Miracle-dz/UniFAR-FTUs huggingface dataset:
Entropic Fragment‐Based Approach to Aptamer Design

Aptamers are short RNA/DNA sequences that are identified through the process of systematic evolution of ligands by exponential enrichment and that bind to diverse biomolecular targets. Aptamers have strong and specific binding through molecular recognition and are promising tools in studying molecular biology. They are recognized as having potential therapeutic and diagnostic clinical applications. The success of the systematic evolution of ligands by exponential enrichment process requires that the RNA/DNA pools used in the process have a sufficient level of sequence diversity and structural complexity. While the systematic evolution of ligands by exponential enrichment technology is well developed, it remains a challenge in the efficient identification of correct aptamers. In this article, we propose a novel information‐driven approach to a theoretical design of aptamer templates based solely on the knowledge regarding the biomolecular target structures. We have investigated both theoretically and experimentally the applicability of the proposed approach by considering two specific targets: the serum protein thrombin and the cell membrane phospholipid phosphatidylserine. Both of these case studies support our method and indicate a promising advancement in theoretical aptamer design. In unfavorable cases where the designed sequences show weak binding affinity, these template sequences can be still modified to enhance their affinities without going through the systematic evolution of ligands by exponential enrichment process.
Large‐scale phenotyping links adult hippocampal neurogenesis to the reaction to novelty

The discovery of adult‐born neurons in the hippocampus has triggered a wide range of studies that link the new neurons to various behavioral functions. However, the role of new neurons in behavior is still equivocal. Conflicting results may be due to the difficulty in manipulating neurogenesis without off‐target effects as well as the statistical approach used, which fail to account for neurogenesis‐independent effects of experimental manipulations on behavior. In this study, we apply a more comprehensive statistical and conceptual approach. Instead of between‐group analyses, we consider the within‐group relationships between neurogenesis and behavior (ANCOVA and mediation analysis) in a large‐scale experiment, in which distinct age‐ (3 and 5 months) and strain‐ (DBA and C57) related differences in basal levels of neurogenesis in mice are compared with a large number (∼1,500) of behavioral read outs. The analysis failed to detect any association between anxiety and motor impulsivity with neurogenesis. However, within‐group adult hippocampal neurogenesis is associated with the reaction to novelty. Specifically, more neurogenesis is associated with a longer latency to explore and a lower frequency of exploratory actions, overall indicative of a phenotype where animals with more neurogenesis were slower to explore a novel environment. This effect is observed in 5‐months‐old, but not in 3‐months‐old mice of both strains. An association between the reaction to novelty and adult neurogenesis can have a major impact on results from previous studies using classical behavioral experiments, in which animals are tested in a—for the animal—novel experimental set‐up. The neurogenesis–novelty association found here is also a necessary link in the relation that has been suggested to exist between neurogenesis and psychiatric disorders marked by a failure to cope with novelty. © 2015 Wiley Periodicals, Inc.
Target‐selectivity of parvalbumin‐positive interneurons in layer II of medial entorhinal cortex in normal and epileptic animals

