Miracle-dz/UniFAR-FTUs huggingface dataset:
Probing the Mutational Interplay between Primary and Promiscuous Protein Functions: A Computational-Experimental Approach

Protein promiscuity is of considerable interest due its role in adaptive metabolic plasticity, its fundamental connection with molecular evolution and also because of its biotechnological applications. Current views on the relation between primary and promiscuous protein activities stem largely from laboratory evolution experiments aimed at increasing promiscuous activity levels. Here, on the other hand, we attempt to assess the main features of the simultaneous modulation of the primary and promiscuous functions during the course of natural evolution. The computational/experimental approach we propose for this task involves the following steps: a function-targeted, statistical coupling analysis of evolutionary data is used to determine a set of positions likely linked to the recruitment of a promiscuous activity for a new function; a combinatorial library of mutations on this set of positions is prepared and screened for both, the primary and the promiscuous activities; a partial-least-squares reconstruction of the full combinatorial space is carried out; finally, an approximation to the Pareto set of variants with optimal primary/promiscuous activities is derived. Application of the approach to the emergence of folding catalysis in thioredoxin scaffolds reveals an unanticipated scenario: diverse patterns of primary/promiscuous activity modulation are possible, including a moderate (but likely significant in a biological context) simultaneous enhancement of both activities. We show that this scenario can be most simply explained on the basis of the conformational diversity hypothesis, although alternative interpretations cannot be ruled out. Overall, the results reported may help clarify the mechanisms of the evolution of new functions. From a different viewpoint, the partial-least-squares-reconstruction/Pareto-set-prediction approach we have introduced provides the computational basis for an efficient directed-evolution protocol aimed at the simultaneous enhancement of several protein features and should therefore open new possibilities in the engineering of multi-functional enzymes.
Infrastructure support increases the capacity of ad hoc wireless networks

In ad hoc wireless networks, one of the hottest research directions has been to increase the throughput capacity scaling with respect to the number of nodes n. Gupta and Kumar (2000) introduced a fixed random network model and showed that the throughput per source-destination pair is Theta(1/root nlogn) when the network is coordinated by a centralized entity. Grossglauser and Tse (2001) introduced a mobile random network model and showed that a source-destination pair acquires a constant throughput of Theta(1) assuming that delays incurred by mobile nodes with low mobility are tolerable.In this paper, we consider the capacity of ad hoc wireless networks with infrastructure support. Although Grossglauser-Tse mobile network model enables Theta(1) per-node throughput scaling, the mobility assumption may be too unrealistic to be accepted in some practical situations. One of the key observations we acquired is that the infrastructure support plays the same role played by the mobility in the Grossglauser-Tse model. We show that nodes can utilize the randomly located infrastructure support instead of mobility when nodes are nearly static. In this case, we show that the per-node throughput of Theta(1) is still achievable when the number of access points grows linearly with respect to the number of nodes. Furthermore. , we show that there is additional per-node throughput improvement of Theta(1) when nodes are mobile.
Alternating Sums Concerning Multiplicative Arithmetic Functions

We deduce asymptotic formulas for the alternating sums $\sum_{n\le x} (-1)^{n-1} f(n)$ and $\sum_{n\le x} (-1)^{n-1} \frac1{f(n)}$, where $f$ is one of the following classical multiplicative arithmetic functions: Euler's totient function, the Dedekind function, the sum-of-divisors function, the divisor function, the gcd-sum function. We also consider analogs of these functions, which are associated to unitary and exponential divisors, and other special functions. Some of our results improve the error terms obtained by Bordell\`{e}s and Cloitre. We formulate certain open problems.
Theophylline improves steroid sensitivity in acute alcoholic hepatitis

