Miracle-dz/UniFAR-FTUs huggingface dataset:
Noise Can Induce Bimodality in Positive Transcriptional Feedback Loops Without Bistability

Bursty, Infrequent Noise In gene regulatory networks, positive feedback loops can give rise to bistability and hysteresis in gene expression, thereby allowing switching mechanisms and memory effects. To and Maheshri (p. 1142; see the Perspective by Levens and Gupta) eschew the commonly held idea that sigmoidal promoter responses are required to achieve a steady-state bimodal response in a positive feedback loop. Instead, using a model and data from an experiment, they favor noisy gene expression and multiple, noncooperative transcription factor binding as an explanation for the bimodal response, and they expect that similar noisy systems are widespread in biology. Noise induced by multiple binding sites, rather than deterministic bistability, may cause bimodal gene expression in yeast. Transcriptional positive-feedback loops are widely associated with bistability, characterized by two stable expression states that allow cells to respond to analog signals in a digital manner. Using a synthetic system in budding yeast, we show that positive feedback involving a promoter with multiple transcription factor (TF) binding sites can induce a steady-state bimodal response without cooperative binding of the TF. Deterministic models of this system do not predict bistability. Rather, the bimodal response requires a short-lived TF and stochastic fluctuations in the TF’s expression. Multiple binding sites provide these fluctuations. Because many promoters possess multiple binding sites and many TFs are unstable, positive-feedback loops in gene regulatory networks may exhibit bimodal responses, but not necessarily because of deterministic bistability, as is commonly thought.
Abundance of Ribosomal RNA Gene Copies Maintains Genome Integrity

Protective Abundance Massively repeated sequences are generally dangerous to genomes because they promote recombination and, potentially, genome instability. Eukaryotic ribosomal RNA genes (rDNA), which are highly transcribed, are organized into large arrays of repeats and have a system that actively maintains these large arrays. In getting to the bottom of this apparent contradiction, Ide et al. (p. 693) found that reducing the number of rDNA repeats in yeast resulted in a marked sensitivity to DNA damage, owing to heavy rDNA transcription preventing repair of compromised DNA replication forks. It appears that the additional copies of rDNA both reduce the ability of transcription to interfere with DNA repair and provide, through the action of condensin, templates for the recombination-based repair of replication-induced damage. In eukaryotes, multiple copies of ribosomal DNA protect it from transcription-induced replication damage. The ribosomal RNA (rDNA) gene repeats are essential housekeeping genes found in all organisms. A gene amplification system maintains large cluster(s) of tandemly repeated copies in the chromosome, with each species having a specific number of copies. Yeast has many untranscribed rDNA copies (extra copies), and we found that when they are lost, the cells become sensitive to DNA damage induced by mutagens. We show that this sensitivity is dependent on rDNA transcriptional activity, which interferes with cohesion between rDNA loci of sister chromatids. The extra rDNA copies facilitate condensin association and sister-chromatid cohesion, thereby facilitating recombinational repair. These results suggest that high concentrations of heavily transcribed genes are toxic to the cells, and therefore amplified genes, such as rDNA, have evolved.
The role of adiponectin receptors in the regulation of synaptic transmission in the hippocampus

In the last two decades adiponectin, member of the adipokines family, gained attention because of its unique antidiabetic effects. However, the presence in the brain of adiponectin receptors and adiponectin itself raised interest because of the possible association with neuropsychiatric diseases. Indeed, clinical studies found altered concentration of adiponectin both in plasma and cerebrospinal fluid in several pathologies including depression, multiple sclerosis, Alzheimer's disease and stroke. Moreover, recent preclinical studies also suggest its involvement in different physiological functions. Despite this evidence very few studies attempted to elucidate the functional role of adiponectin at the synapse. To address this question, here we investigated the effect of Adiporon, an agonist of both adiponectin receptors on synaptic transmission and LTP at Schaffer‐collateral CA1 pathway. Surprisingly, increasing concentration of Adiporon correlated with lower CA1–LTP levels and paired‐pulse ratio, whereas basal transmission was always preserved. Collectively, our data show that the adiponectin system, beyond its involvement in metabolic diseases, plays also a critical role in synaptic activity thereby representing a putative target for the treatment of synaptic pathologies.
A clustering algorithm for identifying hierarchical and overlapping protein complexes in large PPI networks

