Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of MCM2 enhances the sensitivity of ovarian cancer cell to carboplatin

Chemotherapy is widely used for the treatment of ovarian cancer. Since chemotherapy resistance is the major cause of poor prognosis in patients with ovarian cancer, it is important to identify new methods to improve the efficacy of chemotherapy. Minichromosome maintenance complex component 2 (MCM2), which serves an essential role in DNA replication, has been recently identified as a novel proliferation marker with prognostic implications in multiple types of cancer. However, the role of MCM2 in ovarian cancer and its underlying molecular mechanisms remain unclear. Therefore, in the present study, the biological effects of MCM2 were investigated, particularly with respect to DNA damage and repair. In the present study, short hairpin RNA was employed to knockdown MCM2 expression in the A2780 ovarian cancer cell line. The sensitivity of A2780 cells to carboplatin was assessed by cell colony formation assay. The present results suggested that MCM2 knockdown inhibited the proliferation of tumor cells, induced G0/G1 phase arrest and did not exhibit effects on cell apoptosis. However, MCM2 knockdown significantly decreased the colony formation of A2780 cells treated with carboplatin. Furthermore, knockdown of MCM2 together with carboplatin treatment or UV irradiation increased the protein expression level of γ-H2A histone family member X and p53 compared with control cells. The present data suggested that the increased sensitivity to carboplatin may occur via the p53-dependent apoptotic response. Additionally, the present results suggested that knockdown of MCM2 may have therapeutic applications in enhancing the efficacy of carboplatin in patients with ovarian cancer.
The effect of smell and taste of milk during tube feeding of preterm infants (the Taste trial): a protocol for a randomised controlled trial

Introduction Smell and taste of milk are not generally considered when tube feeding preterm infants. Preterm infants have rapid growth, particularly of the brain, and high caloric needs. Enteral feeding is often poorly tolerated which may lead to growth failure and long-term neurodevelopmental impairment. Smell and taste are strong stimulators of digestion and metabolism. We hypothesise that regular smell and taste during tube feeding will improve weight z-scores of very preterm infants at discharge from hospital. Methods and analysis Taste is a randomised, unblinded two-centre trial. Infants born at <29 weeks’ gestation and/or <1250 g at birth and admitted to a participating neonatal intensive care unit are eligible. Randomisation occurs before infants receive two hourly feeds for 24 hours. Infants are randomised to either smell and taste of milk with each tube feed or tube feeding without the provision of smell and taste. The primary outcome is weight z-score at discharge. Secondary outcomes include: days to full enteral feeds, duration of parenteral nutrition, rate of late-onset sepsis, post menstrual age at removal of nasogastric tube and at discharge from hospital, anthropometric data and neurodevelopmental outcomes at 2 years of corrected age. Ethics and dissemination Human Research Ethics Committees of Mater Misericordiae (trial reference number: HREC/16/MHS/112) and the Royal Women’s Hospital (trial reference number: 17/21) last approved the trial protocol (version 4.2; Date: 18 December 2018) and recruitment commenced in May 2017 and November 2017, respectively. The trial results will be published in a peer-reviewed journal and will be presented at national and international conferences. Trial registration number ACTRN12617000583347.
Neurocritical care of high‐risk infants during inter‐hospital transport

The centralisation of neonatal intensive care in recent years has improved mortality, particularly of extremely preterm infants, but similar improvements in morbidity, such as neurodevelopmental impairment, have not been seen. Integral to the success of centralisation are specialised neonatal transport teams who provide intensive care prior to and during retrieval of high‐risk neonates when in‐utero transfer has not been possible. Neonatal retrieval aims to stabilise the clinical condition and then transfer the neonate during a high‐risk period for patient. Transport introduces the hazards of noise and vibration; acceleration and deceleration forces; additional handling and temperature fluctuations. The transport team must stabilise the infant fully prior to transport as when on the move they are limited by space and movement to effectively attend to clinical deterioration. Inborn infants have better neurodevelopmental outcome compared with the outborn and aetiology of this seems to be multifactorial with the impact of transport itself during critical illness, remaining unclear. To improve the neurological outcomes for transported infants, it seems imperative to integrate the advancing intensive care neuromonitoring tools into the transport milieu. This review examines current inter‐hospital transport neuromonitoring and how new modalities might be applied to the neurocritical care delivered by specialist transport teams.
Chronic Cannabis Use and Circulating Bio‐Markers of Neural Health, Stress, and Inflammation in Physically Active Individuals

The purpose of this cross‐sectional study is to compare measures of general health, circulating concentrations of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), c‐reactive protein (CRP), interleukin‐6 (IL‐6) and cortisol in physically active cannabis users (CU) and physically active non‐cannabis users (NU).
Complete Surgical Resection Following Neoadjuvant Dabrafenib Plus Trametinib in BRAFV600E-Mutated Anaplastic Thyroid Carcinoma

