Miracle-dz/UniFAR-FTUs huggingface dataset:
Nociceptive and inflammatory mediator upregulation in a mouse model of chronic prostatitis

Abstract Chronic nonbacterial prostatitis, characterized by genitourinary pain in the pelvic region in the absence of an identifiable cause, is common in adult males. Surprisingly, the sensory innervation of the prostate and mediators that sensitize its innervation have received little attention. We thus characterized a mouse model of chronic prostatitis, focusing on the prostate innervation and how organ inflammation affects gene expression of putative nociceptive markers in prostate afferent somata in dorsal root ganglia (DRG) and mediators in the prostate. Retrograde tracing (fast blue) from the prostate revealed that thoracolumbar and lumbosacral DRG are the principal sources of somata of prostate afferents. Nociceptive markers (eg, transient receptor potential, TREK, and P2X channels) were upregulated in fast blue–labeled thoracolumbar and lumbosacral somata for up to four weeks after inflaming the prostate (intraprostate injection of zymosan). Prostatic inflammation was evident histologically, by monocyte infiltration and a significant increase in mast cell tryptase activity 14, 21, and 28 days after zymosan injection. Interleukin 10 and NGF were also significantly upregulated in the prostate throughout the 4 weeks of inflammation. Open-field pain-related behaviors (eg, rearing) were unchanged in prostate-inflamed mice, suggesting the absence of ongoing nociception, but withdrawal thresholds to lower abdominal pressure were significantly reduced. The increases in IL-10, mast cell tryptase, and NGF in the inflamed prostate were cotemporaneous with reduced thresholds to probing of the abdomen and upregulation of nociceptive markers in DRG somata innervating the prostate. The results provide insight and direction for the study of mechanisms underlying pain in chronic prostatitis.
Functional Analysis of a Class I Holin, P2 Y

ABSTRACT Y is the putative holin gene of the paradigm coliphage P2 and encodes a 93-amino-acid protein. Y is predicted to be an integral membrane protein that adopts an N-out C-in membrane topology with 3 transmembrane domains (TMDs) and a highly charged C-terminal cytoplasmic tail. The same features are observed in the canonical class I lambda holin, the S105 protein of phage lambda, which controls lysis by forming holes in the plasma membrane at a programmed time. S105 has been the subject of intensive genetic, cellular, and biochemical analyses. Although Y is not related to S105 in its primary structure, its characterization might prove useful in discerning the essential traits for holin function. Here, we used physiological and genetic approaches to show that Y exhibits the essential holin functional criteria, namely, allele-specific delayed-onset lethality and sensitivity to the energization of the membrane. Taken together, these results suggest that class I holins share a set of unusual features that are needed for their remarkable ability to program the end of the phage infection cycle with precise timing. However, Y holin function requires the integrity of its short cytoplasmic C-terminal domain, unlike for S105. Finally, instead of encoding a second translational product of Y as an antiholin, as shown for lambda S107, the P2 lysis cassette encodes another predicted membrane protein, LysA, which is shown here to have a Y-specific antiholin character.
InsP3 Signaling in Apicomplexan Parasites

Background: Phosphoinositides (PIs) and their derivatives are essential cellular components that form the building blocks for cell membranes and regulate numerous cell functions. Specifically, the ability to generate myo-inositol 1,4,5-trisphosphate (InsP3) via phospholipase C (PLC) dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to InsP3 and diacylglycerol (DAG) initiates intracellular calcium signaling events representing a fundamental signaling mechanism dependent on PIs. InsP3 produced by PI turnover as a second messenger causes intracellular calcium release, especially from endoplasmic reticulum, by binding to the InsP3 receptor (InsP3R). Various PIs and the enzymes, such as phosphatidylinositol synthase and phosphatidylinositol 4-kinase, necessary for their turnover have been characterized in Apicomplexa, a large phylum of mostly commensal organisms that also includes several clinically relevant parasites. However, InsP3Rs have not been identified in genomes of apicomplexans, despite evidence that these parasites produce InsP3 that mediates intracellular Ca2+ signaling. Conclusion: Evidence to supporting IP3-dependent signaling cascades in apicomplexans suggests that they may harbor a primitive or non-canonical InsP3R. Understanding these pathways may be informative about early branching eukaryotes, where such signaling pathways also diverge from animal systems, thus identifying potential novel and essential targets for therapeutic intervention.
Surgical management of intestinal failure

