Miracle-dz/UniFAR-FTUs huggingface dataset:
Host Defense Peptide Resistance Contributes to Colonization and Maximal Intestinal Pathology by Crohn's Disease-Associated Adherent-Invasive Escherichia coli

ABSTRACT Host defense peptides secreted by colonocytes and Paneth cells play a key role in innate host defenses in the gut. In Crohn's disease, the burden of tissue-associated Escherichia coli commonly increases at epithelial surfaces where host defense peptides concentrate, suggesting that this bacterial population might actively resist this mechanism of bacterial killing. Adherent-invasive E. coli (AIEC) is associated with Crohn's disease; however, the colonization determinants of AIEC in the inflamed gut are undefined. Here, we establish that host defense peptide resistance contributes to host colonization by Crohn's-associated AIEC. We identified a plasmid-encoded genomic island (called PI-6) in AIEC strain NRG857c that confers high-level resistance to α-helical cationic peptides and α- and β-defensins. Deletion of PI-6 sensitized strain NRG857c to these host defense molecules, reduced its competitive fitness in a mouse model of infection, and attenuated its ability to induce cecal pathology. This phenotype is due to two genes in PI-6, arlA, which encodes a Mig-14 family protein implicated in defensin resistance, and arlC, an OmpT family outer membrane protease. Implicit in these findings are new bacterial targets whose inhibition might limit AIEC burden and disease in the gut.
New Iron Acquisition System in Bacteroidetes

ABSTRACT Capnocytophaga canimorsus, a dog mouth commensal and a member of the Bacteroidetes phylum, causes rare but often fatal septicemia in humans that have been in contact with a dog. Here, we show that C. canimorsus strains isolated from human infections grow readily in heat-inactivated human serum and that this property depends on a typical polysaccharide utilization locus (PUL), namely, PUL3 in strain Cc5. PUL are a hallmark of Bacteroidetes, and they encode various products, including surface protein complexes that capture and process polysaccharides or glycoproteins. The archetype system is the Bacteroides thetaiotaomicron Sus system, devoted to starch utilization. Unexpectedly, PUL3 conferred the capacity to acquire iron from serotransferrin (STF), and this capacity required each of the seven encoded proteins, indicating that a whole Sus-like machinery is acting as an iron capture system (ICS), a new and unexpected function for Sus-like machinery. No siderophore could be detected in the culture supernatant of C. canimorsus, suggesting that the Sus-like machinery captures iron directly from transferrin, but this could not be formally demonstrated. The seven genes of the ICS were found in the genomes of several opportunistic pathogens from the Capnocytophaga and Prevotella genera, in different isolates of the severe poultry pathogen Riemerella anatipestifer, and in strains of Bacteroides fragilis and Odoribacter splanchnicus isolated from human infections. Thus, this study describes a new type of ICS that evolved in Bacteroidetes from a polysaccharide utilization system and most likely represents an important virulence factor in this group.
Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

ABSTRACT The bacterial pathogen Pseudomonas aeruginosa causes acute infections associated with significant morbidity and mortality. P. aeruginosa elicits strong innate immune responses in immunocompetent hosts, and the resulting recruitment of neutrophils to the site of infection is necessary for bacterial clearance. P. aeruginosa lipopolysaccharide and flagellin are recognized by extracellular Toll-like receptors, but the most rapid responses to infection occur when cytosolic receptors sense flagellin or type 3 secretion system (T3SS) structural proteins. The subsequent activation of the NLRC4 inflammasome and caspase-1 generates an interleukin-1β (IL-1β) signal that is required for the rapid neutrophilic response. A T3SS effector, exotoxin U (ExoU), can inhibit activation of the NLRC4 inflammasome and caspase-1. Thus, our observation that IL-1 receptor (IL-1R)-mediated signals were still required to initiate a response to ExoU-producing bacteria was unexpected. As both IL-1α and IL-1β signal via the IL-1R, we examined immune responses in mice lacking either of these cytokines. IL-1β-deficient mice responded to ExoU-producing P. aeruginosa bacteria similarly to wild-type animals; however, IL-1α-deficient mice had an attenuated immune response. The situation was reversed following infections by ExoU-negative bacteria: here, IL-1α was dispensable for neutrophil recruitment, while IL-1β was required. IL-1α secretion by macrophages infected with ExoU-producing P. aeruginosa isolates was independent of both caspase-1 and caspase-11. This study documents distinct roles for IL-1α and IL-1β in the response to P. aeruginosa infection as a function of the T3SS effectors produced by the infecting strain. The redundancy of these two cytokines nonetheless allows the infected host to mount a response to ExoU-positive and -negative bacterial isolates.
Improving Gait in Multiple Sclerosis Using Robot-Assisted, Body Weight Supported Treadmill Training

