Miracle-dz/UniFAR-FTUs huggingface dataset:
Academic staff views on external quality audit: post audit evaluation in a private higher education college

Governments in many countries have funded independent agencies to undertake quality audits of higher education institutions. Such agencies ensure that universities and other higher education providers have effective systems and processes to assure quality assurance in core and support areas. While external quality audits have been in place for a decade in Australia, there is limited research on academic staff views on external quality audit in universities and private higher education providers. This article outlines the views of 40 academic staff in a private higher education college who were directly involved in the external quality audit. A survey was undertaken immediately after the external quality audit to collect the views of academic staff on various aspects of the audit including; selfassessment, audit preparations strategy, communication and staff engagement, and the external quality audit process itself. The authors argue that external quality audit, if effectively managed, could be the driver for change and improvement in quality assurance in a small college.
Magnetic resonance imaging results of the PRISMS trial: A randomized, double‐blind, placebo‐controlled study of interferon‐β1a in relapsing‐remitting multiple sclerosis

The PRISMS (Prevention of Relapses and Disability by Interferon‐β1a Subcutaneously in Multiple Sclerosis) trial was a double‐blind, randomized, multicenter, phase III, placebo‐controlled study of interferon‐β1a in 560 patients from 22 centers in 9 countries with clinically definite or laboratory‐supported relapsing‐remitting multiple sclerosis. The patients were randomized to receive recombinant interferon‐β1a (Rebif), 22 μg (6 mIU), 44 μg (12 mIU), or placebo, given subcutaneously, three times weekly for 2 years. All patients underwent biannual proton density/T2‐weighted magnetic resonance imaging scans to determine the overall magnetic resonance imaging disease activity and burden of disease, and a cohort of 205 patients had 11 initial monthly proton density/T2‐weighted and gadolinium‐enhanced/T1‐weighted magnetic resonance imaging scans. Over the 2 years, the placebo group showed a progressive median increase in burden of disease of 10.9%, whereas the 22‐μg group and 44‐μg group showed median decreases of 1.2% and 3.8%, respectively. The number of T2 active lesions and percentage of scans showing T2 activity on the biannual scans were also significantly reduced in both treatment groups compared with placebo, with a clear dose–effect favoring the 44‐μg dose over the 22‐μg dose. In the subgroup undergoing initial monthly scanning, this reduction in activity became statistically significant 2 months after the start of treatment. These results provide strong, objective evidence to support the positive clinical results of reduction in relapses and delay in disease progression. In addition, they also demonstrate a significant dosage effect, favoring the 44‐μg dose. Ann Neurol 1999;46:197–206
A preclinical 188Re tumor therapeutic investigation using MORF/cMORF pretargeting and an antiTAG-72 antibody CC49

The utility of MORF/cMORF pretargeting for the radiotherapy of cancer requires further validation in tumored mice before clinical trials. We now report on a therapeutic study in mice pretargeted with MORF-CC49 (an anti-TAG-72 antibody CC49 conjugated with MORF, a phosphorodiamidate morpholino oligomer) and then targeted by 188Re-cMORF (a 188Re labeled complementary MORF). Before the dose-escalating therapeutic study, a pretargeting study in LS174T tumored mice was performed at tracer levels. By both necropsy and imaging, the tracer study showed that the whole body radioactivity was largely restricted to tumor in the mice pretargeted 48 h earlier with MORF-CC49 and the tumor radioactivity was retained over 90 h. After decay correction, a best-fit to the biodistribution provided the areas under the radioactivity curves (AUCs) used for the radiation dose estimates. The tumor to normal organ AUC ratios in all cases were greater than unity and ranged from 3 (kidneys) to 48 (muscle). Tumor growth was inhibited in the therapy study. At the highest 188Re dose of 1.40 mCi, a complete but temporary tumor remission was evident in 3 out of the 5 animals. Histological examination of tissues from these animals showed no evidence of cytotoxicity to normal tissues but obvious radiation damage to tumor. In conclusion, effective radiotherapy was achieved in a mouse model by MORF/cMORF pretargeting using 188Re as the therapeutic radionuclide and CC49 as the pretargeting antibody.
Mutant Huntingtin Is Secreted via a Late Endosomal/Lysosomal Unconventional Secretory Pathway