Surgery plays a key role in the management of both acute and, less frequently, chronic intestinal failure. Acute intestinal failure frequently requires surgical treatment when it arises as a consequence of intestinal fistulation or obstruction. In specialised clinical practice approximately 50% of acute intestinal failure is associated with intestinal fistulas and in approximately 50% of patients, this condition arises as part of the natural history or complicating treatment for Crohn's disease. A considerable proportion of such patients have abdominal infection and present complex nutritional and metabolic problems. The most important aspect of the surgical management of patients with acute intestinal failure associated with intra-abdominal infection is management of sepsis, since recovery is unlikely in the presence of active infection. Moreover, effective nutritional support and restoration of body composition is not possible if sepsis remains unresolved. Surgical strategies to deal with intra-abdominal infection may involve percutaneous drainage, laparotomy and resection of fistulating segments of intestine and, when infection is persistent and contamination extensive, laparostomy (a technique in which the abdomen is left open and allowed to heal by secondary intention). Surgical treatment should not only be timely and effective, but also aimed at preventing secondary damage to the small intestine, in order to minimise the risk of short bowel syndrome. In some cases a proximal defunctioning stoma may be required, with prolonged nutritional support, using either home total parenteral nutrition or feeding via the defunctioned distal gut (fistuloclysis), pending restoration of intestinal continuity. The role of surgical treatment for patients with short bowel syndrome is less clear. While surgery is frequently required for the management of complications of short bowel syndrome (including gallstones and possibly peptic ulcer disease), the role of intestinal lengthening and tapering procedures (to increase functional intestinal length), and artificial valves, reversed segments and colonic interposition (to reduce intestinal transit) remains controversial. For some patients with short bowel syndrome and, in particular, those with combined intestinal and hepatic failure, intestinal transplantation may become the treatment of choice as long-term results continue to improve.
Manoyl Oxide (13R), the Biosynthetic Precursor of Forskolin, Is Synthesized in Specialized Root Cork Cells in Coleus forskohlii1[W][OPEN]

The first two steps of the biosynthesis of forskolin are active in Coleus forskohlii root cork cells harboring hydrophobic intracellular compartments used for terpenoid storage. Forskolin, a complex labdane diterpenoid found in the root of Coleus forskohlii (Lamiaceae), has received attention for its broad range of pharmacological activities, yet the biosynthesis has not been elucidated. We detected forskolin in the root cork of C. forskohlii in a specialized cell type containing characteristic structures with histochemical properties consistent with oil bodies. Organelle purification and chemical analysis confirmed the localization of forskolin and of its simplest diterpene precursor backbone, (13R) manoyl oxide, to the oil bodies. The labdane diterpene backbone is typically synthesized by two successive reactions catalyzed by two distinct classes of diterpene synthases. We have recently described the identification of a small gene family of diterpene synthase candidates (CfTPSs) in C. forskohlii. Here, we report the functional characterization of four CfTPSs using in vitro and in planta assays. CfTPS2, which synthesizes the intermediate copal-8-ol diphosphate, in combination with CfTPS3 resulted in the stereospecific formation of (13R) manoyl oxide, while the combination of CfTPS1 and CfTPS3 or CfTPS4 led to formation of miltiradiene, precursor of abietane diterpenoids in C. forskohlii. Expression profiling and phylogenetic analysis of the CfTPS family further support the functional diversification and distinct roles of the individual diterpene synthases and the involvement of CfTPS1 to CfTPS4 in specialized metabolism and of CfTPS14 and CfTPS15 in general metabolism. Our findings pave the way toward the discovery of the remaining components of the pathway to forskolin, likely localized in this specialized cell type, and support a role of oil bodies as storage organelles for lipophilic bioactive metabolites.
Women in development.