Background: When achieved, complete surgical resection improves outcomes in anaplastic thyroid carcinoma (ATC). However, most ATC patients present with advanced inoperable disease, often with impending airway obstruction, increased hemorrhage risk, and significant dysphagia. Novel treatment strategies are critically needed to improve disease control and decrease locoregional morbidity. The objective of this study was to determine the feasibility and effectiveness of a neoadjuvant regimen by using dabrafenib with trametinib followed by surgical resection in patients with initially unresectable BRAFV600E-mutated ATC. Methods: Case series of six consecutive patients with BRAFV600E-mutated ATC diagnosed between January 2017 and February 2018. Pathologic confirmation of ATC was obtained before treatment. BRAFV600E status was ascertained via immunohistochemistry or sequencing of circulating tumor DNA. All patients received dabrafenib and trametinib (DT) followed by surgical resection and adjuvant chemoradiation. Three patients also received pembrolizumab. Results: Complete surgical resection was achieved in all patients. Histopathologic analyses of resected specimens showed high pathologic response rates with significantly decreased ATC viability and residual papillary thyroid carcinoma components. Overall survival at six months and one year was 100% and 83%, respectively. Locoregional control rate was 100%. Two patients died of distant metastases without evidence of locoregional disease at 8 and 14 months from diagnosis. The remaining four patients had no evidence of disease at the last follow-up. Conclusions: We report the first series in the literature of BRAFV600E-mutated ATC patients with locoregionally advanced disease treated with DT followed by surgical resection. We demonstrated feasibility of complete resection, decreased need for tracheostomy, high pathologic response rates, and durable locoregional control with symptom amelioration.
Hippocampal neuron loss and astrogliosis in medial temporal lobe epileptic patients with mental disorders.

Hippocampal neuron loss and reactive astrogliosis are pathological features of medial temporal lobe epilepsy. Here, the expression of hippocampal astrogliosisassociated genes are studied in subjects with medial temporal lobe epilepsy and mental disorders (such as depression, anxiety and psychiatric comorbidities). The relationship between functional changes in hippocampus astrocytes and concurrent mental disorders are discussed. Nissl staining identified medial temporal lobe epilepsyinduced neuronal loss in the CA1 region of hippocampus. Quantitative real-time polymerase chain reaction and immunofluorescence technology were used to detect hippocampus glial fibrillary acidic protein, metallothionein, and aquaporin-4. The hippocampus area of subjects with medial temporal lobe epilepsy (with or without mental disorders) were smaller than the control group. Hippocampal neuronal loss and astrogliosis were more obvious in groups of medial temporal lobe epileptic patients with mental disorders. Relative protein levels of glial fibrillary acidic protei, metallothionein-I/II, and aquaporin-4 were significantly higher in subjects with medial temporal lobe epilepsy than seen in controls. Medial temporal lobe epileptic patients with mental disorder or depression had elevated metallothionein-I/II protein level when compared to controls and medial temporal lobe epileptic patients without mental disorder. Protein levels of glial fibrillary acidic protein and aquaporin-4 in medial temporal lobe epileptic patients with mental disorders were significantly lower than that in medial temporal lobe epileptic patients with no mental disorder. It is concluded that functional changes in hippocampus astrocytes are associated with mental disorders in medial temporal lobe epileptic patients and the astrogliosis-related genes of glial fibrillary acidic protein, metallothionein-I/II and aquaporin-4, are involved in this process.
Wild Rats, Laboratory Rats, Pet Rats: Global Seoul Hantavirus Disease Revisited

Recent reports from Europe and the USA described Seoul orthohantavirus infection in pet rats and their breeders/owners, suggesting the potential emergence of a “new” public health problem. Wild and laboratory rat-induced Seoul infections have, however, been described since the early eighties, due to the omnipresence of the rodent reservoir, the brown rat Rattus norvegicus. Recent studies showed no fundamental differences between the pathogenicity and phylogeny of pet rat-induced Seoul orthohantaviruses and their formerly described wild or laboratory rat counterparts. The paucity of diagnosed Seoul virus-induced disease in the West is in striking contrast to the thousands of cases recorded since the 1980s in the Far East, particularly in China. This review of four continents (Asia, Europe, America, and Africa) puts this “emerging infection” into a historical perspective, concluding there is an urgent need for greater medical awareness of Seoul virus-induced human pathology in many parts of the world. Given the mostly milder and atypical clinical presentation, sometimes even with preserved normal kidney function, the importance of simple but repeated urine examination is stressed, since initial but transient proteinuria and microhematuria are rarely lacking.
High thermoelectric cooling performance of n-type Mg3Bi2-based materials

