Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of interleukin-1 beta as a key mediator in the upregulation of Cav3.2–USP5 interactions in the pain pathway

We recently reported that nerve injury or peripheral inflammation triggers an upregulation of the deubiquitinase, USP5 in mouse dorsal root ganglion and spinal dorsal horn. This leads to dysregulated ubiquitination of Cav3.2 T-type calcium channels, thus increasing Cav3.2 channel plasma membrane expression and nociceptive signaling in the primary afferent pain pathway. This phenomenon could be recapitulated by noninvasive, optogenetic activation of transient receptor potential vanilloid-1–expressing nociceptors, indicating that neuronal activity is a key player in this process. Given the relevance of the pro-inflammatory cytokine interleukin-1 beta in many forms of pathological pain, we hypothesized that interleukin-1 beta may be a critical cofactor required to drive upregulation of interactions between USP5 and Cav3.2 channels. Here, we report that gene expression, as well as protein levels for interleukin-1 beta and the endogenous interleukin-1 receptor-I antagonist, IL-1Ra are unaltered following conditioning stimulation of optogenetically targeted cutaneous nociceptors, indicating that neuronal activity is not a driver of interleukin-1 beta signaling. In contrast, co-immunoprecipitation experiments revealed that intrathecal administration of interleukin-1 beta in wild-type mice led to an increase in the interaction between USP5 and Cav3.2 in the spinal dorsal horn. Moreover, disruption of the interaction between USP5 and Cav3.2 with TAT peptides suppressed acute nocifensive responses produced by interleukin-1 beta, which was similar to that achieved by elimination of T-type channel activity with the channel blockers, mibefradil, or TTA-A2. Finally, this upregulation could be maintained in dorsal root ganglion neuron cultures exposed overnight to interleukin-1 beta, while the copresence of interleukin-1 receptor antagonist or the dampening of neuronal cell activity with tetrodotoxin attenuated this response. Altogether, our findings identify interleukin-1 beta as an upstream trigger for the upregulation of interactions between USP5 and Cav3.2 channels in the pain pathway, presumably by triggering increased firing activity in afferent fibers.
Influence of HAART on the Clinical Course of HIV-1-Infected Patients With Progressive Multifocal Leukoencephalopathy: Results of an Observational Multicenter Study

Background:The aim of this study was to analyze the incidence of new cases, survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy (PML), and the characteristics of PML-associated immune reconstitution inflammatory syndrome (IRIS). Methods:Multicenter observational cohort study of all HIV-1-infected patients newly diagnosed of PML in 7 hospitals in Barcelona (Spain) from 2002 to 2006. The annual incidence of PML was calculated. Survival was estimated using the Kaplan-Meier method. IRIS was defined as new onset or rapid worsening of PML shortly after initiation of highly active antiretroviral therapy together with a decline in HIV-1 viral load and rising of CD4 lymphocytes. Results:Sixty-one new cases of PML were diagnosed. The mean survival time was 15 months [95% confidence interval (CI), 11 to 19]. The Kaplan-Meier estimates of the probability of survival were 47.7% (95% CI, 35 to 59) at 6 months, 38.6% (95% CI, 25 to 51) at 12 months, 35.1% (95% CI, 22 to 48) at 24 months, and 25.1% (95% CI, 10 to 40) at 36 months. IRIS was diagnosed in 14 (23%) cases. Mortality was similar in patients with and without IRIS. Conclusions:PML continues to be one of the deadliest opportunistic infections in acquired immunodeficiency syndrome patients. The development of PML-associated IRIS has no influence on prognosis.
A genome scan for all-cause end-stage renal disease in African Americans.