The author reports on travel in the Philippines, Malaysia, Sri Lanka, and Pakistan, and conditions she found affecting development. Development for women in the Philippines has been hampered by a dichotomy between home economics and agricultural work. Although the majority of students in agriculture are women, many village cooperatives have been formed with less than 10% women members. Malaysia has a high level of education; development projects can easily be implemented. The National Association of Women's Institutes of Peninsular Malaysia (NAWIPM) emphasizes training for rural women. Its activiti include nursuries, poultry raising, home improvement, cooperatives, and income generating projects such as catering and tailoring. As in the Philippines ther is an important Muslim minority; Muslim women lag behind other Sri Lankans in education. The Mahila Samiti is the organization which trains rural women i some 1500 chapters. The women of Pakistan have the greatest need for assistance. Less than 15% Pakistan women are literate; their enrollment in school lags far behind the boys. The All Pakistan Women's Association works on problems of development through its Nutrition Education Training Courses. The centers have begun poultry raising and gardening as parts of its program.
Variation-aware Flip-Flop energy optimization for ultra low voltage operation

This paper presents an energy optimization method for a Flip-Flop (FF) circuit in a presence of manufacturing process variation. The optimal FF circuit can be obtained by simultaneously scaling the supply voltage and the transistor size with achieving a specific high yield of the circuit. Lowering the supply voltage is one of the most effective approaches for decreasing the energy consumption of the circuit. However, the increased variation in nano scale semiconductor devices causes a malfunction of FFs especially for the very low voltage operation. Therefore, it is a challenging goal for the nano scale FFs to achieve the high yield and extremely low energy consumption simultaneously. This paper proposes an approximation method for accurately estimating a minimum possible operating voltage (VDDmin) of FFs with a small number of Monte-Carlo trials. After that, for a given FF, we find a set of optimal supply voltage and the transistor sizes, which minimizes the energy consumption of the FF with achieving the specific high-sigma yield (e.g., 5σ yield). Post layout Monte-Carlo simulation results obtained using a commercial 28 nm process technology model demonstrate that the energy consumption of a FF optimized with our approach can be reduced by 17% at the best case with achieving 5σ yield.
Regional cerebral blood flow and glucose utilization in spontaneously epileptic EL mice.

UNLABELLED The dynamics of the relative regional cerebral blood flow (rCBF) and regional glucose utilization (rGU) were examined in spontaneously epileptic EL mice in the interictal, ictal and postictal states, using autoradiography with 125I-N-isopropyl-p-iodoamphetamine (IMP) and 14C-2-deoxyglucose (DG), respectively. METHODS EL mice were used in the study, which have previously been used as a model of the idiopathic human epilepsy. EL mice develop secondary generalized tonic-clonic convulsions, and ddY and EL(o) mice, which do not experience seizures, were used as controls. IMP and DG, respectively, were injected in EL mice in the interictal, ictal and postictal states. We examined the relative rCBF and rGU from the obtained autoradiograms of mouse brain sections. RESULTS No significant changes in the relative rCBF were obtained in the hippocampus in the course of epileptic seizures. In contrast, significant increases in the relative rGU were observed in the hippocampus in the ictal and early postictal states. The dissociation between the dynamics of the rCBF and rGU were found in the event of epileptic seizures of EL mice. CONCLUSION The flow metabolism dissociation in the ictal and early postictal states is of both conceptual and practical interest, while the reason for the dissociation of rCBF from the rGU in epileptics seizures remains to be established. Our results emphasize the importance of estimating both cerebral perfusion and glucose metabolism in epilepsy.
Interrogation of Inhibitor of Nuclear Factor κB α/Nuclear Factor κB (IκBα/NF-κB) Negative Feedback Loop Dynamics

