1997, 18 patients underwent minimally invasive aortic valve surgery through three different incisions: right parasternal minithoracotomy (three cases), upper ministernotomy (11 cases), and transverse sternotomy (four cases). No special surgical instrumentation was used. Aortic valve replacement was carried out in 17 patients and aortic valve repair in one patient. The patients ranged in age from 42 to 86 years (mean 64 years). Concomitant procedures involving the aortic root and the ascending aorta were performed in five patients. RESULTS There was no mortality and no complications related to the procedure or the access. There was no instability or paradoxical movement of the chest wall. One patient was reoperated for postoperative bleeding. All patients were discharged from hospital within the usual time. No attempts were made to discharge them earlier, even if they recovered quickly. CONCLUSIONS Of the three incisions used, the upper ministernotomy seemed to be the safest and easiest to perform. Through this incision, both the aorta and the right atrium could be cannulated, the right ventricle was accessible, and concomitant procedures on the ascending aorta could be carried out. The drawback of minimal access aortic valve surgery in general is that it is difficult to de-air the heart and more difficult to master intra- and postoperative complications should they occur.
An Albian demise of the carbonate platform in the Manín Unit (Western Carpathians, Slovakia)

Abstract The production of platform carbonates of the Manín Unit (Manín Straits, Central Western Carpathians) belonging to the Podhorie and Manín formations and formed by remains of rudists and benthic foraminifers (Urgonian-type carbonates), was previously assumed to terminate during the Aptian. First, we show that these deposits were primarily formed on the upper slope (Podhorie Formation) and in a fore-reef environment (Manín Formation). Second, biostratigraphic data indicate that the shallow-water production persisted up to the Albian, just as it did in another succession of the Manín Unit. The Podhorie Fm contains colomiellids (Colomiella recta, C. mexicana) and calcareous dinoflagellates (Calcisphaerula innominata) that indicate the Albian age. It also contains planktonic foraminifers (Ticinella roberti, Ticinella cf. primula, Ticinella cf. madecassiana, Ticinella cf. praeticinensis) of the Albian Ticinella primula Zone. The Podhorie Formation passes upwards into peri-reefal facies of the Manín Fm where we designate the Malý Manín Member on the basis of rudists shell fragments and redeposited orbitolinids. Microfacies associations share similarities with the Urgonian-type microfacies from Mediterranean Tethys and allow us to restrict the growth and the demise of the carbonate platform. δ13C and δ18O isotopes change over a broad range of both formations: δ13C is in the range +1.03 to +4.20 ‰ V-PDB and δ18O is in the range −0.14 to −5.55 ‰ V-PDB. Although a close correlation between δ13C and δ18O indicates diagenetic overprint, a long-term increase of δ13C can indicate a gradual increase in the aragonite production and/or increasing effects of oceanic water masses in the course of the Albian, prior to the final platform drowning. Carbonate platform evolution was connected with submarine slumps and debris flows leading to redeposition and accumulation of carbonate lithoclasts and bioclastic debris on the slope. Our study confirms that the growth of carbonate platforms in the Central Western Carpathians was stopped and the platform collapsed during the Albian, in contrast to the westernmost Tethys. A hardground formed during the Late Albian is overlain by Albian - Cenomanian marls of the Butkov Formation with calcisphaerulid limestones characterized by planktonic foraminifers of the Parathalmanninella appenninica Zone and calcareous dinoflagellates of the Innominata Acme Zone.
Addressing viscous effects in acoustic full-waveform inversion