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the expansion of a CAG triplet in the gene encoding for huntingtin (Htt). The resulting mutant protein (mHtt) with extended polyglutamine (polyQ) sequence at the N terminus leads to neuronal degeneration both in a cell-autonomous and a non-cell-autonomous manner. Recent studies identified mHtt in the extracellular environment and suggested that its spreading contributes to toxicity, but the mechanism of mHtt release from the cell of origin remains unknown. In this study, we performed a comprehensive, unbiased analysis of secretory pathways and identified an unconventional lysosomal pathway as an important mechanism for mHtt secretion in mouse neuroblastoma and striatal cell lines, as well as in primary neurons. mHtt secretion was dependent on synaptotagmin 7, a regulator of lysosomal secretion, and inhibited by chemical ablation of late endosomes/lysosomes, suggesting a lysosomal secretory pattern. mHtt was targeted preferentially to the late endosomes/lysosomes compared with wild-type Htt. Importantly, we found that late endosomal/lysosomal targeting and secretion of mHtt could be inhibited efficiently by the phosphatidylinositol 3-kinase and neutral sphingomyelinase chemical inhibitors, Ly294002 and GW4869, respectively. Together, our data suggest a lysosomal mechanism of mHtt secretion and offer potential strategies for pharmacological modulation of its neuronal secretion. SIGNIFICANCE STATEMENT This is the first study examining the mechanism of mutant huntingtin (mHTT) secretion in an unbiased manner. We found that the protein is secreted via a late endosomal/lysosomal unconventional secretory pathway. Moreover, mHtt secretion can be reduced significantly by phosphatidylinositol 3-kinase and neutral sphingomyelinase inhibitors. Understanding and manipulating the secretion of mHtt is important because of its potentially harmful propagation in the brain.
Promoting modern family planning among Tanzania’s nomadic communities.

Use of modern family planning among nomadic communities in many African countries is still limited. A study in Kilindi District of Tanzania revealed that although many nomadic youth know about modern family planning methods they do not use them due to various factors including cultural beliefs sexual norms stigma and fear long distances to health facilities and male dominance in decision making. (excerpt)
MMP2-9 Cleavage of Dystroglycan Alters the Size and Molecular Composition of Schwann Cell Domains

Myelinating glial cells exhibit a spectacular cytoarchitecture, because they polarize on multiple axes and domains. How this occurs is essentially unknown. The dystroglycan–dystrophin complex is required for the function of myelin-forming Schwann cells. Similar to other tissues, the dystroglycan complex in Schwann cells localizes with different dystrophin family members in specific domains, thus promoting polarization. We show here that cleavage of dystroglycan by matrix metalloproteinases 2 and 9, an event that is considered pathological in most tissues, is finely and dynamically regulated in normal nerves and modulates dystroglycan complex composition and the size of Schwann cell compartments. In contrast, in nerves of Dy2j/2j mice, a model of laminin 211 deficiency, metalloproteinases 2 and 9 are increased, causing excessive dystroglycan cleavage and abnormal compartments. Pharmacological inhibition of cleavage rescues the cytoplasmic defects of Dy2j/2j Schwann cells. Thus, regulated cleavage may be a general mechanism to regulate protein complex composition in physiological conditions, whereas unregulated processing is pathogenic and a target for treatment in disease.
Sensitization of (colon) cancer cells to death receptor related therapies