The medial entorhinal cortex layer II (MEClayerII) is a brain region critical for spatial navigation and memory, and it also demonstrates a number of changes in patients with, and animal models of, temporal lobe epilepsy (TLE). Prior studies of GABAergic microcircuitry in MEClayerII revealed that cholecystokinin‐containing basket cells (CCKBCs) select their targets on the basis of the long‐range projection pattern of the postsynaptic principal cell. Specifically, CCKBCs largely avoid reelin‐containing principal cells that form the perforant path to the ipsilateral dentate gyrus and preferentially innervate non‐perforant path forming calbindin‐containing principal cells. We investigated whether parvalbumin containing basket cells (PVBCs), the other major perisomatic targeting GABAergic cell population, demonstrate similar postsynaptic target selectivity as well. In addition, we tested the hypothesis that the functional or anatomic arrangement of circuit selectivity is disrupted in MEClayerII in chronic TLE, using the repeated low‐dose kainate model in rats. In control animals, we found that PVBCs innervated both principal cell populations, but also had significant selectivity for calbindin‐containing principal cells in MEClayerII. However, the magnitude of this preference was smaller than for CCKBCs. In addition, axonal tracing and paired recordings showed that individual PVBCs were capable of contacting both calbindin and reelin‐containing principal cells. In chronically epileptic animals, we found that the intrinsic properties of the two principal cell populations, the GABAergic perisomatic bouton numbers, and selectivity of the CCKBCs and PVBCs remained remarkably constant in MEClayerII. However, miniature IPSC frequency was decreased in epilepsy, and paired recordings revealed the presence of direct excitatory connections between principal cells in the MEClayerII in epilepsy, which is unusual in normal adult MEClayerII. Taken together, these findings advance our knowledge about the organization of perisomatic inhibition both in control and in epileptic animals. © 2015 Wiley Periodicals, Inc.
Theta burst stimulation‐induced LTP: Differences and similarities between the dorsal and ventral CA1 hippocampal synapses

The hippocampal synapses display a conspicuous ability for long‐term plasticity, which is thought to contribute to learning and memory. Previous research has shown that long‐term potentiation (LTP) greatly differs between the dorsal (DH) and ventral (VH) CA1 hippocampal synapses when induced by high‐frequency stimulation. In this study, using rat hippocampal slices and more physiologically relevant activity patterns based on the frequency of the theta rhythm (i.e., theta‐burst stimulation, TBS) we found that the DH compared with the VH displayed a higher ability for induction and stability of NMDA receptor‐dependent LTP of the field excitatory postsynaptic potential. Nevertheless, the maximal magnitude of LTP was similar in the two hippocampal segments. Blockade of GABAB receptors prevented the LTP induction by the minimal effective TBS and reduced the magnitude of LTP induced by longer TBS. TBS produced a three‐fold higher facilitation of the synaptic burst responses in the DH compared with the VH, accompanied by a strong enhancement in the postsynaptic excitation in the DH but mostly depression in the VH. The DH displayed NMDA receptor‐dependent and NMDA receptor‐independent facilitation, but the facilitation in the VH was only NMDA receptor‐dependent. Also, the TBS‐associated activity of GABAB receptors was higher in the DH than in the VH. The different response profiles during TBS could underlie the differences in LTP between the two hippocampal segments. L‐type voltage‐dependent calcium channels (L‐VDCC) and the metabotropic glutamate receptor‐5 (mGluR5) equally contributed in DH and VH to compound LTP induced by relatively long TBS. We propose that these dorsoventral differences in synaptic plasticity reflect specializations of the intrinsic circuitry of the hippocampus, that are involved in the distinct information processing performed by the two hippocampal segments and could effectively support the contribution of the dorsal and the ventral hippocampal segment to single event memory and to emotional memory respectively. © 2016 Wiley Periodicals, Inc.
Hippocampal‐cortical contributions to strategic exploration during perceptual discrimination

The hippocampus is crucial for long‐term memory; its involvement in short‐term or immediate expressions of memory is more controversial. Rodent hippocampus has been implicated in an expression of memory that occurs on‐line during exploration termed “vicarious trial‐and‐error” (VTE) behavior. VTE occurs when rodents iteratively explore options during perceptual discrimination or at choice points. It is strategic in that it accelerates learning and improves later memory. VTE has been associated with activity of rodent hippocampal neurons, and lesions of hippocampus disrupt VTE and associated learning and memory advantages. Analogous findings of VTE in humans would support the role of hippocampus in active use of short‐term memory to guide strategic behavior. We therefore measured VTE using eye‐movement tracking during perceptual discrimination and identified relevant neural correlates with functional magnetic resonance imaging. A difficult perceptual‐discrimination task was used that required visual information to be maintained during a several second trial, but with no long‐term memory component. VTE accelerated discrimination. Neural correlates of VTE included robust activity of hippocampus and activity of a network of medial prefrontal and lateral parietal regions involved in memory‐guided behavior. This VTE‐related activity was distinct from activity associated with simply viewing visual stimuli and making eye movements during the discrimination task, which occurred in regions frequently associated with visual processing and eye‐movement control. Subjects were mostly unaware of performing VTE, thus further distancing VTE from explicit long‐term memory processing. These findings bridge the rodent and human literatures on neural substrates of memory‐guided behavior, and provide further support for the role of hippocampus and a hippocampal‐centered network of cortical regions in the immediate use of memory in on‐line processing and the guidance of behavior.
The Discovery of Novel β‐Secretase Inhibitors: Pharmacophore Modeling, Virtual Screening, and Docking Studies