Background. The majority of patients with multiple sclerosis (MS) develop progressive gait impairment, which can start early in the disease and worsen over a lifetime. A promising outpatient intervention to help improve gait function with potential for addressing this treatment gap is task-repetitive gait training. Methods. Body weight supported treadmill training (BWSTT) with or without robotic assistance (Lokomat) was tested using a randomized crossover design in 13 patients with relapsing-remitting, secondary progressive or primary progressive MS. Patients received 6 training sessions over 3 weeks of each intervention. Outcomes included changes in the timed 25-foot walk (T25FW), the 6-minute walk treadmill test (6MW) distance, the Kurtzke Expanded Disability Status Scale (EDSS), as well as double-limb support time and step length ratio. Results. There were no major differences in outcomes between treatment groups. The study population significantly improved on gait outcomes and the EDSS following BWSTT, including a 31% improvement in the T25FW, a 38.5% improvement in the 6MW, and a 1-point gain for the EDSS. Differences in pre/post changes were noted depending on gender, disease subtype, affected limb, and baseline EDSS. Conclusions. Although no differences in gait outcomes or the EDSS were found between treatment groups, this small pilot study of task-repetitive gait training resulted in significant within-subject improvements. BWSTT appears to be an activity-dependent intervention with potential to reduce gait impairment in MS.
In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A2

ABSTRACT We have previously shown that secreted phospholipases A2 (sPLA2s) from animal venoms inhibit the in vitro development of Plasmodium falciparum, the agent of malaria. In addition, the inflammatory-type human group IIA (hGIIA) sPLA2 circulates at high levels in the serum of malaria patients. However, the role of the different human sPLA2s in host defense against P. falciparum has not been investigated. We show here that 4 out of 10 human sPLA2s, namely, hGX, hGIIF, hGIII, and hGV, exhibit potent in vitro anti-Plasmodium properties with half-maximal inhibitory concentrations (IC50s) of 2.9 ± 2.4, 10.7 ± 2.1, 16.5 ± 9.7, and 94.2 ± 41.9 nM, respectively. Other human sPLA2s, including hGIIA, are inactive. The inhibition is dependent on sPLA2 catalytic activity and primarily due to hydrolysis of plasma lipoproteins from the parasite culture. Accordingly, purified lipoproteins that have been prehydrolyzed by hGX, hGIIF, hGIII, and hGV are more toxic to P. falciparum than native lipoproteins. However, the total enzymatic activities of human sPLA2s on purified lipoproteins or plasma did not reflect their inhibitory activities on P. falciparum. For instance, hGIIF is 9-fold more toxic than hGV but releases a lower quantity of nonesterified fatty acids (NEFAs). Lipidomic analyses of released NEFAs from lipoproteins demonstrate that sPLA2s with anti-Plasmodium properties are those that release polyunsaturated fatty acids (PUFAs), with hGIIF being the most selective enzyme. NEFAs purified from lipoproteins hydrolyzed by hGIIF were more potent at inhibiting P. falciparum than those from hGV, and PUFA-enriched liposomes hydrolyzed by sPLA2s were highly toxic, demonstrating the critical role of PUFAs. The selectivity of sPLA2s toward low- and high-density (LDL and HDL, respectively) lipoproteins and their ability to directly attack parasitized erythrocytes further explain their anti-Plasmodium activity. Together, our findings indicate that 4 human sPLA2s are active against P. falciparum in vitro and pave the way to future investigations on their in vivo contribution in malaria pathophysiology.
The Fagerstrom test for nicotine dependence and its relationship to NRT use and readiness‐to‐quit