Background: Understanding the biological significance of feedback loops requires interrogation at multiple scales. Results: A nuclear factor κB (NF-κB) negative feedback reporter revealed stimulus-specific dynamics in cells and animals in vivo. Conclusion: Circulating tumor necrosis factor α (TNFα) doses are perceived by the liver as pulses. Significance: Bioluminescent imaging of live single cells and cell populations revealed reproducible behaviors that informed interpretation of in vivo data. Full understanding of the biological significance of negative feedback processes requires interrogation at multiple scales as follows: in single cells, cell populations, and live animals in vivo. The transcriptionally coupled IκBα/NF-κB negative feedback loop, a pivotal regulatory node of innate immunity and inflammation, represents a model system for multiscalar reporters. Using a κB5→IκBα-FLuc bioluminescent reporter, we rigorously evaluated the dynamics of ΙκBα degradation and subsequent NF-κB transcriptional activity in response to diverse modes of TNFα stimulation. Modulating TNFα concentration or pulse duration yielded complex, reproducible, and differential ΙκBα dynamics in both cell populations and live single cells. Tremendous heterogeneity in the transcriptional amplitudes of individual responding cells was observed, which was greater than the heterogeneity in the transcriptional kinetics of responsive cells. Furthermore, administration of various TNFα doses in vivo generated ΙκBα dynamic profiles in the liver resembling those observed in single cells and populations of cells stimulated with TNFα pulses. This suggested that dose modulation of circulating TNFα was perceived by hepatocytes in vivo as pulses of increasing duration. Thus, a robust bioluminescent reporter strategy enabled rigorous quantitation of NF-κB/ΙκBα dynamics in both live single cells and cell populations and furthermore, revealed reproducible behaviors that informed interpretation of in vivo studies.
Modeling induced pluripotent stem cells from fibroblasts of Duchenne muscular dystrophy patients

The generation of disease-specific induced pluripotent stem cell (iPS cell) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and for drug screening. Such innovation enables us to obtain autologous cell sources for regenerative medicine. Herein, we report the generation and characterization of iPS cells from the fibroblasts of patients with a family history of Duchenne muscular dystrophy (DMD); these fibroblasts were obtained from patients at 22 gestational weeks of age and exhibit exon duplication from exons 16 to 42. The DMD-iPS cells were generated by the ectopic expression of four transcription factors: OCT4, SOX2, KLF4, and c-MYC; the DMD-iPS cells expressed several pluripotency markers and could be differentiated into various somatic cell types both in vitro and in vivo. Furthermore, DMD-iPSCs showed the differentiation potential to neuronal lineage. Thus, DMD-iPS cells are expected to serve as an in vitro disease model system, which will lay a foundation for the production of autologous cell therapies that avoid immune rejection and enable the correction of gene defects prior to tissue reconstitution.
Extensive structural remodeling of the injured spinal cord revealed by phosphorylated MAP1B in sprouting axons and degenerating neurons

Spinal cord injury (SCI) results in loss of sensory and motor function because injured axons do not regenerate and neurons that die are not replaced. Nevertheless, there is evidence for spontaneous reorganization of spared pathways (i.e. sprouting) that could be exploited to improve functional recovery. The extent of morphological remodeling after spinal cord injury is, however, not understood. We have previously shown that a phosphorylated form of microtubule‐associated protein‐1B, MAP1B‐P, is expressed by growing axons, but is detected in intact adult SC in fibers exhibiting a somatotopic distribution of myelinated sensory fibers. We now demonstrate that after adult SCI, MAP1B‐P is up‐regulated in other classes of axons. We used immunohistochemistry to show changing levels and distributions of MAP1B‐P after a right thoracic hemisection of adult rat spinal cord. MAP1B‐P labeling suggests rearrangements of the axonal circuitry that go well beyond previous descriptions. MAP1B‐P‐positive fibers are present in ectopic locations in gray matter in both dorsal and ventral horns and around the central canal. Double staining reveals that primary sensory and descending serotonergic and corticospinal axons are MAP1B‐P positive. In white matter, high MAP1B‐P expression is found on terminal enlargements near the injury, reflecting retraction of transected axons. MAP1B‐P also accumulates in pre‐apoptotic neuronal somata axotomized by the lesion, indicating association of MAP1B‐P not only with axon extension and retraction, but also with neuronal degeneration. Finally, we provide evidence that MAP1B phosphorylation is correlated with activation of JNK MAP‐kinase, providing a step towards unraveling the mechanisms of regulation of this plasticity‐related cytoskeletal protein.
A pedigree‐based experiment reveals variation in salinity and thermal tolerance in the salmon louse, Lepeophtheirus salmonis