The objective of the ONCODEATH consortium [EU Research Consortium “ONCODEATH” (2006–2010)] was to achieve sensitization of solid tumor cells to death receptor related therapies using rational mechanism-based drug combinations of targeted therapies. In this collaborative effort, during a period of 42 mo, cell and animal model systems of defined oncogenes were generated. Exploitation of generated knowledge and tools enabled the consortium to achieve the following research objectives: (1) elucidation of tumor components which confer sensitivity or resistance to TRAIL-induced cell death; (2) providing detailed knowledge on how small molecule Hsp90, Aurora, Choline kinase, BRAF inhibitors, DNA damaging agents, HDAC and DNMT inhibitors affect the intrinsic apoptotic amplification and execution machineries; (3) optimization of combined action of TRAIL with these therapeutics for optimum effects with minimum concentrations and toxicity in vivo. These findings provide mechanistic basis for a pharmacogenomic approach, which could be exploited further therapeutically, in order to reach novel personalized therapies for cancer patients.
The Histopathology of Malignant Lymphoma

It has been possible to reinterpret non‐Hodgkin's lymphomas by applying subtle histological, cytological, and cytochemical techniques and electron microscopy as well as by using modern immunological methods and immune chemical analyses. This has led to the differentiation of four main groups of low‐grade and three main groups of high‐grade malignant lymphomas. Most non‐Hodgkin's lymphomas are derived from the B‐lymphocyte system. Only some of the lymphocytic, a small fraction of the lymphoblastic, and very few immunoblastic lymphomas originate from the T‐lymphocyte system. True reticulosarcomas are very rare and will have to be redefined.
The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy

DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients.
Enhanced Neuronal Activity in the Medial Prefrontal Cortex during Social Approach Behavior

Although the medial prefrontal cortex (mPFC) is known to play a crucial role in rodent social behavior, little is known about mPFC neural correlates of social behavior. In the present study, we examined single-neuron activity in the mPFC of mice performing a modified version of the three-chamber test. We found that a subset of mPFC neurons elevate discharge rates when approaching a stranger mouse but not when approaching an inanimate object or an empty chamber. Our results reveal mPFC neural activity that is correlated with social approach behavior in a widely used social-interaction paradigm. These findings might be helpful for future investigations of mPFC neural processes underlying social interaction in health and disease. SIGNIFICANCE STATEMENT Although the prefrontal cortex is known to play a crucial role in rodent social behavior, little is known about prefrontal neural correlates of social behavior. This study shows that the activity of a subset of prefrontal neurons increases in association with social approach behavior during a three-chamber test—a widely used behavioral paradigm. Such responses might be a signature of prefrontal neural processes underlying social approach behavior.
Representation of Multidimensional Stimuli: Quantifying the Most Informative Stimulus Dimension from Neural Responses

A common way to assess the function of sensory neurons is to measure the number of spikes produced by individual neurons while systematically varying a given dimension of the stimulus. Such measured tuning curves can then be used to quantify the accuracy of the neural representation of the stimulus dimension under study, which can in turn be related to behavioral performance. However, tuning curves often change shape when other dimensions of the stimulus are varied, reflecting the simultaneous sensitivity of neurons to multiple stimulus features. Here we illustrate how one-dimensional information analyses are misleading in this context, and propose a framework derived from Fisher information that allows the quantification of information carried by neurons in multidimensional stimulus spaces. We use this method to probe the representation of sound localization in auditory neurons of chinchillas and guinea pigs of both sexes, and show how heterogeneous tuning properties contribute to a representation of sound source position that is robust to changes in sound level. SIGNIFICANCE STATEMENT Sensory neurons' responses are typically modulated simultaneously by numerous stimulus properties, which can result in an overestimation of neural acuity with existing one-dimensional neural information transmission measures. To overcome this limitation, we develop new, compact expressions of Fisher information-derived measures that bound the robust encoding of separate stimulus dimensions in the context of multidimensional stimuli. We apply this method to the problem of the representation of sound source location in the face of changes in sound source level by neurons of the auditory midbrain.
The Clinical Use of Low-Dose Multidetector Row Computed Tomography for Breast Cancer Patients in the Prone Position