This article describes the identification of two small molecular inhibitors for β‐secretase by integrating virtual screening with fluorescence resonance energy transfer bioassay. A ligand‐based pharmacophore model was developed, and the sequential virtual screening of ZINC database was performed using the acquired pharmacophore model and molecular docking. Biological evaluation of 10 virtual hits led to the identification of two novel inhibitors with IC50 values of 4.76 and 0.31 μm, respectively. These two moderate inhibitors could represent new potentials for the development of anti‐Alzheimer’s disease agents.
Midazolam sedation and local anaesthesia compared with general anaesthesia for paediatric outpatient dental surgery

Midazolam sedation may offer an alternative to general anaesthesia for dental treatment in children. This study evaluated the efficacy and safety of i.v. midazolam with local anaesthesia in uncooperative paediatric dental patients. Thirty children (aged 2–10 years, physical status ASA 1 or 2) were randomized into two groups to receive general anaesthesia (group G) or local anaesthesia during sedation with i.v. midazolam (group M). Incremental doses of midazolam 0.05 mgkg‐1 were given to a sedative endpoint of 2 on a Sedation Scale of 5–0 (hyperactive–asleep), or 0.4 mgkg‐1 maximum, then as needed to maintain the same level of sedation. Amnesia was tested at the sedative endpoint by showing the child a tinkling ball and checking recall 1 h after surgery. Recovery was assessed by the Post‐Anesthetic Recovery Scale at 3 h (0–10) with 10 representing readiness for discharge. Questionnaires were completed by the dentist and anaesthetist during recovery and by telephone to the parents 1–2 weeks later. Dental treatment was completed according to protocol in 11 of the 15 patients in group M (sedative doses: 0.27 0.09 mgkg‐1, mean SD) and all patients in group G. Recovery was similar in both groups, with discharge criteria met after 1 h 30 min in all but one group M patient. None had recall for intra‐operative events. However, the variability of responsiveness makes midazolam unreliable when used alone to facilitate dental treatment, and the high dose requirements make close monitoring of paediatric patients mandatory.
Denaturing gradient gel electrophoresis (DGGE)-based monitoring of intestinal lactobacilli and bifidobacteria of pigs during a feeding trial

The aim of this study was to determine the influence of different feeding strategies on the gut microbiota of organic growing-finishing pigs. A total of 76 pigs were allocated to four different dietary treatments (control, probiotics, maize silage and grass silage). Effects of the applied probiotic preparation on the composition of the intestinal and faecal microbiota were monitored. By using a DGGE (denaturing gradient gel electrophoresis)-based methodology, fingerprints of the intestinal microbiota were obtained. The total microbial DNA was isolated from faecal and colon samples and amplified with PCR using different primer sets to detect bifidobacteria and lactobacilli. PCR products were separated using DGGE and the resulting profiles were compared with the findings of the other dietary treatments. Bands were excised from the gels and sequenced for further identification. Particularly two different DGGE profiles of bifidobacteria were observed, while lactobacilli showed larger variety within the dietary treatments.
Determination of titanium dioxide supplements in different matrices using two methods involving photometer and inductively coupled plasma optical emission spectrometer measurements

