Miracle-dz/UniFAR-FTUs huggingface dataset:
Combination Immunotherapy: Taking Cancer Vaccines to the Next Level

With the advent of checkpoint blockade therapies, immunotherapy is now a critical modality for the treatment of some cancers. While some patients respond well to checkpoint blockade, many do not, necessitating the need for other forms of therapy. Vaccination against malignancy has been a long sought goal of science. For cancers holding a microbial etiology, vaccination has been highly effective in reducing the incidence of disease. However, vaccination against established malignancy has been largely disappointing. In this review, we discuss efforts to develop diverse vaccine modalities in the treatment of cancer with a particular focus on melanoma. Recent work has suggested that vaccines targeting patient-specific tumor mutations may be more relevant than those targeting unmutated proteins. Nonetheless, tumor cells utilize many strategies to evade host immunity. It is likely that the full potential of cancer vaccination will only be realized when vaccines are combined with other therapies targeting tumor immunoevasive mechanisms. By modulating inhibitory molecules, regulatory immune cells, and the metabolic resources and demands of T cells, scientists and clinicians can ensure vaccine-stimulated T cells are fully functional within the immunosuppressive tumor microevironment.
Fecal Shedding of Campylobacter andArcobacter spp. in Dairy Cattle

ABSTRACT Campylobacter jejuni, Campylobacter coli, and Arcobacter spp. were detected in feces of healthy dairy cows by highly specific multiplex-PCR assays. For C. jejuni, at this one-time sampling, cows from 80.6% of farm operations (n = 31) and 37.7% of individual dairy cattle fecal samples (n = 2,085) were positive. Farm management factors were correlated with prevalence in herds in which >25% of cows were positive for C. jejuni. Statistical significance was set at a P of 0.20. Using these criteria, application of manure with broadcast spreaders (P = 0.17), feeding of whole cottonseed or hulls (P = 0.17) or alfalfa (P = 0.15), and accessibility of feed to birds (P = 0.17) were identified as possible risk factors for C. jejuni infection. C. coli was detected in at least one animal in 19.4% of operations and 1.8% of individual cows (n = 2,085). At the herd level, use of broadcaster spreaders was not a risk factor for C. coliinfection. For Arcobacter, cows from 71% of dairy operations (n = 31) and 14.3% of individual dairy cattle fecal samples (n = 1,682) were positive. At the herd level, for Arcobacter spp. , feeding of alfalfa (P = 0.11) and use of individual waterers (P = 0.19) were protective. This is the first description of Arcobacter spp. in clinically healthy dairy cattle and the first attempt to correlate their presence with C. jejuni.
Increasing the Antimicrobial Activity of Nisin-Based Lantibiotics against Gram-Negative Pathogens

ABSTRACT Lantibiotics are ribosomally synthesized and posttranslationally modified antimicrobial compounds containing lanthionine and methyl-lanthionine residues. Nisin, one of the most extensively studied and used lantibiotics, has been shown to display very potent activity against Gram-positive bacteria, and stable resistance is rarely observed. By binding to lipid II and forming pores in the membrane, nisin can cause the efflux of cellular constituents and inhibit cell wall biosynthesis. However, the activity of nisin against Gram-negative bacteria is much lower than that against Gram-positive bacteria, mainly because lipid II is located at the inner membrane, and the rather impermeable outer membrane in Gram-negative bacteria prevents nisin from reaching lipid II. Thus, if the outer membrane-traversing efficiency of nisin could be increased, the activity against Gram-negative bacteria could, in principle, be enhanced. In this work, several relatively short peptides with activity against Gram-negative bacteria were selected from literature data to be fused as tails to the C terminus of either full or truncated nisin species. Among these, we found that one of three tails (tail 2 [T2; DKYLPRPRPV], T6 [NGVQPKY], and T8 [KIAKVALKAL]) attached to a part of nisin displayed improved activity against Gram-negative microorganisms. Next, we rationally designed and reengineered the most promising fusion peptides. Several mutants whose activity significantly outperformed that of nisin against Gram-negative pathogens were obtained. The activity of the tail 16 mutant 2 (T16m2) construct against several important Gram-negative pathogens (i.e., Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter aerogenes) was increased 4- to 12-fold compared to that of nisin. This study indicates that the rational design of nisin can selectively and significantly improve its outer membrane-permeating capacity as well as its activity against Gram-negative pathogens. IMPORTANCE Lantibiotics are antimicrobial peptides that are highly active against Gram-positive bacteria but that have relatively poor activity against most Gram-negative bacteria. Here, we modified the model lantibiotic nisin by fusing parts of it to antimicrobial peptides with known activity against Gram-negative bacteria. The appropriate selection of peptidic moieties that could be attached to (parts of) nisin could lead to a significant increase in its inhibitory activity against Gram-negative bacteria. Using this strategy, hybrids that outperformed nisin by displaying 4- to 12-fold higher levels of activity against relevant Gram-negative bacterial species were produced. This study shows the power of modified peptide engineering to alter target specificity in a desired direction.
Subclinical Enteric Parasitic Infections and Growth Faltering in Infants in São Tomé, Africa: A Birth Cohort Study