BACKGROUND In an attempt to map the genes predisposing to the common, complex aetiologies of end-stage renal disease (ESRD), we performed a genome-wide scan in 1023 individuals with chronic kidney disease (946 dialysis dependent and 77 with advanced chronic renal failure) from 483 African American families. METHODS The study sample comprised 563 ESRD-affected sibling pairs, with nephropathy attributed to diabetes mellitus, chronic glomerular disease or hypertension. Multipoint non-parametric linkage (NPL) analysis methods were employed. RESULTS NPL regression provided modest evidence of linkage to 13q33.3 near D13S796 [log of the odds (LOD) = 1.72], 9q34.3 near D9S1826 (LOD = 1.22), 4p15.32 near D4S2639 (LOD = 1.11) and 1q25.1 near D1S1589 (LOD = 1.01). Adjusting for the evidence of linkage at the other loci using NPL regression analysis provided evidence for linkage to 4p15.32, 9q34.3 and 13q33.3. NPL regression interaction and ordered subset analysis (OSA) suggested that the evidence for linkage to ESRD significantly increased with higher body mass index (BMI) at 13q33.3 (LOD = 4.94 in 61% of families with the highest BMI). Additionally, OSA suggested that linkage significantly improved in the 13% of families with earliest age at ESRD onset (LOD = 3.05 at 2q32.1) and in the 16% of families with latest age at ESRD onset (LOD = 2.47 at 10q26.3). CONCLUSIONS Multipoint single-locus linkage analysis provided modest evidence of linkage to all-cause ESRD in African Americans on 13q33.3, and NPL regression and OSA suggested that evidence for linkage in this region markedly increased in obese families. This region, as well as 9q34.3, 4p15.32 and 1q25.1, should receive priority in the search for loci contributing to ESRD susceptibility in African Americans.
Analyzing gene expression data in terms of gene sets: methodological issues

MOTIVATION Many statistical tests have been proposed in recent years for analyzing gene expression data in terms of gene sets, usually from Gene Ontology. These methods are based on widely different methodological assumptions. Some approaches test differential expression of each gene set against differential expression of the rest of the genes, whereas others test each gene set on its own. Also, some methods are based on a model in which the genes are the sampling units, whereas others treat the subjects as the sampling units. This article aims to clarify the assumptions behind different approaches and to indicate a preferential methodology of gene set testing. RESULTS We identify some crucial assumptions which are needed by the majority of methods. P-values derived from methods that use a model which takes the genes as the sampling unit are easily misinterpreted, as they are based on a statistical model that does not resemble the biological experiment actually performed. Furthermore, because these models are based on a crucial and unrealistic independence assumption between genes, the P-values derived from such methods can be wildly anti-conservative, as a simulation experiment shows. We also argue that methods that competitively test each gene set against the rest of the genes create an unnecessary rift between single gene testing and gene set testing.
The impact of over 80 years of land cover changes on bee and wasp pollinator communities in England

Change in land cover is thought to be one of the key drivers of pollinator declines, and yet there is a dearth of studies exploring the relationships between historical changes in land cover and shifts in pollinator communities. Here, we explore, for the first time, land cover changes in England over more than 80 years, and relate them to concurrent shifts in bee and wasp species richness and community composition. Using historical data from 14 sites across four counties, we quantify the key land cover changes within and around these sites and estimate the changes in richness and composition of pollinators. Land cover changes within sites, as well as changes within a 1 km radius outside the sites, have significant effects on richness and composition of bee and wasp species, with changes in edge habitats between major land classes also having a key influence. Our results highlight not just the land cover changes that may be detrimental to pollinator communities, but also provide an insight into how increases in habitat diversity may benefit species diversity, and could thus help inform policy and practice for future land management.
Nickel and calcium ions modify the characteristics of the acetylcholine receptor‐channel complex at the frog neuromuscular junction.