Thrifty thermoelectric cooling Currently available thermoelectric devices for cooling rely on expensive bismuth telluride. Mao et al. systematically developed a far less expensive n-type magnesium-bismuth–based material with good thermoelectric properties. They built a device that could generate a temperature difference of up to 90 kelvin when coupled with a commercially available p-type material. Such materials should provide an excellent basis for cost-effective thermoelectric cooling technology. Science, this issue p. 495 An optimized magnesium bismuth material has good thermoelectric properties useful for cooling devices. Thermoelectric materials have a large Peltier effect, making them attractive for solid-state cooling applications. Bismuth telluride (Bi2Te3)–based alloys have remained the state-of-the-art room-temperature materials for many decades. However, cost partially limited wider use of thermoelectric cooling devices because of the large amounts of expensive tellurium required. We report n-type magnesium bismuthide (Mg3Bi2)–based materials with a peak figure of merit (ZT) of ~0.9 at 350 kelvin, which is comparable to the commercial bismuth telluride selenide (Bi2Te3–xSex) but much cheaper. A cooling device made of our material and p-type bismuth antimony telluride (Bi0.5Sb1.5Te3) has produced a large temperature difference of ~91 kelvin at the hot-side temperature of 350 kelvin. n-type Mg3Bi2-based materials are promising for thermoelectric cooling applications.
Tetrahydrocannabinol (THC) Detection using Semiconductor-enriched Single-Walled Carbon Nanotube Chemiresistors.

Semiconductor-enriched single-walled carbon nanotubes (s-SWCNT) have potential for application as chemiresistor for the detection of breath compounds including tetrahydrocannabinol (THC), the main psychoactive compound found in the marijuana plant. Herein we show that chemiresistor devices fabricated from s-SWCNT ink using dielectrophoresis can be incorporated into a hand-held breathalyzer with sensitivity toward THC generated from a bubbler containing analytical standard in ethanol and a heated sample evaporator that releases compounds from steel wool. The steel wool was used to capture THC from exhaled marijuana smoke. The generation of the THC from the bubbler and heated breath sample chamber was confirmed using UV-Vis absorption spectroscopy and mass spectrometry, respectively. Enhanced selectivity toward THC over more volatile breath components such as CO2, water, ethanol, methanol, and acetone was achieved by delaying the sensor reading to allow for the desorption of these compounds from the chemiresistor surface. Additionally, machine learning algorithms were utilized to improve the selective detection of THC with better accuracy at increasing quantities of THC delivered to the chemiresistor.
Participation in daily life for adults with profound intellectual (and multiple) disabilities: How high do they climb on Shier’s ladder of participation?

Participation is the goal of Swedish disability policy, but it is difficult to achieve for adults with profound intellectual (and multiple) disabilities (PI(M)D). Since these adults are dependent on others in every aspect of their lives, others control their ability to participate in everyday life decisions. This study used observations, analyzed with Shier’s ladder of participation, to elucidate and describe participation in daily life for adults with PI(M)D living in a group home. The results showed that the adults often reached the first three levels of Shier’s ladder, one adult reached the fourth level once, and no one reached the fifth level. Participation on a higher level, therefore, seems hard to reach for adults. Staff members’ attitudes toward the adults’ capability can also be a barrier to participation. Applying Shier’s ladder of participation can provide valuable information that might lead to increased participation in daily life for adults with PI(M)D.
Shear Rheology of Unentangled and Marginally Entangled Ring Polymer Melts from Large-Scale Nonequilibrium Molecular Dynamics Simulations

We present results for the steady state shear rheology of non-concatenated, unentangled and marginally entangled ring poly(ethylene oxide) (PEO) melts from detailed, atomistic nonequilibrium molecular dynamics (NEMD) simulations, and compare them to the behavior of the corresponding linear melts. The applied flow field spans a wide range of shear rates, from the linear (Newtonian) to the highly non-linear (described by a power law) regime. For all melts studied, rings are found to exhibit shear thinning but to a lesser degree compared to linear counterparts, mostly due to their reduced deformability and stronger resistance to alignment in the direction of flow. These features are attributed to the more compact structure of ring molecules compared to linear chains; the latter are capable of adopting wider and more open conformations even under shear due to the freedom provided by the free ends. Similar to linear melts, rings also exhibit a first and a second normal stress coefficient; the latter is negative. The ratio of the magnitude of the two coefficients remains practically constant with shear rate and is systematically higher than the corresponding one for linear melts. Emphasis was also given to the statistics of terminal (re-orientational) relaxation times which we computed by analyzing all chains in the simulated systems one by one; it was demonstrated that long time dynamics are strongly heterogeneous both for rings and (especially) linears. Repeating the analysis under flow conditions, and as expected, we found that the applied flow field significantly suppresses dynamic heterogeneity, especially for high shear rates well beyond the Newtonian plateau. Finally, a detailed geometrical analysis revealed that the average population of ring–ring threading events in the longest melt studied here (the PEO-5k ring) remains practically unaffected by the imposed flow rate even at strong shear rates, except for multi-threadings which disappear. To further analyze this peculiar and rather unexpected effect, we computed the corresponding survival times and penetration lengths, and found that the overwhelming majority of threadings under shear are extremely weak constraints, as they are characterized by very small penetration lengths, thus also by short survival times. They are expected therefore to play only a minor (if any) role on chain dynamics.
Neuroinflammation and Functional Connectivity in Alzheimer's Disease: Interactive Influences on Cognitive Performance