Corticosteroid therapy has shown some benefit in severe acute alcoholic hepatitis (AAH); however, this is limited by uncertainty in patient selection and variable clinical response. Theophylline has been shown to ameliorate impaired steroid sensitivity in chronic obstructive pulmonary disease by facilitating corticosteroid‐induced silencing of proinflammatory genes. We aimed to explore the mechanistic basis of the variable response to corticosteroid therapy seen in patients with AAH and to address the extent to which theophylline can improve this response. The ability of dexamethasone to inhibit phytohemagglutinin‐induced lymphocyte proliferation was assessed by 3H‐thymidine incorporation in 12 severe AAH patients and age‐matched and sex‐matched controls. Steroid sensitivity was measured in terms of Imax, the maximum inhibition of proliferation. The effect of 10−5 M theophylline and, in survivors, change in Imax during recovery were observed. Lymphocyte steroid sensitivity was found to be significantly reduced in AAH compared with controls (Imax 67[±4.5]% versus 95[±2.3]%, P = 0.0002) and correlated with clinical markers of steroid responsiveness. In survivors, Imax increased in recovery. Theophylline 10−5 M significantly increased lymphocyte steroid sensitivity (Imax 86[±6.6]% versus 67[±5.0]%, P = 0.027). Conclusion: Acute alcoholic hepatitis is associated with significant lymphocyte steroid insensitivity, which improves in recovery and can be ameliorated ex vivo by theophylline. This offers potential to rationalize corticosteroid prescribing in AAH and, furthermore, justifies investigation of this novel role for an existing pharmacological agent in this common and frequently fatal condition. (HEPATOLOGY 2010;)
Evolutionary and experimental change in egg volume, heterochrony of larval body and juvenile rudiment, and evolutionary reversibility in pluteus form

SUMMARY Heterochronic developmental plasticity of the juvenile rudiment and larval body of sea urchin larvae occurs in response to supply of food. Evolutionary increase in egg size can also be associated with earlier development of the juvenile rudiment. We examined effects of egg volume of feeding larvae on this heterochrony and other changes in larval form. (1) Evolutionary and experimental enlargements of egg volume did not accelerate formation of the rudiment relative to the larval body. Development of the larval body and juvenile rudiment was compared for the echinoids Strongylocentrotus purpuratus (with an egg of 78–82 μm) and Strongylocentrotus droebachiensis (with an egg of 150–160 μm diameter). Development of both larval body and rudiment were accelerated in S. droebachiensis relative to S. purpuratus but with greater acceleration of the larval body, so that the rudiment of S. droebachiensis was initiated at a later larval stage even though at an earlier age. Also, experimentally doubling the egg volume of S. purpuratus did not accelerate development of the juvenile rudiment relative to the larval body. (2) Both species exhibited similar plasticity in timing of rudiment development in response to food supplies. (3) Doubling egg volume of S. purpuratus produced a larval form more similar to that of S. droebachiensis. This result mirrors previous experiments in which larvae from half embryos of S. droebachiensis were more similar to larvae of S. purpuratus. Many of the effects of egg volume on larval form are similar against either species' genetic background and are thus evolutionarily reversible effects on larval form.
Making a silk purse out of two sow's ears: young children's use of comparison in category learning.

Comparison mechanisms have been implicated in the development of abstract, relational thought, including object categorization. D. Gentner and L. L. Namy (1999) found that comparing 2 perceptually similar category members yielded taxonomic categorization, whereas viewing a single member of the target category elicited shallower perceptual responding. The present experiments tested 2 predictions that follow from Gentner and Namy's (1999) model: (a) Comparison facilitates categorization only when the targets to be compared share relational commonalities, and (b) providing common labels for targets invites comparison, whereas providing conflicting labels deters it. Four-year-olds participated in a forced-choice task. They viewed 2 perceptually similar target objects and were asked to "find another one. " Results suggest an important role for comparison in lexical and conceptual development.
Treadmill exercise alleviates nigrostriatal dopaminergic loss of neurons and fibers in rotenone-induced Parkinson rats