The salmon louse is a highly abundant ectoparasitic copepod of salmonids in the North Pacific and Atlantic. Widespread and rapid development of resistance to chemical agents used to delouse salmonids on marine farms is now threatening the continued development of the aquaculture industry and have served as a potent catalyst for the development of alternative pest management strategies. These include freshwater and warm‐water treatments to which the louse is sensitive. However, given the well‐documented evolutionary capacity of this species, the risk of developing tolerance towards these environmental treatments cannot be dismissed. Two common‐garden experiments were performed using full‐sibling families of lice identified by DNA parentage testing to investigate whether one of the fundamental premises for evolution, in this context genetic variation in the capacity of coping with fresh or warm water, exists within this species. Significant differences in survival were observed among families in both experiments, although for the salinity experiment, it was not possible to unequivocally disentangle background mortality from treatment‐induced mortality. Thus, our data demonstrate genetic variation in tolerance of warm water and are suggestive of genetic variation in salinity tolerance. We conclude that extensive use of these environmental‐based treatments to delouse salmonids on commercial farms may drive lice towards increased tolerance.
Benthic eukaryotic diversity in the Guaymas Basin hydrothermal vent environment

Molecular microbial ecology studies have revealed remarkable prokaryotic diversity in extreme hydrothermal marine environments. There are no comparable reports of culture-independent surveys of eukaryotic life in warm, anoxic marine sediments. By using sequence comparisons of PCR-amplified small subunit ribosomal RNAs, we characterized eukaryotic diversity in hydrothermal vent environments of Guaymas Basin in the Gulf of California. Many sequences from these anoxic sediments and the overlaying seawater represent previously uncharacterized protists, including early branching eukaryotic lineages or extended diversity within described taxa. At least two mechanisms, with overlapping consequences, account for the eukaryotic community structure of this environment. The adaptation to anoxic environments is evidenced by specific affinity of environmental sequences to aerotolerant anaerobic species in molecular trees. This pattern is superimposed against a background of widely distributed aerophilic and aerotolerant protists, some of which may migrate into and survive in the sediment whereas others (e.g., phototrophs) are simply deposited by sedimentary processes. In contrast, bacterial populations in these sediments are primarily characteristic of anoxic, reduced, hydrocarbon-rich sedimentary habitats.
Regeneration of the Infarcted Heart With Stem Cells Derived by Nuclear Transplantation

Abstract— Nuclear transfer techniques have been proposed as a strategy for generating an unlimited supply of rejuvenated and histocompatible stem cells for the treatment of cardiac diseases. For this purpose, c-kit–positive fetal liver stem cells obtained from cloned embryos were injected in the border zone of infarcted mice to induce tissue reconstitution. Cloned embryos were derived from somatic cell fusion between nuclei of cultured LacZ-positive fibroblasts and enucleated oocytes of a different mouse strain. We report that regenerating myocardium replaced 38% of the scar at 1 month. The rebuilt tissue expressed LacZ and was composed of myocytes and vessels connected with the coronary circulation. Myocytes were functionally competent and expressed contractile proteins, desmin, connexin43, and N-cadherin. These structural characteristics indicated that the new myocytes were electrically and mechanically coupled. Similarly, the formed coronary arterioles and capillary structures contained blood and contributed, therefore, to tissue oxygenation. Cardiac replacement resulted in an improvement of ventricular hemodynamics and in a reduction of diastolic wall stress. These beneficial effects were obtained by stem cell transdifferentiation and commitment to the cardiac cell lineages. Myocardial growth was independent from fusion of the injected stem cells with preexisting partner cells. In conclusion, c-kit–positive stem cells derived by nuclear transfer cloning restore infarcted myocardium. Although problems currently plague nuclear transplantation, including the potential for epigenetic and imprinting abnormalities, stem cells derived from cloned embryos are sufficiently normal to repair damaged tissue in vivo. Importantly, the magnitude of myocardial regeneration obtained in this study is significantly superior to that achieved with adult bone marrow cells.