In conventional full-waveform inversion (FWI), viscous effects are typically neglected, and this is likely to adversely affect the recovery of P-wave velocity. We have developed a strategy to mitigate viscous effects based on the use of matching filters with the aim of improving the performance of acoustic FWI. The approach requires an approximate estimate of the intrinsic attenuation model, and it is one to three times more expensive than conventional acoustic FWI. First, we perform 2D synthetic tests to study the impact of viscoacoustic effects on the recorded wavefield and analyze how that affects the recovered velocity models after acoustic FWI. Then, we apply the current method on the generated data and determine that it mitigates viscous effects successfully even in the presence of noise. We find that having an approximate estimate for intrinsic attenuation, even when these effects are strong, leads to improvements in resolution and a more accurate recovery of the P-wave velocity. Then, we implement and develop our method on a 2D field data set using Gabor transforms to obtain an approximate intrinsic attenuation model and inversion frequencies of up to 24 Hz. The analysis of the results indicates that there is an improvement in terms of resolution and continuity of the layers on the recovered P-wave velocity model, leading to an improved flattening of gathers and a closer match of the inverted velocity model with the migrated seismic data.
Should Patients With Peritoneal Carcinomatosis of Colorectal Origin With Synchronous Liver Metastases Be Treated With a Curative Intent? A Case-Control Study

Objective:This study aimed to assess the prognostic impact of liver metastases (LM) in patients with colorectal peritoneal carcinomatosis (PC) who underwent complete cytoreductive surgery and resection of LM, followed by intraperitoneal chemotherapy. Background:Synchronous surgical treatment of PC and LM with curative intent remains controversial. Methods:From a prospective database, all patients with PC and synchronous LM who had undergone cytoreductive surgery and LM resection followed by intraperitoneal chemotherapy were matched with patients with PC alone according to the following criteria: age, peritoneal cancer index (PCI), site and lymph node involvement (pN) of primary cancer, and postoperative chemotherapy. Results:From 1993 to 2009, 37 patients with PC and LM were matched with 61 patients with PC alone. After a mean follow-up of 36 months, 3-year overall survival (OS) and disease-free survival rates were significantly lower in patients with PC and LM, respectively, 40% and 66% (P = 0.04) and 6% and 27% (P = 0.001). A PCI of 12 or more [odds ratio (OR): 4.6], a pN+ status (OR: 3.3), no adjuvant chemotherapy (OR: 3.0), and presence of LM (OR: 2.0) were identified as independent factors for poor OS. Three groups were singled out: (1) patients with a low PCI (<12) and no LM (median OS: 76 months); (2) patients with a low PCI (<12) and 1 or 2 LM (median OS: 40 months); and (3) patients with a high PCI (≥12) or patients with 3 LMs or more (median OS: 27 months). Conclusions:This case-control study seems to confirm that prolonged survival can be achieved in highly selected patients operated on for limited PC and fewer than 3 LM.
The volatile metabolome of Klebsiella pneumoniae in human blood

Klebsiella pneumoniae is an important cause of bloodstream infections in critically-ill patients, with mortality exceeding 50% for infections caused by antibiotic-resistant strains. Despite its importance as a bacteremia-causing agent, there is little known about the metabolism of K. pneumoniae during growth in pure human blood. Here, we comprehensively profile the volatile metabolites produced by K. pneumoniae during growth in human blood to approximately mid-exponential (7 h) and early stationary (12 h) phases using 2D gas chromatography–time-of-flight mass spectrometry (GC×GC-TOFMS). We identified 33 volatile molecules that were significantly more abundant in K. pneumoniae cultures relative to sterile blood, of which 22 were detected in cultures only. We identified nine molecules that have not previously been reported as K. pneumoniae-associated headspace volatiles, four of which we believe to be novel bacterial-associated volatiles. We also identified a set of 17 volatile molecules that discriminate between 7 h and 12 h K. pneumoniae cultures, indicating either growth phase or cell density-associated changes in the composition of headspace volatiles. Our analysis of the volatile molecules produced by K. pneumoniae during growth in human blood using GC×GC-TOFMS has doubled the number of volatiles reported for this organism in blood-containing media, and increased the total number of K. pneumoniae-associated volatiles by 20%. The volatile molecules produced by K. pneumoniae in blood may represent novel biomarkers for the diagnosis of bacteremia.