The associations between enteric pathogenic parasites and growth in infants in São Tomé were explored using a refined anthropometric approach to recognize early growth faltering. A birth cohort study was conducted with follow-up to 24 months of age. Microscopic examination for protozoa and soil-transmitted helminths was performed. Anthropometric assessments included: z-scores for weight-for-length (WLZ), length-for-age (LAZ), weight (WAVZ) and length velocities (LAVZ), length-for-age difference (LAD), and wasting and stunting risk (≤−1 SD). Generalized additive mixed effects regression models were used to explore the associations between anthropometric parameters and enteric parasitic infections and cofactors. A total of 475 infants were enrolled, and 282 completed the study. The great majority of infants were asymptomatic. Giardia lamblia was detected in 35.1% of infants in at least one stool sample, helminths in 30.4%, and Cryptosporidium spp. in 14.7%. Giardia lamblia and helminth infections were significantly associated with mean decreases of 0.10 in LAZ and 0.32 in LAD, and of 0.16 in LAZ and 0.48 in LAD, respectively. Cryptosporidium spp. infection was significantly associated with a mean decrease of 0.43 in WAVZ and 0.55 in LAVZ. The underestimated association between subclinical parasitic enteric infections and mild growth faltering in infants should be addressed in public health policies.
Ensemble-based Author Identification Using Character N-grams

This paper deal s with the problem of identifying the most likely author of a text. Several thousands of character n-grams, rather than lexical or syntactic information, are used to repr esent the style of a text. Thus, the author i dentification task can be viewed as a single-l abel multiclass classifi cation problem of high dimensional feature space and sparse data. In order to cope with such propert ies, we propose a suitable learning ensemble based on featur e set subspacing. Perf ormance results on two well-tested benchmark text corpora for author identifi cation show that this classification scheme is quite effective, signif icantly improving the best r eported results so far. Additionally , this approach is proved to be quite stable in comparison with suppor t vector machines when using limited number of training texts, a condition usually met in this kind of problem.
Aberrant methylation‐mediated downregulation of long noncoding RNA C5orf66‐AS1 promotes the development of gastric cardia adenocarcinoma