1. Miniature end‐plate currents (m.e.p.c.s) and acetylcholine induced current noise were recorded from the cutaneous pectoris muscle of the frog with the voltage‐clamp technique. Analysis of current noise was used to estimate mean single channel current and the mean lifetime of an open channel. 2. Adding Ni2+ or Ca2+ to the bathing solution reduced the amplitude of the m.e. p.c. s. Ten mM‐Ni2+ decreased the amplitude 64%, while raising Ca2+ from 2 to 10mM decreased the amplitude 35%. 3. The decreased amplitude of the m.e. p.c. in Ni2+ and increased Ca2+ can be explained by a decrease in single channel current. Ten mM‐Ni2+ decreased mean single channel current 64% while raising Ca2+ from 2 to 10 mM decreased single channel current 28%. 4. The decrease in single channel current was due to a decrease in the driving potential and single channel conductance. Ten mM‐Ni2+ and Ca2+ shifted the reversal potential for the m.e. p.c. about 10 mV negative from the control value of ‐4.6 mV; at the same time single channel conductance was decreased 59% in Ni2+ and 18% in increased Ca2+. 5. In contrast to the similar direction of effects of Ni2+ and Ca2+ on m.e. p.c. amplitude, reversal potential, and single channel conductance, Ni2+ and Ca2+ had different effects on m.e. p.c. time course. Ten mM‐Ni2+ increased the time constant of m.e. p.c. decay 80% while raising Ca2+ from 2 to 10 mM decreased the time constant of decay 17%. 6. Ni2+ and Ca2+ also had different effects on single channel lifetimes. Ten mM‐Ni2+ increased channel lifetime about 50%, while raising Ca2+ from 2 to 10 mM did not significantly affect channel lifetime. 7. These results suggest that changes in single channel lifetime and conductance due to ionic influences are not necessarily tightly coupled. The results also suggest that the effects of both Ni2+ and Ca2+ on channel lifetime cannot be accounted for in terms of a simple surface potential hypothesis.
Subverting Toll-Like Receptor Signaling by Bacterial Pathogens

Pathogenic bacteria are detected by pattern-recognition receptors (PRRs) expressed on innate immune cells, which activate intracellular signal transduction pathways to elicit an immune response. Toll-like receptors are, perhaps, the most studied of the PRRs and can activate the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) pathways. These pathways are critical for mounting an effective immune response. In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways. This mini-review highlights the diverse mechanisms that bacterial pathogens have evolved to manipulate the innate immune response, with a particular focus on those that target MAPK and NF-κB signaling pathways. Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection.
Major Depression in the Transition to Adulthood: The Impact of Active and Past Depression on Young Adult Functioning

This study examined the association between active and past major depression and deficits in young adult functioning using data from a longitudinal community study (N = 354). Three groups were compared: (1) participants with a 1-year diagnosis of major depression at age 26 (active group); (2) those who experienced major depression during the transition to adulthood, ages 18–25, but did not have active depression at age 26 (past group); and (3) individuals not meeting diagnostic criteria for depression during the transition period. Results highlight serious deficits in psychosocial functioning at age 26 linked to both active and past depression. Although participants with active depression experienced the greatest number of problems, those with past depression evidenced similar deficits across many important domains of functioning. The significant impairments characterizing those with past depression indicate the need for continued monitoring to decrease the risk of recurrence and the establishment of a chronic course of illness.
The Voronoi Diagram of Three Lines

We give a complete description of the Voronoi diagram, in ℝ3, of three lines in general position, that is, that are pairwise skew and not all parallel to a common plane. In particular, we show that the topology of the Voronoi diagram is invariant for three such lines. The trisector consists of four unbounded branches of either a nonsingular quartic or of a nonsingular cubic and a line that do not intersect in real space. Each cell of dimension two consists of two connected components on a hyperbolic paraboloid that are bounded, respectively, by three and one of the branches of the trisector. We introduce a proof technique which relies heavily upon modern tools of computer algebra and is of interest in its own right.This characterization yields some fundamental properties of the Voronoi diagram of three lines. In particular, we present linear semi-algebraic tests for separating the two connected components of each two-dimensional Voronoi cell and for separating the four connected components of the trisector. This enables us to answer queries of the form, given a point, determine in which connected component of which cell it lies. We also show that the arcs of the trisector are monotonic in some direction. These properties imply that points on the trisector of three lines can be sorted along each branch using only linear semi-algebraic tests.
The Sponsor Alliance Inventory: Assessing the Therapeutic Bond Between 12-Step Attendees and Their Sponsors.