With the development of high-throughput technique, protein-protein interactions (PPIs) are increasing fast and available conveniently, which make it possible to identify protein complexes in PPI network[1-7]. Many evidences have demonstrated that protein complexes are overlapping and hierarchically organized in PPI networks[8-9], which requires protein complex detection methods can identify both overlapping and hierarchical protein complexes in a PPI network. Meanwhile, the large size of PPI network requires protein complex detection methods based on PPI network running fast. Up to now, few methods can achieve all above requirements.
Direct Evidence for Spinal Cord Involvement in Placebo Analgesia

Functional magnetic resonance imaging of the human spinal cord reveals a mechanism for placebo analgesia. Placebo analgesia is a prime example of the impact that psychological factors have on pain perception. We used functional magnetic resonance imaging of the human spinal cord to test the hypothesis that placebo analgesia results in a reduction of nociceptive processing in the spinal cord. In line with behavioral data that show decreased pain responses under placebo, pain-related activity in the spinal cord is strongly reduced under placebo. These results provide direct evidence for spinal inhibition as one mechanism of placebo analgesia and highlight that psychological factors can act on the earliest stages of pain processing in the central nervous system.
Mantle Shear-Wave Velocity Structure Beneath the Hawaiian Hot Spot

Earth's Plume Plumbing Volcanic hot spots, such as the one that continues to build the Hawaiian Islands, are thought to form by one of two mechanisms: Either mantle plumes bring hot, buoyant material to the surface from deep within the Earth's interior, or extensive processing of the upper mantle by plate tectonics causes localized volcanism in stressed or heterogeneous crust. Wolfe et al. (p. 1388; see the cover; see the news story by Kerr) used an extensive array of ocean-bottom and land-based seismometers to reveal the structure of the mantle beneath Hawaii. These high-resolution images reveal a high-temperature plume originating from the lower mantle. Extensive seismological data support a mantle plume origin for the Hawaiian volcanic hot spot. Defining the mantle structure that lies beneath hot spots is important for revealing their depth of origin. Three-dimensional images of shear-wave velocity beneath the Hawaiian Islands, obtained from a network of sea-floor and land seismometers, show an upper-mantle low-velocity anomaly that is elongated in the direction of the island chain and surrounded by a parabola-shaped high-velocity anomaly. Low velocities continue downward to the mantle transition zone between 410 and 660 kilometers depth, a result that is in agreement with prior observations of transition-zone thinning. The inclusion of SKS observations extends the resolution downward to a depth of 1500 kilometers and reveals a several-hundred-kilometer-wide region of low velocities beneath and southeast of Hawaii. These images suggest that the Hawaiian hot spot is the result of an upwelling high-temperature plume from the lower mantle.
Carbonic anhydrase inhibitor acetazolamide shifts synaptic vesicle recycling to a fast mode at the mouse neuromuscular junction

Acetazolamide (AZ), a molecule frequently used to treat different neurological syndromes, is an inhibitor of the carbonic anhydrase (CA), an enzyme that regulates pH inside and outside cells. We combined fluorescent FM styryl dyes and electrophysiological techniques at ex vivo levator auris longus neuromuscular junctions (NMJs) from mice to investigate the modulation of synaptic transmission and vesicle recycling by AZ. Transmitter release was minimally affected by AZ, as evidenced by evoked and spontaneous end‐plate potential measurements. However, optical evaluation with FM‐styryl dyes of vesicle exocytosis elicited by 50 Hz stimuli showed a strong reduction in fluorescence loss in AZ treated NMJ, an effect that was abolished by bathing the NMJ in Hepes. The remaining dye was quenched by bromophenol, a small molecule capable of diffusing inside vesicles. Furthermore, in transgenic mice expressing Synaptophysin‐pHluorin (SypHy), the fluorescence responses of motor nerve terminals to a 50 Hz train of stimuli was decrease to a 50% of controls in the presence of AZ. Immunohistochemistry experiments to evaluate the state of the Myosin light chain kinase (MLCK), an enzyme involved in vesicle recycling, demonstrated that MLCK phosphorylation was much stronger in the presence than AZ than in its absence in 50 Hz stimulated NMJs. We postulate that AZ, via cytosol acidification and activation of MLCK, shifts synaptic vesicle recycling to a fast (kiss‐and‐run) mode, which changes synaptic performance. These changes may contribute to the therapeutic action reported in many neurological syndromes like ataxia, epilepsy, and migraine.
Dysregulated Humoral Immunity to Nontyphoidal Salmonella in HIV-Infected African Adults