As a long non‐coding RNA, C5orf66‐AS1 is located at 5q31.1. Downregulation and aberrant hypermethylation of C5orf66‐AS1 have been detected in a limited several tumors. However, the biological role and distribution of methylated CpG sites of C5orf66‐AS1 in gastric cardia adenocarcinoma (GCA) development and prognosis are poorly clarified. The present study was to investigate the expression status and function of C5orf66‐AS1 in GCA, and to detect the distribution of methylated CpG sites within the three CpG islands of the promoter and gene body of C5orf66‐AS1, further to clarify its prognostic value in GCA patients. C5orf66‐AS1 was significantly downregulated in GCA tissues and cell lines, and the expression level was associated with TNM stage, pathological differentiation, lymph node metastasis, and distant metastasis or recurrence. The expression level of C5orf66‐AS1 was significantly increased in cancer cells after treated with 5‐Aza‐dC. Further methylation analysis demonstrated that the aberrant hypermethylation of the regions around the transcription start site of C5orf66‐AS1 was more tumor specific and was associated with its expression. Moreover, Sp1 may upregulate C5orf66‐AS1 expression and CpG sites hypermethylation within the binding sites may abrogate Sp1 binding. In addition, C5orf66‐AS1 inhibited gastric cancer cell proliferation and invasion, and the dysregulation and hypermethylation of the regions around the transcription start site of C5orf66‐AS1 were associated with poorer GCA patients’ survival. These findings suggest that aberrant hypermethylation‐mediated downregulation of C5orf66‐AS1 may play important roles in GCA tumorigenesis and C5orf66‐AS1 may serve as a potential prognostic marker in predicting GCA patients’ survival.
AN OSSEOUS STUDY OF MORPHOLOGICAL ASPECT OF ACETABULUM OF HIP BONE

BACKGROUND: The geometric discrepancies between the natural acetabulum and implant can result in painful iliopsoas impingement attributable to prosthetic overlap at the anterior acetabular ridge 1 . Largest hip failure occurs from prosthetic loosening may be because of weak interface originally 2 . Precise knowledge of acetabulum is required to understand mechanics of joint and planning for suitable prosthesis. The present study was taken to find the morphological variations of acetabulum. MATERIALS AND METHODS: All available 152 dry hip bone (74 belonged to right side and 78 to left side) of unknown age and sex were examined from the collection of the Anatomy department. Morphological variation of the shapes of anterior acetabular ridge was noted and transverse diameter and depth of acetabulum of hip bones were measured with the help of vernier callipers. RESULTS: Curved shaped anterior rim of acetabulum was found in 57 (37.5%) followed by straight shaped in 48(31.6%), irregular shaped in 28(18.4%) and angular shaped in 19(12.5%) specimens. Average maximum transverse diameter of acetabulum was measured 4.79 cm on right side and 4.83 cm on left side. Average depth of acetabulum was measured 2.71 cm on right side and 2.65 cm on left side. CONCLUSION: The present study will be helpful to orthopaedicians, radiologists and prosthetists for better understanding of pathophysiology of hip region and to design suitable size of prosthetics which are more functional to prevent common complications like dislocations and iliopsoas impingement.
Phosphorylation of a Central Clock Transcription Factor Is Required for Thermal but Not Photic Entrainment

Transcriptional/translational feedback loops drive daily cycles of expression in clock genes and clock-controlled genes, which ultimately underlie many of the overt circadian rhythms manifested by organisms. Moreover, phosphorylation of clock proteins plays crucial roles in the temporal regulation of clock protein activity, stability and subcellular localization. dCLOCK (dCLK), the master transcription factor driving cyclical gene expression and the rate-limiting component in the Drosophila circadian clock, undergoes daily changes in phosphorylation. However, the physiological role of dCLK phosphorylation is not clear. Using a Drosophila tissue culture system, we identified multiple phosphorylation sites on dCLK. Expression of a mutated version of dCLK where all the mapped phospho-sites were switched to alanine (dCLK-15A) rescues the arrythmicity of Clk out flies, yet with an approximately 1.5 hr shorter period. The dCLK-15A protein attains substantially higher levels in flies compared to the control situation, and also appears to have enhanced transcriptional activity, consistent with the observed higher peak values and amplitudes in the mRNA rhythms of several core clock genes. Surprisingly, the clock-controlled daily activity rhythm in dCLK-15A expressing flies does not synchronize properly to daily temperature cycles, although there is no defect in aligning to light/dark cycles. Our findings suggest a novel role for clock protein phosphorylation in governing the relative strengths of entraining modalities by adjusting the dynamics of circadian gene expression.
The Neural Basis of Maternal Bonding