AIMS Within 12-step mutual-help organizations (MHOs), a sponsor plays a key recovery-specific role analogous to a 'lay therapist', serving as a role model, support and mentor. Research shows that attendees who have a sponsor have higher rates of abstinence and remission from substance use disorder (SUD), yet, while myriad formal psychotherapy studies demonstrate the therapeutic significance of the alliance between patients and professional clinicians on treatment outcomes, very little is known about the influence of the 'therapeutic alliance' between 12-step members and their sponsor. Greater knowledge about this key 12-step relationship could help explain greater degrees of 12-step effects. To bridge this gap, this study sought to develop and test a measure assessing the 12-step sponsee-sponsor therapeutic alliance--the Sponsor Alliance Inventory (SAI). METHOD Young adults (N = 302) enrolled in a prospective effectiveness study who reported having a 12-step sponsor during the study (N = 157) were assessed at treatment entry, and 3, 6 and 12 months later on the SAI, their 12-step MHO attendance, involvement and percent days abstinent (PDA). RESULTS Principal axis extraction revealed a single, 10-item, internally consistent (α's ≥ 0.95) scale that explained the majority of variance and was largely invariant to primary substance, gender and time. Criterion validity was also supported with higher SAI scores predicting greater proximal 12-step attendance, involvement and PDA. CONCLUSION The SAI may serve as a brief, valid measure to assess the degree of sponsee-sponsor 'therapeutic alliance' within 12-step communities and may help augment explanatory models estimating the effects of MHOs on recovery outcomes.
International Journal of Behavioral Nutrition and Physical Activity Social Support for Youth Physical Activity: Importance of Siblings, Parents, Friends and School Support across a Segmented School Day

Background: Whilst evidence exists for the influence of encouragement on physical activity participation, the diversity of support sources and the type of physical activity examined previously is limited. This study examined the importance of perceived encouragement from parents, siblings/cousins, friends, and schools on participation levels across three time-specific activity opportunities that are available during a school day (after-school physical activities, lunchtime activity, and active transportation to and from school).
Effect of Low-Dose Continuous Estrogen and Progesterone Therapy with Calcium and Vitamin D on Bone in Elderly Women

TO THE EDITOR: Recker and colleagues' relevant study reports on how continuous low-dose hormone replacement therapy (HRT) with adequate calcium and vitamin D intake provides a bone-sparing effect in elderly women. The authors also found that no significant bone losses occurred in patients who received placebo plus calcium and vitamin D. The usefulness of bone mineral density measurements in the identification of persons with risk for bone fracture has recently been questioned (2). Other studies have addressed the importance of resorptive markers, such as pyridinolones and N-telopeptide, as indicators of active resorption and risk for fracture and as indicators of treatment response. Recker and colleagues did not report on these measures, nor did they provide the fracture rate during the 3.5 years of the study. Vitamin D has been found to decrease parathyroid hormone-related bone resorption (3). In fact, low levels of vitamin D have been associated with acute fractures in postmenopausal women (4). Thus, it would be interesting to investigate how calcium and vitamin D treatment modify pyridinolones and N-telopeptide values compared with HRT. Hormone replacement therapy is the cornerstone of prevention of postmenopausal osteoporosis. However, given the potential side effects of HRT, its use is still controversial for many patients. Alternative therapies could be offered to elderly patients if found to be effective in preventing bone resorption.
Semantic Dependency Parsing of NomBank and PropBank: An Efficient Integrated Approach via a Large-scale Feature Selection

We present an integrated dependency-based semantic role labeling system for English from both NomBank and PropBank. By introducing assistant argument labels and considering much more feature templates, two optimal feature template sets are obtained through an effective feature selection procedure and help construct a high performance single SRL system. From the evaluations on the date set of CoNLL-2008 shared task, the performance of our system is quite close to the state of the art. As to our knowledge, this is the first integrated SRL system that achieves a competitive performance against previous pipeline systems.
Role of the α1G T-Type Calcium Channel in Spontaneous Absence Seizures in Mutant Mice