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease (AD). We tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [11C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 patients (12 females/16 males) with clinical diagnosis of probable AD or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy controls (8 females/6 males). Source-based “inflammetry” was used to extract principal components of [11C]PK11195 PET signal variance across all participants. rs-fMRI data were preprocessed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal covariance between neuroinflammation and brain connectivity profiles, in relation to the diagnostic group (patients, controls) and cognitive status. Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, frontal, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits. Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer's disease. Neuroinflammation, and its association with functionally-relevant reorganization of brain networks, is proposed as a target for emerging immunotherapeutic strategies aimed at preventing or slowing the emergence of dementia. SIGNIFICANCE STATEMENT Neuroinflammation is an important aspect of Alzheimer's disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit. Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between neuro inflammation and functional network connectivity is relevant to cognitive impairment. We suggest that future studies should address how neuroinflammation relates to network function as AD progresses, and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.
Testicular toxicity of gentamicin in adult rats: Ameliorative effect of lycopene

The current study was aimed to investigate the ameliorative effect of lycopene against gentamicin-induced testicular toxicity in adult rat testes. Pretreatment with lycopene (4 mg/kg/day) significantly prevented the decrease in the absolute testes weight and relative testes weight and the reduction in sperm count, motility, viability, and daily sperm production in gentamicin (100 mg/kg/day)-treated rats. Gentamicin significantly decreased the level of serum testosterone and testicular lactate dehydrogenase-X and G6PDH activities but a marked increase was observed upon pretreatment with lycopene. Testicular caspase-3 and -9 activities were significantly increased but lycopene showed significant protection from gentamicin-induced apoptosis. Oxidative stress was induced by gentamicin treatment as evidenced by increased hydrogen peroxide level and lipid peroxidation and decreased the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities and glutathione content. These alterations were effectively prevented by lycopene pretreatment. Histopathological examination showed loss of spermatogenesis and morphological abnormalities of the testis after treatment with gentamycin. These abnormalities were effectively normalized by pretreatment with lycopene. In conclusion, gentamicin decreases rat testes weight and inhibits spermatogenesis. It induces oxidative stress and apoptosis by possible mitochondrial dysfunction. These data provide insight into the mode of action of gentamicin-induced testicular toxicity and the beneficial role provided by lycopene to restore the suppressed spermatogenesis.
Expansion of base excision repair compensates for a lack of DNA repair by oxidative dealkylation in budding yeast

The Mag1 and Tpa1 proteins from budding yeast (Saccharomyces cerevisiae) have both been reported to repair alkylation damage in DNA. Mag1 initiates the base excision repair pathway by removing alkylated bases from DNA, and Tpa1 has been proposed to directly repair alkylated bases as does the prototypical oxidative dealkylase AlkB from Escherichia coli. However, we found that in vivo repair of methyl methanesulfonate (MMS)-induced alkylation damage in DNA involves Mag1 but not Tpa1. We observed that yeast strains without tpa1 are no more sensitive to MMS than WT yeast, whereas mag1-deficient yeast are ∼500-fold more sensitive to MMS. We therefore investigated the substrate specificity of Mag1 and found that it excises alkylated bases that are known AlkB substrates. In contrast, purified recombinant Tpa1 did not repair these alkylated DNA substrates, but it did exhibit the prolyl hydroxylase activity that has also been ascribed to it. A comparison of several of the kinetic parameters of Mag1 and its E. coli homolog AlkA revealed that Mag1 catalyzes base excision from known AlkB substrates with greater efficiency than does AlkA, consistent with an expanded role of yeast Mag1 in repair of alkylation damage. Our results challenge the proposal that Tpa1 directly functions in DNA repair and suggest that Mag1-initiated base excision repair compensates for the absence of oxidative dealkylation of alkylated nucleobases in budding yeast. This expanded role of Mag1, as compared with alkylation repair glycosylases in other organisms, could explain the extreme sensitivity of Mag1-deficient S. cerevisiae toward alkylation damage.