Titanium dioxide (TiO2) is a viable marker in digestibility studies using different animal species. The photometrical analysis is based on an intense orange colour following the addition of hydrogen peroxide to an acid solution. The measurement using inductively coupled plasma optical emission spectrometry (ICP-OES) is a method for analysing more than one element from the same sample preparation. The present study was conducted to investigate whether an established ICP-OES element analysis following acid-based hydrolysis is appropriate for titanium analysis. Defined amounts of TiO2 were added to samples obtained in studies with cows, pigs and turkeys and recoveries were determined. It was shown that supplemented TiO2 can be determined in samples of feeds, faeces or excreta, and digesta using a method based on photometric or ICP-OES measurement. The differences between the true and measured titanium concentrations indicate that using the ICP-OES method leads to a higher accuracy of determination.
Effect of decreasing ideal protein levels on performance results and nitrogen efficiency of growing-finishing gilts

This study examined the effect of decreasing ideal protein concentrations on performance and nutrient efficiency. The experimental diets contained 100%, 90%, 80% or 70% of the ideal dietary protein level (Diet 100%, 90%, 80% and 70%, respectively) estimated in previous experiments with pigs of the same genetic background. The four different treatments were divided among 16 pens of six pigs each. The average initial and final body weight were 20.8 ± 1.1 and 107 ± 3 kg, respectively. Three-phase feeding was applied (BW 20–40 kg, 40–70 kg and 70–110 kg). The dietary ileal digestible (ID) methionine + cystine, threonine, tryptophan, isoleucine, valine, and leucine contents expressed as percent of ID lysine were 63, 72, 22, 60, 68, and >100%, respectively. The lysine to protein ratio was kept constant at 6.8%. Between 21 and 106 kg BW the best performance was achieved on Diet 90%. Diet 70% led to significantly worse results. Although lean meat percentage did not differ, protein content of the carcass was lower on Diet 70% than on Diets 90% and 100%. Decreased protein concentrations increased crude protein efficiency and consequently decreased nitrogen excretion most at the 80% level. If protein varies together with digestible amino acid content, it can be concluded that Diet 80% may be the best choice for the environment and for profitability. If protein content stays at a fixed level, Diet 90% may be the safest choice.
Structural alterations in chronic lymphocytic leukaemia. Cytogenetic and FISH analysis

In this study, we described cytogenetics and fluorescence in situ hybridization (FISH) analysis performed in chronic lymphocytic leukaemia (CLL) patients with structural alterations. Results were correlated with clinical characteristics. A total of 38 CLL patients: 16 cases with complex and 22 with simple karyotypes were studied. For comparison of clinical parameters, a control group of 78 CLL patients with normal karyotype and without FISH genomic alterations were also evaluated. We found 38 structural abnormalities not previously described in the literature, 28 (74%) of them were translocations. In cases with complex karyotypes, chromosomes 6, 8 and 13 were the most frequently involved in new alterations (nine each), followed by chromosomes 12, 14 and 15 (six each). Chromosome 8p was particularly involved in losses, being 8p21‐pter the commonest region of overlap. Cases with simple karyotypes, showed del(6q) as the most frequent alteration (39%). Del(9)(q11) was recurrent in our series. Analysis of clinical parameters showed significant differences in white blood count (p = 0.005) and platelet count (p = 0.015) between patients with structural alterations and the control group. In addition, patients with structural alterations had a significantly shorter time to first treatment (TFT) (29 months) than the control group (69 months) (p = 0.037). Cases with complex karyotypes had a lower proportion of patients in Rai 0 clinical stage (15.4% vs 75%) (p = 0.005) and higher β2 microglobulin levels (3.3 vs 2.5 µg/mL) (p = 0.037) than those with simple karyotypes. Furthermore, a shorter TFT (13 months) and overall survival (56 months) in the complex karyotypes group compared with controls (69 and 144 months, respectively) (p = 0.015 and p = 0.005, respectively) were also found. Our results support the importance of cytogenetic analysis for clinical outcome in CLL and suggest that the diversity of genomic alterations is much greater than previously appreciated. Copyright © 2012 John Wiley & Sons, Ltd.
Treosulfan–fludarabine–thiotepa conditioning before allogeneic haemopoietic stem cell transplantation for patients with advanced lympho‐proliferative disease. A single centre study