Scores on the Fagerstrom Test for Nicotine Dependence are used as a basis for recommending nicotine replacement therapy (NRT) as an aid to smoking cessation on a number of commercial websites. This study investigated (a) whether dependence on nicotine per se was necessary to score highly on the FTND and (b) whether successful quitters using NRT, with matched scores on the FTND, would report greater difficulty in stopping than successful quitters not using NRT. The paper reports a study with two inter‐related parts. In the first part, 24 smokers and 24 never‐smokers completed the FTND. The never‐smokers were asked to respond as if they were smokers. No significant differences were found between groups either at the total or individual‐item level, suggesting that results can derive from motivated or strategic responding. In part 2, 28 ex‐smokers were matched for age, gender, and FTND scores. Half had used NRT (nicotine patches) and half had not. NRT users reported that smoking was subjectively harder to give up (p<0.05). There was a general attribution across both NRT and non‐NRT groups to internal psychological factors being important for cessation. It is suggested that both high‐dependent scores on the FTND and NRT use are consequences of common motivation and a general ‘readiness to quit’.
Love's Executioner, and Other Tales of Psychotherapy

Self-portraiture is possibly the vainest of art forms, whether it be on paper or canvas. It suffers most when the artist is either only marginally talented or, even worse, amateurish. Dr Yalom is neither. He is professor of psychiatry at Stanford University and author of a classic work on group therapy. Love's Executioner is in keen contrast to those usually trite works commonly depicting how the young intern wades through his newly discovered state of humility and exhaustion along relatively well-lit training pathways toward physicianhood. Somehow, these almost universal experiences are presented to an enthralled public that vicariously enjoys these "original" discoveries, which could only be precious to the ingenue. Love's Executioner tells the stories of ten patients. More than a presentation in the fashion of titillating psychological vignettes, but also offering more than typically sterile case presentations, it depicts a psychiatrist's adventures in a number of clinical situations that,
Upper Extremity Function in Persons with Tetraplegia: Relationships Between Strength, Capacity, and the Spinal Cord Independence Measure

Objective. To quantify the relationship between the Spinal Cord Independence Measure III (SCIM III), arm and hand muscle strength, and hand function tests in persons with tetraplegia. Methods. A total of 29 individuals with tetraplegia (motor level between cervical 4 and thoracic 1; sensory-motor complete and incomplete) participated. The total score, category scores, and separate items of the SCIM III were compared to the upper extremity motor score (UEMS), an extended manual muscle test (MMT) for 11 upper extremity muscles, and 6 functional capacity tests of the hand. Spearman's correlation coefficients (r s) and regression analyses were performed. Results. The SCIM III sum score correlated well with the sum scores of the 3 tests (r s ≥ .76). The SCIM III self-care category correlated better with the tests ( r s ≥ .80) compared to the other categories (r s ≤ .72). The SCIM III self-care item “grooming” highly correlated with muscle strength and hand capacity items (r s ≥ .80). A combination of hand muscle tests and the key grasping task explained over 90% of the variability in the self-care category scores. Conclusions. The SCIM III self-care category reflects upper extremity performance as it contains especially useful and valid items that relate to upper extremity function and capacity tests.
Intracellular Trafficking of AIP56, an NF-κB-Cleaving Toxin from Photobacterium damselae subsp. piscicida

ABSTRACT AIP56 (apoptosis-inducing protein of 56 kDa) is a metalloprotease AB toxin secreted by Photobacterium damselae subsp. piscicida that acts by cleaving NF-κB. During infection, AIP56 spreads systemically and depletes phagocytes by postapoptotic secondary necrosis, impairing the host phagocytic defense and contributing to the genesis of infection-associated necrotic lesions. Here we show that mouse bone marrow-derived macrophages (mBMDM) intoxicated by AIP56 undergo NF-κB p65 depletion and apoptosis. Similarly to what was reported for sea bass phagocytes, intoxication of mBMDM involves interaction of AIP56 C-terminal region with cell surface components, suggesting the existence of a conserved receptor. Biochemical approaches and confocal microscopy revealed that AIP56 undergoes clathrin-dependent endocytosis, reaches early endosomes, and follows the recycling pathway. Translocation of AIP56 into the cytosol requires endosome acidification, and an acidic pulse triggers translocation of cell surface-bound AIP56 into the cytosol. Accordingly, at acidic pH, AIP56 becomes more hydrophobic, interacting with artificial lipid bilayer membranes. Altogether, these data indicate that AIP56 is a short-trip toxin that reaches the cytosol using an acidic-pH-dependent mechanism, probably from early endosomes. Usually, for short-trip AB toxins, a minor pool reaches the cytosol by translocating from endosomes, whereas the rest is routed to lysosomes for degradation. Here we demonstrate that part of endocytosed AIP56 is recycled back and released extracellularly through a mechanism requiring phosphoinositide 3-kinase (PI3K) activity but independent of endosome acidification. So far, we have been unable to detect biological activity of recycled AIP56, thereby bringing into question its biological relevance as well as the importance of the recycling pathway.
Detecting mobile botnets through machine learning and system calls analysis