Parkinson disease is one of the common brain diseases caused by dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. In the present study, the effects of treadmill exercise on motor performance, dopaminergic loss of neurons and fibers, and α-synuclein expression in the nigrostriatum were evaluated using rotenone-induced Parkinson rats. For the induction of Parkinson rats, 3-mg/kg rotenone was injected, once a day for 14 consecutive days. Treadmill running was conducted for 30 min once a day during 14 consecutive days. Rota-rod test for motor balance and coordination and immunohistochemistry for tyrosine hydroxylase and α-synuclein in the nigrostriatum were performed. In the present study, motor balance and coordination was disturbed by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated motor dysfunction in the rotenone-induced Parkinson rats. Nigrostriatal dopaminergic loss of neurons and fibers was occurred by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated nigrostriatal dopaminergic loss of neurons and fibers in the rotenone-induced Parkinson rats. α-Synuclein expression in the nigrostriatum was enhanced by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise suppressed α-synuclein expression in the rotenone-induced Parkinson rats. Treadmill exercise improved motor function through preservation of nigrostriatal dopaminergic neurons and fibers and suppression of nigrostriatal formation of Lewy bodies in rotenone-induced Parkinson rats.
Robustness of Synchronization of Heterogeneous Agents by Strong Coupling and a Large Number of Agents

This technical note studies robustness of synchronization against heterogeneity of multi-agent systems. Here, heterogeneity also includes uncertainties and external disturbances in each agent. In order to effectively deal with the heterogeneous agents, we introduce the concept of the averaged dynamics which is the average of all agents' dynamics, and then claim that two sources enhance the robustness of synchronized behavior against heterogeneity of agents' dynamics. First, in spite of the heterogeneity of agents' dynamics, we show that strong coupling among agents makes the trajectories of all agents arbitrarily close to the averaged dynamics. Second, in the averaged dynamics, the effect of variations in each agent gets smaller as the number of agents increases. Simulation results confirm the claim that a large number of agents with strong couplings have robust synchronization.
Analysis of the importance of family in the development of sense of coherence during adolescence

Aims: The aim of this work was to study the influence of several family dimensions on sense of coherence (SOC) in adolescence, controlling the possible effects from the demographic variables, gender and age. Methods: The sample consisted of 7580 adolescents between the ages of 13 and 18, who had taken part in the 2010 edition of the WHO Health Behaviour in School-aged Children study in Spain. Results: The results showed that there were no significant gender differences in SOC levels. However, age had a significant influence on SOC. Higher levels of SOC were found in adolescents aged 13 and 14 compared to older participants. Family variables explained 18% of SOC variability, with affection, easy communication with parents, and parental knowledge as the most outstanding variables. In addition, positive relationships between parents and family affluence had a significant role in explaining SOC levels. Conclusions: The results suggest that the family context plays an important role in providing meaningful experiences for the development of a strong SOC in adolescence.
A Highly Efficient Reconfigurable Charge Pump Energy Harvester With Wide Harvesting Range and Two-Dimensional MPPT for Internet of Things

A monolithic microwatt-level charge pump energy harvester is proposed for smart nodes of Internet of Things (IOT) networks. Due to the variation of the available voltage and power in IOT scenarios, the charge pump was optimized by the proposed architecture and circuit level innovations. First, a reconfigurable charge pump is introduced to provide the hybrid conversion ratios (CRs) as 1[1/3]× up to 8× for minimizing the charge redistribution loss. Second, the reconfigurable feature also dynamically tunes to maximum power point tracking (MPPT) with the frequency modulation, resulting in a two-dimensional (2-D) MPPT. Therefore, the voltage conversion efficiency (VCE) and the power conversion efficiency (PCE) are enhanced and flattened. Third, the constanton-time (COT) scheme from the regulation part was reused with the proposed MPPT arbiter as a sensing approach, which eliminates the conventional power hungry current sensor. The proposed energy harvester is capable of harvesting various energy sources, such as a photovoltaic (PV) cell and a thermoelectric generator (TEG), with a wide input range from 0.45 to 3 V and a regulated 3.3 V output voltage for the IOT smart nodes. Measured results showed that the harvester achieved a flattened and improved PCE as high as 89% for ultra-low power operation capability below 50 μW.
Optimally Cutting a Surface into a Disk