In recent years, with the aim of reducing transplant‐related mortality, new conditioning regimens have been explored in patients not eligible for conventional haemopoietic stem cell transplantation. In this setting, we investigated safety and feasibility of the treosulfan–fludarabine–thiotepa combination prior to allogeneic haemopoietic stem cell transplantation in patients with advanced lympho‐proliferative diseases and at high transplant risk. Twenty‐seven consecutive patients, median age 43 years (range 19–60), entered this study. All of them were affected by lympho‐proliferative disease in advanced phase and have been heavily pre‐treated. The median haemopoietic stem cell transplant co‐morbidity index was 1 (range 0–3). Twenty‐five patients had regular engraftment, while the remaining two patients were not evaluable for early deaths. Non‐haematological toxicity was limited. No patient developed veno‐occlusive disease. The estimated probability of overall survival and progression‐free survival with a median follow‐up of 40 months was 52% (95% confidence interval 33–73) and 50% (95% confidence interval 30–70) respectively. Six patients have relapsed; all of them were not in remission before transplantation. The treosulfan–fludarabine–thiotepa combination is a reduced toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional myeloablative transplant regimens. Longer follow‐up and prospective randomized studies are necessary to evaluate this regimen. Copyright © 2015 John Wiley & Sons, Ltd.
Effects of dietary supplementation of rumen-protected folic acid on rumen fermentation, degradability and excretion of urinary purine derivatives in growing steers

ABSTRACT The present experiment was undertaken to determine the effects of dietary addition of rumen-protected folic acid (RPFA) on ruminal fermentation, nutrient degradability, enzyme activity and the relative quantity of ruminal cellulolytic bacteria in growing beef steers. Eight rumen-cannulated Jinnan beef steers averaging 2.5 years of age and 419 ± 1.9 kg body weight were used in a replicated 4 × 4 Latin square design. The four treatments comprised supplementation levels of 0 (Control), 70, 140 and 210 mg RPFA/kg dietary dry matter (DM). On DM basis, the ration consisted of 50% corn silage, 47% concentrate and 3% soybean oil. The DM intake (averaged 8.5 kg/d) was restricted to 95% of ad libitum intake. The intake of DM, crude protein (CP) and net energy for growth was not affected by treatments. In contrast, increasing RPFA supplementation increased average daily gain and the concentration of total volatile fatty acid and reduced ruminal pH linearly. Furthermore, increasing RPFA supplementation enhanced the acetate to propionate ratio and reduced the ruminal ammonia N content linearly. The ruminal effective degradability of neutral detergent fibre from corn silage and CP from concentrate improved linearly and was highest for the highest supplementation levels. The activities of cellobiase, xylanase, pectinase and α-amylase linearly increased, but carboxymethyl-cellulase and protease were not affected by the addition of RPFA. The relative quantities of Butyrivibrio fibrisolvens, Ruminococcus albus, Ruminococcus flavefaciens and Fibrobacter succinogenes increased linearly. With increasing RPFA supplementation levels, the excretion of urinary purine derivatives was also increased linearly. The present results indicated that the supplementation of RPFA improved ruminal fermentation, nutrient degradability, activities of microbial enzymes and the relative quantity of the ruminal cellulolytic bacteria in a dose-dependent manner. According to the conditions of this experiment, the optimum supplementation level of RPFA was 140 mg/kg DM.
Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma (TUBA study)

Complete response (CR) after treatment for multiple myeloma is associated with superior progression‐free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto‐HCT) between 2010 and 2012. If patients did not achieve CR after auto‐HCT, BD consolidation therapy was added to target CR.