HIV and Salmonella HIV-positive individuals who are infected with nontyphoidal strains of Salmonella enterica often succumb to high morbidity and mortality. Why this is the case is unknown. MacLennan et al. (p. 508; see the Perspective by Moir and Fauci) have uncovered a dysregulated antibody response to Salmonella that is the likely culprit. Sera from HIV-infected individuals do a poor job of killing S. Typhimurium, despite surprisingly elevated antibody titers. Experiments showed that HIV-infected serum inhibited the power of normal serum to kill Salmonella. Inhibition was specific to antibodies against lipopolysaccharide (LPS), a component of the cell wall of Salmonella. Hence, HIV-infected sera was able to kill Salmonella strains lacking LPS, and removing LPS immunoglobulin G from infected sera permitted Salmonella killing. Thus, not only does HIV cause defects in cell-mediated immunity but it also seems to impair humoral immunity, with severe consequences for multiple infections. Abnormal antibody responses produced in HIV-infected individuals are ineffective at clearing food-poisoning bacteria. Nontyphoidal Salmonellae are a major cause of life-threatening bacteremia among HIV-infected individuals. Although cell-mediated immunity controls intracellular infection, antibodies protect against Salmonella bacteremia. We report that high-titer antibodies specific for Salmonella lipopolysaccharide (LPS) are associated with a lack of Salmonella-killing in HIV-infected African adults. Killing was restored by genetically shortening LPS from the target Salmonella or removing LPS-specific antibodies from serum. Complement-mediated killing of Salmonella by healthy serum is shown to be induced specifically by antibodies against outer membrane proteins. This killing is lost when excess antibody against Salmonella LPS is added. Thus, our study indicates that impaired immunity against nontyphoidal Salmonella bacteremia in HIV infection results from excess inhibitory antibodies against Salmonella LPS, whereas serum killing of Salmonella is induced by antibodies against outer membrane proteins.
Plasmapheresis and the Immunobiology of Myasthenia Gravis

Advances in the elucidation of the etiopathogenesis of myasthenia gravis have come rapidly in the past half decade. The advent of therapeutic plasmapheresis stands out as a practical, clinical outgrowth of this enhanced understanding of the immunobiology of myasthenia. This new therapeutic modality and the immunologic studies leading to its inception have captured the fancy of both clinicians and investigators, so it is appropriate that knowledge of the state of the art be made available to as wide an audience as possible. That task has been effectively accomplished in this volume, which contains a series of papers presented at an international symposium on plasmapharesis and the immunobiology of myasthenia held in San Francisco, June 1978. The book is divided into five parts, the first of which consists of ten papers dealing with the immunobiology of the acetylcholine receptor. Part 2 deals with thymectomy and thoracic duct drainage, their indications and
Mountaintop Mining Consequences

Damage to ecosystems and threats to human health and the lack of effective mitigation require new approaches to mining regulation. There has been a global, 30-year increase in surface mining (1), which is now the dominant driver of land-use change in the central Appalachian ecoregion of the United States (2). One major form of such mining, mountaintop mining with valley fills (MTM/VF) (3), is widespread throughout eastern Kentucky, West Virginia (WV), and southwestern Virginia. Upper elevation forests are cleared and stripped of topsoil, and explosives are used to break up rocks to access buried coal (fig. S1). Excess rock (mine “spoil”) is pushed into adjacent valleys, where it buries existing streams.
Shoulder Strength after Open versus Arthroscopic Stabilization