Background Accumulating evidence suggests that mothers show a different pattern of brain responses when viewing their own compared to other infants. However, there is inconsistency across functional imaging studies regarding the key areas involved, and none have examined relationships between brain and behavioural responses to infants. We examined the brain regions activated when mothers viewed videos of their own infant contrasted with an unknown infant, and whether these are associated with behavioural and self-reported measures of mother-infant relations. Method Twenty right-handed mothers viewed alternating 30-sec blocks of video of own 4–9 month infant and an unfamiliar matched infant, interspersed with neutral video. Whole brain functional magnetic resonance images (fMRI) were acquired on a 1.5T Philips Intera scanner using a TR of 2.55 s. Videotaped mother-infant interactions were systematically evaluated blind to family information to generate behavioural measures for correlational analysis. Results Enhanced blood oxygenation functional imaging responses were found in the own versus unknown infant contrast in the bilateral precuneus, right superior temporal gyrus, right medial and left middle frontal gyri and left amygdala. Positive mother-infant interaction (less directive parent behaviour; more positive/attentive infant behaviour) was significantly associated with greater activation in several regions on viewing own versus unknown infant, particularly the middle frontal gyrus. Mothers' perceived warmth of her infant was correlated with activations in the same contrast, particularly in sensory and visual areas. Conclusion This study partially replicates previous reports of the brain regions activated in mothers in response to the visual presentation of their own infant. It is the first to report associations between mothers' unique neural responses to viewing their own infant with the quality of her concurrent behaviour when interacting with her infant and with her perceptions of infant warmth. These findings provide support for developing fMRI as a potential biomarker of parenting risk and change.
Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding

The FHIT gene is inactivated early in the development of many human tumors, and Fhit-deficient mice have increased cancer incidence. Viral reexpression of Fhit kills Fhit-deficient cells by induction of apoptosis. Fhit, a member of branch 2 of the histidine-triad superfamily of nucleoside monophosphate hydrolases and transferases, is a diadenosine polyphosphate hydrolase, the active-site histidine of which is not required for tumor suppression. To provide a rigorous test of the hypothesis that Fhit function depends on forming a complex with substrates, we designed a series of alleles of Fhit intended to reduce substrate-binding and/or hydrolytic rates, characterized these mutants biochemically, and then performed quantitative cell-death assays on cancer cells virally infected with each allele. The allele series covered defects as great as 100,000-fold in kcat and increases as large as 30-fold in KM. Nonetheless, when mutant FHIT genes were expressed in two human cancer cell lines containing FHIT deletions, reductions in apoptotic activity correlated exclusively with KM. Mutants with 2- and 7-fold increases in KM significantly reduced apoptotic indices, whereas the mutant with a 30-fold increase in KM retained little cellular function. These data indicate that the proapoptotic function of Fhit is limited by substrate binding and is unrelated to substrate hydrolysis.
Latent Sensitization: A Model for Stress‐Sensitive Chronic Pain

Latent sensitization is a rodent model of chronic pain that reproduces both its episodic nature and its sensitivity to stress. It is triggered by a wide variety of injuries ranging from injection of inflammatory agents to nerve damage. It follows a characteristic time course in which a hyperalgesic phase is followed by a phase of remission. The hyperalgesic phase lasts between a few days to several months, depending on the triggering injury. Injection of μ‐opioid receptor inverse agonists (e.g., naloxone or naltrexone) during the remission phase induces reinstatement of hyperalgesia. This indicates that the remission phase does not represent a return to the normal state, but rather an altered state in which hyperalgesia is masked by constitutive activity of opioid receptors. Importantly, stress also triggers reinstatement. Here we describe in detail procedures for inducing and following latent sensitization in its different phases in rats and mice. © 2015 by John Wiley & Sons, Inc.
Feral Pig Populations Are Structured at Fine Spatial Scales in Tropical Queensland, Australia