Abstract We consider the problem of cutting a subset of the edges of a polyhedral manifold surface, possibly with boundary, to obtain a single topological disk, minimizing either the total number of cut edges or their total length. We show that this problem is NP-hard in general, even for manifolds without boundary and for punctured spheres. We also describe an algorithm with running time nO(g+k), where n is the combinatorial complexity, g is the genus, and k is the number of boundary components of the input surface. Finally, we describe a greedy algorithm that outputs a O(log2g)-approximation of the minimum cut graph in O(g2n log n) time.
Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein

To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs) of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II), and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of pMHC formation or TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.
Use of FMRI to predict recovery from unipolar depression with cognitive behavior therapy.

OBJECTIVE In controlled treatment trials, 40%-60% of unmedicated depressed individuals respond to cognitive behavior therapy (CBT). The authors examined whether pretreatment neural reactivity to emotional stimuli accounted for this variation. METHOD Unmedicated depressed individuals (N=14) and never depressed comparison subjects (N=21) underwent fMRI during performance of a task sensitive to sustained emotional information processing. Afterward, depressed participants completed 16 sessions of CBT. RESULTS Participants whose sustained reactivity to emotional stimuli was low in the subgenual cingulate cortex (Brodmann's area 25) and high in the amygdala displayed the strongest improvement with CBT. CONCLUSIONS The presence of emotion regulation disruptions, which are targeted in CBT, may be the key to recovery with this intervention.
Fibroblast Growth Factor‐23 Concentration in Dogs with Chronic Kidney Disease

Background Chronic kidney disease (CKD) is associated with hyperphosphatemia, decreased vitamin D metabolite concentrations, and hyperparathyroidism. This syndrome is known as CKD‐mineral bone disorder (CKD‐MBD). Recently, it has been shown that an increase in fibroblast growth factor‐23 (FGF‐23) concentration is an early biomarker of CKD in people. It is an independent risk factor for both progression of renal disease and survival time in humans and cats with CKD. Information about FGF‐23 in healthy dogs and those with CKD is lacking. Objectives To measure FGF‐23 concentration in dogs with different stages of CKD and determine its association with factors involved in CKD‐MBD, including serum phosphorus and parathyroid hormone (PTH) concentrations. A secondary aim was to validate an ELISA for measurement of plasma FGF‐23 concentration in dogs. Animals Thirty‐two client‐owned dogs with naturally occurring CKD and 10 healthy control dogs. Methods Prospective cross‐sectional study. An FGF‐23 ELISA was used to measure plasma FGF‐23 concentration in dogs and their association with serum creatinine, phosphorus, calcium, and PTH concentrations. Results Plasma FGF‐23 concentrations increased with severity of CKD and were significantly different between IRIS stages 1 and 2 versus stages 3 and 4 (P < .0001). Increases in FGF‐23 concentrations were more frequent than hyperparathyroidism or hyperphosphatemia in this cohort. Serum creatinine and phosphorus concentrations were the strongest independent predictors of FGF‐23 concentration. Conclusions and clinical importance Plasma FGF‐23 concentrations increase in dogs with CKD as disease progresses. Plasma FGF‐23 concentrations appear to be useful for further study of the pathophysiology of CKD‐MBD in dogs.
MDA-5 Is Cleaved in Poliovirus-Infected Cells