Botnets have been a serious threat to the Internet security. With the constant sophistication and the resilience of them, a new trend has emerged, shifting botnets from the traditional desktop to the mobile environment. As in the desktop domain, detecting mobile botnets is essential to minimize the threat that they impose. Along the diverse set of strategies applied to detect these botnets, the ones that show the best and most generalized results involve discovering patterns in their anomalous behavior. In the mobile botnet field, one way to detect these patterns is by analyzing the operation parameters of this kind of applications. In this paper, we present an anomaly-based and host-based approach to detect mobile botnets. The proposed approach uses machine learning algorithms to identify anomalous behaviors in statistical features extracted from system calls. Using a self-generated dataset containing 13 families of mobile botnets and legitimate applications, we were able to test the performance of our approach in a close-to-reality scenario. The proposed approach achieved great results, including low false positive rates and high true detection rates.
Behavioral and Neurophysiological Effects of Repetitive Transcranial Magnetic Stimulation on the Minimally Conscious State

Background. In 2007, Schiff et al reported a patient in a minimally conscious state (MCS) who responded to deep brain stimulation (DBS), but clinicians cannot predict which patients might respond prior to the implantation of electrodes. Methods. A patient in a MCS for 5 years participated in an ABA design alternating between repetitive transcranial magnetic stimulation (rTMS) and peripheral nerve stimulation. rTMS (condition A) involved the delivery of 10 trains of 100 stimuli at 20 Hz using a stimulator with a 70-mm figure-of-eight coil to elicit a contraction of the abductor pollicis brevis. Condition B used median nerve electrical stimulation. Results. After peripheral stimulation, the patient did not exhibit clinical, behavioral, or electroencephalographic (EEG) changes. The frequency of specific and meaningful behaviors increased after rTMS, along with the absolute and relative power of the EEG δ, β, and α bands. Conclusion. These results suggest that rTMS may improve awareness and arousal in MCS. If these results are reproducible, rTMS may identify subgroups of MCS patients who might benefit from DBS.
Customized interactive robotic treatment for stroke: EMG-triggered therapy

A system for electromyographic (EMG) triggering of robot-assisted therapy (dubbed the EMG game) for stroke patients is presented. The onset of a patient's attempt to move is detected by monitoring EMG in selected muscles, whereupon the robot assists her or him to perform point-to-point movements in a horizontal plane. Besides delivering customized robot-assisted therapy, the system can record signals that may be useful to better understand the process of recovery from stroke. Preliminary experiments aimed at testing the proposed system and gaining insight into the potential of EMG-triggered, robot-assisted therapy are reported.
Klebsiella pneumoniae Yersiniabactin Promotes Respiratory Tract Infection through Evasion of Lipocalin 2