Alterations in thalamic T-type Ca2+ channels are thought to contribute to the pathogenesis of absence seizures. Here, we found that mice with a null mutation for the pore-forming α1A subunits of P/Q-type channels (α1A–/– mice) were prone to absence seizures characterized by typical spike-and-wave discharges (SWDs) and behavioral arrests. Isolated thalamocortical relay (TC) neurons from these mice showed increased T-type Ca2+ currents in vitro. To examine the role of increased T-currents in α1A–/– TC neurons, we cross-bred α1A–/– mice with mice harboring a null mutation for the gene encoding α1G, a major isotype of T-type Ca2+ channels in TC neurons. α1A–/–/α1G–/– mice showed a complete loss of T-type Ca2+ currents in TC neurons and displayed no SWDs. Interestingly, α1A–/–/α1G+/– mice had 75% of the T-type Ca2+ currents in TC neurons observed in α1A+/+/α1G+/+ mice and showed SWD activity that was quantitatively similar to that in α1A–/–/α1G+/+ mice. Similar results were obtained using double-mutant mice harboring the α1G mutation plus another mutation also used as a model for absence seizures, i.e., lethargic (β4lh/lh), tottering (α1Atg/tg), or stargazer (γ2stg/stg). The present results reveal that α1G T-type Ca2+ channels play a critical role in the genesis of spontaneous absence seizures resulting from hypofunctioning P/Q-type channels, but that the augmentation of thalamic T-type Ca2+ currents is not an essential step in the genesis of absence seizures.
A Role for the Chaperone Complex BAG3-HSPB8 in Actin Dynamics, Spindle Orientation and Proper Chromosome Segregation during Mitosis

The co-chaperone BAG3, in complex with the heat shock protein HSPB8, plays a role in protein quality control during mechanical strain. It is part of a multichaperone complex that senses damaged cytoskeletal proteins and orchestrates their seclusion and/or degradation by selective autophagy. Here we describe a novel role for the BAG3-HSPB8 complex in mitosis, a process involving profound changes in cell tension homeostasis. BAG3 is hyperphosphorylated at mitotic entry and localizes to centrosomal regions. BAG3 regulates, in an HSPB8-dependent manner, the timely congression of chromosomes to the metaphase plate by influencing the three-dimensional positioning of the mitotic spindle. Depletion of BAG3 caused defects in cell rounding at metaphase and dramatic blebbing of the cortex associated with abnormal spindle rotations. Similar defects were observed upon silencing of the autophagic receptor p62/SQSTM1 that contributes to BAG3-mediated selective autophagy pathway. Mitotic cells depleted of BAG3, HSPB8 or p62/SQSTM1 exhibited disorganized actin-rich retraction fibres, which are proposed to guide spindle orientation. Proper spindle positioning was rescued in BAG3-depleted cells upon addition of the lectin concanavalin A, which restores cortex rigidity. Together, our findings suggest the existence of a so-far unrecognized quality control mechanism involving BAG3, HSPB8 and p62/SQSTM1 for accurate remodelling of actin-based mitotic structures that guide spindle orientation.
AGEMAP: A Gene Expression Database for Aging in Mice

We present the AGEMAP (Atlas of Gene Expression in Mouse Aging Project) gene expression database, which is a resource that catalogs changes in gene expression as a function of age in mice. The AGEMAP database includes expression changes for 8,932 genes in 16 tissues as a function of age. We found great heterogeneity in the amount of transcriptional changes with age in different tissues. Some tissues displayed large transcriptional differences in old mice, suggesting that these tissues may contribute strongly to organismal decline. Other tissues showed few or no changes in expression with age, indicating strong levels of homeostasis throughout life. Based on the pattern of age-related transcriptional changes, we found that tissues could be classified into one of three aging processes: (1) a pattern common to neural tissues, (2) a pattern for vascular tissues, and (3) a pattern for steroid-responsive tissues. We observed that different tissues age in a coordinated fashion in individual mice, such that certain mice exhibit rapid aging, whereas others exhibit slow aging for multiple tissues. Finally, we compared the transcriptional profiles for aging in mice to those from humans, flies, and worms. We found that genes involved in the electron transport chain show common age regulation in all four species, indicating that these genes may be exceptionally good markers of aging. However, we saw no overall correlation of age regulation between mice and humans, suggesting that aging processes in mice and humans may be fundamentally different.