ABSTRACT Infections with RNA viruses are sensed by the innate immune system through membrane-bound Toll-like receptors or the cytoplasmic RNA helicases RIG-I and MDA-5. It is believed that MDA-5 is crucial for sensing infections by picornaviruses, but there have been no studies on the role of this protein during infection with poliovirus, the prototypic picornavirus. Beginning at 4 h postinfection, MDA-5 protein is degraded in poliovirus-infected cells. Levels of MDA-5 declined beginning at 6 h after infection with rhinovirus type 1a or encephalomyocarditis virus, but the protein was stable in cells infected with rhinovirus type 16 or echovirus type 1. Cleavage of MDA-5 is not carried out by either poliovirus proteinase 2Apro or 3Cpro. Instead, degradation of MDA-5 in poliovirus-infected cells occurs in a proteasome- and caspase-dependent manner. Degradation of MDA-5 during poliovirus infection correlates with cleavage of poly(ADP) ribose polymerase (PARP), a hallmark of apoptosis. Induction of apoptosis by puromycin leads to cleavage of both PARP and MDA-5. The MDA-5 cleavage product observed in cells treated with puromycin is ∼90 kDa, similar in size to the putative cleavage product observed in poliovirus-infected cells. Poliovirus-induced cleavage of MDA-5 may be a mechanism to antagonize production of type I interferon in response to viral infection.
Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function

The tight junction protein claudin-10 is known to exist in two isoforms, resulting from two alternative exons, 1a and 1b (Cldn10a, Cldn10b). Here, we identified and characterized another four claudin-10 splice variants in mouse and human. One (Cldn10a_v1) results from an alternative splice donor site, causing a deletion of the last 57 nucleotides of exon 1a. For each of these three variants one further splice variant was identified (Cldn10a_v2, Cldn10a_v3, Cldn10b_v1), lacking exon 4. When transfected into MDCK cells, Cldn10a, Cldn10a_v1 and Cldn10b were inserted into the tight junction, whereas isoforms of splice variants lacking exon 4 were retained in the endoplasmic reticulum. Cldn10a transfection into MDCK cells confirmed the previously described increase in paracellular anion permeability. Cldn10a_v1 transfection had no direct effect, but modulated Cldn10a-induced organic anion permeability. At variance with previous reports in MDCK-II cells, transfection of high-resistance MDCK-C7 cells with Cldn10b dramatically decreased transepithelial resistance, increased cation permeability, and changed monovalent cation selectivity from Eisenman sequence IV to X, indicating the presence of a high field-strength binding site that almost completely removes the hydration shell of the permeating cations. The extent of all these effects strongly depended on the endogenous claudins of the transfected cells.
Arthroscopic Stabilization of Anterior Shoulder Instability

T he treatment of recurrent anterior glenohumeral instability has been a topic of debate in the recent literature. Current operative management of shoulder instability has included a variety of open and arthroscopic surgical procedures. Open techniques for anterior reconstruction have been quite successful in preventing recurrent dislocations and continue to be the gold standard of care. In an attempt to address some of the disadvantages associated with open procedures, arthroscopic stabilization procedures have been developed. Arthroscopic capsuloligamentous repair has several clear advantages including better cosmesis, decreased peri-operative morbidity, and a possible decrease in the loss of external rotation. Advances in arthroscopic equipment and improved arthroscopic techniques have increased the popularity of arthroscopic stabilization. Recent improvements in the results of arthroscopic stabilization are related to the understanding that the Bankart lesion is not the “essential lesion” surgeons once thought. The art of diagnosing the anatomic pathology associated with instability and proper patient selection continues to evolve. Most previous reports of arthroscopic stabilization have included small numbers of patients, variable patient pathology, and a variety of surgical techniques, making comparisons between stabilization procedures difficult. Arthroscopy can be valuable in both the confirmation of the degree and severity of the instability and to potentially correct the pathoanatomy responsible for the instability.
Demonstration Abstract: Wireless Ad Hoc Podcasting

Podcasting has become a very popular and successful Internet service in a short time. This success illustrates the interest for participatory broadcasting, in its actual form however, podcasting is only available with fixed infrastructure support to retrieve publicized episodes. We aim at releasing this limitation and present herein our podcasting system architecture together with a prototype implementation based on opportunistic wireless networking that allows us to extend podcasting to ad hoc domains.