Feral pigs occur throughout tropical far north Queensland, Australia and are a significant threat to biodiversity and World Heritage values, agriculture and are a vector of infectious diseases. One of the constraints on long-lasting, local eradication of feral pigs is the process of reinvasion into recently controlled areas. This study examined the population genetic structure of feral pigs in far north Queensland to identify the extent of movement and the scale at which demographically independent management units exist. Genetic analysis of 328 feral pigs from the Innisfail to Tully region of tropical Queensland was undertaken. Seven microsatellite loci were screened and Bayesian clustering methods used to infer population clusters. Sequence variation at the mitochondrial DNA control region was examined to identify pig breed. Significant population structure was identified in the study area at a scale of 25 to 35 km, corresponding to three demographically independent management units (MUs). Distinct natural or anthropogenic barriers were not found, but environmental features such as topography and land use appear to influence patterns of gene flow. Despite the strong, overall pattern of structure, some feral pigs clearly exhibited ancestry from a MU outside of that from which they were sampled indicating isolated long distance dispersal or translocation events. Furthermore, our results suggest that gene flow is restricted among pigs of domestic Asian and European origin and non-random mating influences management unit boundaries. We conclude that the three MUs identified in this study should be considered as operational units for feral pig control in far north Queensland. Within a MU, coordinated and simultaneous control is required across farms, rainforest areas and National Park Estates to prevent recolonisation from adjacent localities.
Criminal thinking shifts among male prisoners participating in a cognitive‐based education programme

BACKGROUND Many prisoners rationalise criminal behaviour, and this type of thinking has been linked to recidivism. Correctional programmes for modifying criminal thinking can reshape how offenders view themselves and their circumstances. AIM Our aim was to test whether participation in a cognitive-based curriculum called Steps to Economic and Personal Success (STEPS) was associated with changes in criminal thinking. METHODS The STEPS curriculum is delivered in 15 video-based facilitated classes. A pre-intervention/post-intervention survey design was applied to 128 adult male prisoners who completed the programme. Criminal thinking was measured by the Texas Christian University Criminal Thinking Scale, a self-report instrument with the six domains: entitlement, justification, power orientation, cold heartedness, criminal rationalisation and personal irresponsibility. RESULTS Participants had lower scores in most of the criminal thinking domains after the intervention than before, with largest reductions in justification and power orientation. CONCLUSION Findings provide evidence that attitudes to crime can be changed in a correctional setting, and the programme under study shows promise as an effective intervention for changing these attitudes among prisoners. Future research should build on these findings to examine whether and how such changes are related to desistance from offending behaviours. Copyright © 2017 John Wiley & Sons, Ltd.
Does Emotion Directly Tune the Scope of Attention?

Considerable research supports a fixed link between affect and attentional scope, with positive affect producing a focus on the forest, so to speak, and negative affect producing a focus on the trees. New research, however, reveals greater flexibility in this link than is commonly assumed. Research consistent with the idea that affective feelings merely influence whether people act on briefly dominant tendencies to focus broadly or narrowly is presented. Implications of these new findings for research on affect and attention are discussed.
Evolution of management of anorectal malformation through the ages

Introduction: Anorectal malformations comprise a wide spectrum of diseases, which can affect boys and girls, and involve the distal anus and rectum as well as the urinary and genital tracts. They occur in approximately 1 in 3500 to 5000 live births. Since the early era of its management, its treatment has gone through an enormous phase of evolution leading from gloomy outcome in the past to nearly 100% survival in the modern era. Material and Methods: The literature on anorectal malformation was extensively reviewed for exploring the evolution of surgery for anorectal malformations. The management of anorectal malformation for the last 20 years at our center is presented. The results of the traditional staged repair compared to single-stage repair are discussed. Result: The surgical approach to repairing these defects changed dramatically in 1980 from sacroperineal to posterior sagittal anorectoplasty. Now it is time to shift toward single-stage repair whenever possible which has equivalent or better results yet less morbidity than the staged repair.