Background With current techniques, the main difference between arthroscopic and open shoulder stabilization is the violation of the subscapularis tendon. No studies have looked at strength differences of internal and external rotation between these groups. Hypothesis Internal rotation strength deficits will exist in patients having undergone an open shoulder stabilization procedure compared with an arthroscopic one. Study Design Piggy-back randomized controlled trial; Level of evidence, 1. Methods Forty-eight patients (38 men, 10 women), average age, 30.6 years (range, 18–59 years), were randomized to either open (n = 24) or arthroscopic (n = 24) shoulder stabilization. Rehabilitation protocols were standardized. At a mean follow-up of 19.4 months (range, 12–36 months) from surgery, patients underwent isokinetic strength testing (concentric and eccentric peak moments at 60 deg/s and 180 deg/s). Measurements were body-mass normalized. Primary outcome was internal rotation strength at 60 deg/s. Results There were no significant differences between groups with respect to age, gender, or operative limb. There were no statistical differences between operative groups for the primary outcome of internal concentric strength at 60 deg/s (mean difference, 0.011 N·m/kg; 95% confidence interval, −0.043 to 0.066; P = .677) or secondary strength measures. When compared with the contralateral limb, strength deficits existed for both surgical groups for both internal and external rotation. Regression analysis demonstrated that arm dominance is a factor in strength deficits. Conclusion The results of this trial suggest there are no side-to-side isokinetic strength deficits between patients having an open stabilization using a subscapularis splitting approach versus arthroscopic stabilization for anterior traumatic shoulder instability at 1 year after surgery. Strength deficits exist in both groups when compared with the contralateral limb.
Proximal Hamstring Strains of Stretching Type in Different Sports

Background Hamstring strains can be of at least 2 types, 1 occurring during high-speed running and the other during motions in which the hamstring muscles reach extreme lengths, as documented for sprinters and dancers. Hypothesis Hamstring strains in different sports, with similar injury situations to dancers, also show similarities in symptoms, injury location, and recovery time. Study Design Case series (prognosis); Level of evidence, 4. Methods Thirty subjects from 21 different sports were prospectively included. All subjects were examined clinically and with magnetic resonance imaging (MRI). The follow-up period lasted until the subjects returned to or finished their sport activity. Results All injuries occurred during movements reaching a position with combined extensive hip flexion and knee extension. They were located proximally in the posterior thigh, close to the ischial tuberosity. The injuries were often complex, but 83% involved the semimembranosus and its proximal free tendon. Fourteen subjects (47%) decided to end their sports activity. For the remaining 16 subjects, the median time for return to sport was 31 weeks (range, 9-104). There were no significant correlations between specific clinical or MRI parameters and time to return to sport. Conclusions In different sports, an injury situation in which the hamstring muscles reach extensive length causes a specific injury to the proximal posterior thigh, earlier described in dancers. Because of the prolonged recovery time associated with this type of injury, correct diagnosis, based on history and palpation, and adequate information to the subject are essential.
Photosynthesis in the Open Ocean

A little-understood electron flow pathway helps cyanobacteria to adapt to high-light, low-nutrient ocean environments. Global primary productivity (the fixation of carbon dioxide, CO2, into organic matter) fuels food production on land and in the sea. About half of this CO2 fixation occurs in the sea, mainly by a type of phytoplankton called cyanobacteria (1). Recent reports (2–4) have shown that a key characteristic of oxygenic photosynthesis—the electron flux through photosynthetic reaction centers coupled to oxygen (O2) evolution—is variable, thus uncoupling oxygen cycling from CO2 fixation. This insight has implications for how phytoplankton have adapted to the marine environment and for how we measure the productivity of the oceans.
Single Photon Emission Computed Tomography and Apolipoprotein E in Alzheimer's Disease: Impact of the ε4 Allele on Regional Cerebral Blood Flow