Purpose: To investigate the clinical use of low-dose multidetector row computed tomography (MDCT) for staging of invasive breast cancers with patients in the prone position. Methods: Three hundred twenty-two patients with 334 pathologically-verified breast cancers had low-dose MDCT breast imaging in the prone position for tumor staging before treatment between May 2006 and June 2010. We designed an additional computed tomography table pad with a hole for prone positioning. Patients lay prone on the table pad and the breasts were positioned within the rectangular hole. We obtained dynamic breast imaging from the lower neck to the lung base with the following parameters: 120 kVp, 50 mAs, and 3-mm reconstruction intervals. We evaluated the extent of the primary tumor, lymph nodal status, and distant metastasis in lung or bone, then assessed tumor staging based on the TNM classification of breast cancer. The assessed staging compared to the pathologic results for diagnostic accuracy. Results: Among the 334 invasive breast cancers, the overall diagnostic accuracy of tumor staging was 88.3% and the accuracy values of each tumor stage were 89.6% in T1, 90.8% in T2, 81.0% in T3, and 89.3% in T4. The overall diagnostic accuracy of lymph nodal staging was 86.3% and the accuracy values in each nodal stage were 82.9% in N0, 88.0% in N1, 89.7% in N2, and 93.3% in N3. Based on breast computed tomography scans, we detected distant metastases in 30 cases (7 lungs, 10 bones, 7 lungs and bones, and 6 livers). Conclusion: Lowdose MDCT scanning for invasive breast cancer patients in the prone position is a feasible imaging technique for tumor staging before treatment to evaluate primary breast tumors, lymph nodes, lungs, or thoracic bones with reduced radiation doses.
The Computational and Neural Basis of Rhythmic Timing in Medial Premotor Cortex

The neural underpinnings of rhythmic behavior, including music and dance, have been studied using the synchronization-continuation task (SCT), where subjects initially tap in synchrony with an isochronous metronome and then keep tapping at a similar rate via an internal beat mechanism. Here, we provide behavioral and neural evidence that supports a resetting drift-diffusion model (DDM) during SCT. Behaviorally, we show the model replicates the linear relation between the mean and standard-deviation of the intervals produced by monkeys in SCT. We then show that neural populations in the medial premotor cortex (MPC) contain an accurate trial-by-trial representation of elapsed-time between taps. Interestingly, the autocorrelation structure of the elapsed-time representation is consistent with a DDM. These results indicate that MPC has an orderly representation of time with features characteristic of concatenated DDMs and that this population signal can be used to orchestrate the rhythmic structure of the internally timed elements of SCT. SIGNIFICANCE STATEMENT The present study used behavioral data, ensemble recordings from medial premotor cortex (MPC) in macaque monkeys, and computational modeling, to establish evidence in favor of a class of drift-diffusion models of rhythmic timing during a synchronization-continuation tapping task (SCT). The linear relation between the mean and standard-deviation of the intervals produced by monkeys in SCT is replicated by the model. Populations of MPC cells faithfully represent the elapsed time between taps, and there is significant trial-by-trial relation between decoded times and the timing behavior of the monkeys. Notably, the neural decoding properties, including its autocorrelation structure are consistent with a set of drift-diffusion models that are arranged sequentially and that are resetting in each SCT tap.
mGluR1 and mGluR5 Synergistically Control Cholinergic Synaptic Transmission in the Thalamic Reticular Nucleus