ABSTRACT Klebsiella pneumoniae is a pathogen of increasing concern because of multidrug resistance, especially due to K. pneumoniae carbapenemases (KPCs). K. pneumoniae must acquire iron to replicate, and it utilizes iron-scavenging siderophores, such as enterobactin (Ent). The innate immune protein lipocalin 2 (Lcn2) is able to specifically bind Ent and disrupt iron acquisition. To determine whether K. pneumoniae must produce Lcn2-resistant siderophores to cause disease, we examined siderophore production by clinical isolates (n = 129) from respiratory, urine, blood, and stool samples and by defined siderophore mutants through genotyping and liquid chromatography-mass spectrometry. Three categories of K. pneumoniae isolates were identified: enterobactin positive (Ent+) (81%), enterobactin and yersiniabactin positive (Ent+ Ybt+) (17%), and enterobactin and salmochelin (glycosylated Ent) positive (Ent+ gly-Ent+) with or without Ybt (2%). Ent+ Ybt+ strains were significantly overrepresented among respiratory tract isolates (P = 0.0068) and β-lactam-resistant isolates (P = 0.0019), including the epidemic KPC-producing clone multilocus sequence type 258 (ST258). In ex vivo growth assays, gly-Ent but not Ybt allowed evasion of Lcn2 in human serum, whereas siderophores were dispensable for growth in human urine. In a murine pneumonia model, an Ent+ strain was an opportunistic pathogen that was completely inhibited by Lcn2 but caused severe, disseminated disease in Lcn2 −/− mice. In contrast, an Ent+ Ybt+ strain was a frank respiratory pathogen, causing pneumonia despite Lcn2. However, Lcn2 retained partial protection against disseminated disease. In summary, Ybt is a virulence factor that is prevalent among KPC-producing K. pneumoniae isolates and promotes respiratory tract infections through evasion of Lcn2.
Recovery of Coordinated Gait

Background. No single intervention restores the coordinated components of gait after stroke. Objective. The authors tested the multimodal Gait Training Protocol, with or without functional electrical stimulation (FES), to improve volitional walking (without FES) in patients with persistent (>6 months) dyscoordinated gait. Methods. A total of 53 subjects were stratified and randomly allocated to either FES with intramuscular (IM) electrodes (FES-IM) or No-FES. Both groups received 1.5-hour training sessions 4 times a week for 12 weeks of coordination exercises, body weight–supported treadmill training (BWSTT), and over-ground walking, provided with FES-IM or No-FES. The primary outcome was the Gait Assessment and Intervention Tool (G.A.I.T.) of coordinated movement components, with secondary measures, including manual muscle testing, isolated leg movements (Fugl-Meyer scale), 6-Minute Walk Test, and Locomotion/Mobility subscale of the Functional Independence Measure (FIM). Results. No baseline differences in subject characteristics and measures were found. The G.A.I.T. showed an additive advantage with FES-IM versus No-FES (parameter statistic 1.10; P = .045, 95% CI = 0.023-2.179) at the end of training. For both FES-IM and No-FES, a within-group, pre/posttreatment gain was present for all measures (P < .05), and a continued benefit from mid- to posttreatment (P < .05) was present. For FES-IM, recovered coordinated gait persisted at 6-month follow-up but not for No-FES. Conclusion. Improved gait coordination and function were produced by the multimodal Gait Training Protocol. FES-IM added significant gains that were maintained for 6 months after the completion of training.
Atrophy and Intramuscular Fat in Specific Muscles of the Thigh

Purpose. Sarcopenia and increased fat infiltration in muscle may play a role in the functional impairment and high risk for diabetes in stroke. Our purpose was to compare muscle volume and muscle attenuation across 6 muscles of the paretic and nonparetic thigh and examine the relationships between intramuscular fat and insulin resistance and between muscle volume and strength in stroke patients. Methods. Stroke participants (70; 39 men, 31 women) aged 40 to 84 years, BMI = 16 to 45 kg/m2 underwent multiple thigh CT scans, total body scan by DXA (dual-energy X-ray absorptiometry), peak oxygen intake (VO2peak) graded treadmill test, 6-minute walk, fasting blood draws, and isokinetic strength testing. Results. Muscle volume is 24% lower and subcutaneous fat volume is 5% higher in the paretic versus nonparetic thigh. Muscle attenuation (index of amount of fat infiltration in muscle) is 17% higher in the nonparetic midthigh than the paretic. The semitendinosis/semimembranosis, biceps femoris, sartorius, vastus (medialis/lateralis), and rectus femoris have lower (between 9% and 19%) muscle areas on the paretic than the nonparetic thigh. Muscle attenuation is 15% to 25% higher on the nonparetic than the paretic side for 5 of 6 muscles. The nonparetic midthigh muscle attenuation is negatively associated with insulin. Eccentric peak torque of the nonparetic leg and paretic leg are associated with the corresponding muscle volume. Conclusions. The skeletal muscle atrophy, increased fat around and within muscle, and ensuing muscular weakness observed in chronic stroke patients relates to diabetes risk and may impair functional mobility and independence.