The aim of this study was to examine the impact of the apolipoprotein E (APOE) ε4 allele on semiquantitative regional cerebral blood flow (rCBF) in Alzheimer's disease. Single photon emission computed tomography tech netium (SPECT) with (99m)Tc d,1-hexamethyl propylenamine oxine was used to determine rCBF in 41 consecutive patients (18 males/23 females) with probable Alzheimer's disease according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria (mean age 71.0 years; range 54-85). The mean Mini-Mental State Examination (MMSE) score was 20.4 (range 10-30). After normalization of CBF to mean blood flow in the cerebellum, values for rCBF in several cortical regions of interest, side-to-side asymmetry indices, and anterior-posterior ratios were calculated. Determination of the APOE genotype from blood samples was performed using restriction enzyme polymerase chain reaction technique. Multivariate regression analyses and the Wilcoxon rank-sum test for unpaired data (Mann-Whitney) were used for statistical analysis. The patients comprised 27 APOE ε4-positive and 14 APOE ε4-negative individuals. Five patients were APOE ε4 homozygotes. APOE ε4-positive patients had significantly reduced rCBF in the right frontal and left occipital lobes. On nonparametric analysis, the most prominent differences between ε4-negative and ε4-positive patients were demonstrated in subregions representing the frontal association cortex (Mann-Whitney, P < .01). Age- stratified analysis suggested that these findings could be demonstrated predominantly in the elderly patients. The results of this study suggest that the APOE genotype in itself may have an impact on the pattern of rCBF deficits in Alzheimer's disease. The more pronounced reduction of rCBF in frontal association cortex observed in elderly APOE ε4-positive patients might predict clinical progression. (J Geriatr Psychiatry Neurol 2001; 14:42-51).
Reefs as Cradles of Evolution and Sources of Biodiversity in the Phanerozoic

Cradle of Diversity Is the biological diversity of reefs a result of attracting species that originated elsewhere, or are they particularly important as cradles of evolution? Kiessling et al. (p. 196; see the cover) examine a large database of fossil benthic marine organisms dating back to the Cambrian to test these questions. It seems that reefs, even in comparison to other shallow marine environments, were indeed important during the origination of new species, including ones that migrate elsewhere. Analysis of fossil evidence indicates that reefs were disproportionally important in the origination of new species. Large-scale biodiversity gradients among environments and habitats are usually attributed to a complex array of ecological and evolutionary factors. We tested the evolutionary component of such gradients by compiling the environments of the geologically oldest occurrences of marine genera and using sampling standardization to assess if originations tended to be clustered in particular environments. Shallow, tropical environments and carbonate substrates all tend to have harbored high origination rates. Diversity within these environments tended to be preferentially generated in reefs, probably because of their habitat complexity. Reefs were also prolific at exporting diversity to other environments, which might be a consequence of low-diversity habitats being more susceptible to invasions.
Asian Monsoon Transport of Pollution to the Stratosphere

Riding the Monsoon Most air transport from the troposphere to the stratosphere occurs in the tropics, but additional transport may occur in areas of strong upward convection. Randel et al. (p. 611, published online 25 March) report satellite measurements of atmospheric hydrogen cyanide over the region where the Asian summer monsoon occurs, which indicate that air is transported from the surface to deep within the stratosphere. This mechanism represents a pathway for pollutants to enter the global stratosphere, where they might affect ozone chemistry, aerosol characteristics, and radiative properties. Satellite observations of atmospheric hydrogen cyanide reveal that the Asian monsoon transports air deep into the stratosphere. Transport of air from the troposphere to the stratosphere occurs primarily in the tropics, associated with the ascending branch of the Brewer-Dobson circulation. Here, we identify the transport of air masses from the surface, through the Asian monsoon, and deep into the stratosphere, using satellite observations of hydrogen cyanide (HCN), a tropospheric pollutant produced in biomass burning. A key factor in this identification is that HCN has a strong sink from contact with the ocean; much of the air in the tropical upper troposphere is relatively depleted in HCN, and hence, broad tropical upwelling cannot be the main source for the stratosphere. The monsoon circulation provides an effective pathway for pollution from Asia, India, and Indonesia to enter the global stratosphere.