Acetylcholine (ACh) signaling is involved in a wide range of processes, including arousal, attention, and learning. An increasing number of studies indicate that cholinergic control of these functions is highly deterministic, mediated by synaptic afferents that generate reliable and precise responses in postsynaptic neurons. However, mechanisms that govern plastic changes of cholinergic synaptic strength are poorly understood, even though they are likely critical in shaping the impact of cholinergic inputs on neuronal networks. We have recently shown that in the thalamic reticular nucleus (TRN), synaptic release of ACh generates excitatory–inhibitory biphasic postsynaptic responses, mediated by the activation of α4β2 nicotinic (nAChRs) and M2 muscarinic receptors (mAChRs), respectively. Here, using voltage-clamp recordings from TRN neurons in thalamocortical slices of mice, we demonstrate that the activation of Group I metabotropic glutamate receptors (mGluRs) by ambient or synaptically released glutamate evokes transient increases of nicotinic EPSCs. Additionally, we find that the selective Group I mGluR agonist DHPG [(S)-3,5-dihydroxyphenylglycine] evokes long-term potentiation of nicotinic EPSCs (mGluR-nLTP), dependent on increases in postsynaptic Ca2+ concentration and the activation of phospholipase C. Both the induction and the maintenance of mGluR-nLTP require synergistic activation of mGluR1 and mGluR5. Together, our results show that postsynaptic Group I mGluRs are critically involved in the regulation of cholinergic synaptic strength on different time scales, suggesting that cholinergic control of local thalamic circuits is highly context-dependent and regulated by the overall levels of glutamatergic afferent activity. SIGNIFICANCE STATEMENT Cholinergic signaling controls information processing and plasticity in neuronal circuits, but the mechanisms underlying the regulation of cholinergic synaptic strength on different time scales are unknown. Here we identify mGluR1 and mGluR5 as key elements in the dynamic regulation of cholinergic synaptic inputs onto neurons of the TRN. Our findings highlight potential mechanisms that regulate cholinergic signaling in the mammalian brain.
Homologous recombination-based adenovirus vector system for tumor cell-specific gene delivery

Cancer gene therapy requires tumor-specific delivery and expression of a transgene to maximize antitumor efficacy and minimize side effects. In this study, we developed a new tumor-targeting, homologous recombination-based adenovirus vector system, HRAVS. HRAVS is composed of two adenovirus vectors, Ad.CMV. IR containing reverse sequence (IR) and a CMV promoter and Ad.IR. EGFP comprising the report gene EGFP and IR. For improved viral DNA replication and transgene expression, the E1a gene was added to HRAVS to generate the enhanced HRAVS, EHRAVS, which consists of Ad.CMV. IR and Ad.IR. EGFP/E1a. The optimal vector composition ratio of Ad.CMV. IR to Ad.IR. EGFP or Ad.IR. EGFP/E1a was identified as 30:70 based on EGFP expression efficiency in tumor cells. The transgene expression of HRAVS and EHRAVS was efficiently and specifically activated in tumor cells only and not in normal cells. Moreover, compared with HRAVS, EHRAVS infection led to higher virus yields and transgene expression and higher toxicity to tumor cells, and these results could be related to the involvement of E1a genes. The results in present study suggest the need for in vivo antitumor study using these new dual-Ad vector systems based on the homologous recombination.
Diagnostic and prognostic value of plasma microRNA deregulation in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is uncommon worldwide but often highly invasive in late stages. Due to its special location and lack of specific symptoms, NPC is hardly detected in regular medical examination at the beginning. Development of sensitive and specific biomarkers should help to save lives against this type of disease. In the present report, we investigated the value of plasma miRNAs for diagnosis and prognosis of NPC. Using candidate approach, we selected 21 miRNAs from literature to compare their expression levels in the plasma of NPC patients and controls. As a result, 5 miRNAs showed diagnostic potentials (P < 0.01). Among them, miR-16, -21, -24, and -155 had increased levels in NPC patients, whereas the level of miR-378 was decreased. There was a negative correlation between plasma miRNA expression and cancer progression, where miR-21 was statistically significant in T and N staging and miR-16 and 24 were significant in N staging only. Combination of miR-16, -21, -24, -155, and -378 gives 87.7% of sensitivity and 82.0% of specificity for NPC diagnosis. Without miR-16, combination of the rest 4 miRNAs gives the same sensitivity but a slightly reduced specificity. After treatment, all 5 miRNAs were somewhat back to normal levels in patients without cancer recurrence but the prognostic value was not statistically significant. In conclusion, plasma miRNA expression is a useful biomarker for NPC diagnosis but not for its prognosis. More importantly, it is simple, effective, and non-invasive. Combination of several plasma miRNAs can increase both NPC diagnostic sensitivity and specificity.