Miracle-dz/UniFAR-FTUs huggingface dataset:
Lipoproteome screening of the Lyme disease agent identifies inhibitors of antibody-mediated complement killing

Significance Spirochetal pathogens encode an abundance of lipoproteins that can provide a critical interface with the host environment. Borrelia burgdorferi, the model species for spirochetal biology, must survive an enzootic life cycle defined by fluctuations between vector (tick) and vertebrate host. While B. burgdorferi expresses over 80 surface lipoproteins—many of which likely contribute to host survival—the B. burgdorferi lipoproteome is poorly characterized. Here, we generated a platform to rapidly identify targets of B. burgdorferi surface lipoproteins and identified two paralogs that confer resistance to antibody-initiated complement killing that may promote survival in immunocompetent hosts. This work expands our understanding of complement evasion mechanisms and points toward a discovery approach for identifying host–pathogen interactions central to spirochete pathogenesis.
Retrograde transport of CDMPR depends on several machineries as analyzed by sulfatable nanobodies

Nanobody toolkit enables the quantitative analysis of endosome-to-TGN transport of the mannose-6-phosphate receptor in cells depleted of retrograde transport machineries Retrograde protein transport from the cell surface and endosomes to the TGN is essential for membrane homeostasis in general and for the recycling of mannose-6-phosphate receptors (MPRs) for sorting of lysosomal hydrolases in particular. We used a nanobody-based sulfation tool to more directly determine transport kinetics from the plasma membrane to the TGN for the cation-dependent MPR (CDMPR) with and without rapid or gradual inactivation of candidate machinery proteins. Although knockdown of retromer (Vps26), epsinR, or Rab9a reduced CDMPR arrival to the TGN, no effect was observed upon silencing of TIP47. Strikingly, when retrograde transport was analyzed by rapamycin-induced rapid depletion (knocksideways) or long-term depletion by knockdown of the clathrin adaptor AP-1 or of the GGA machinery, distinct phenotypes in sulfation kinetics were observed, suggesting a potential role of GGA adaptors in retrograde and anterograde transport. Our study illustrates the usefulness of derivatized, sulfation-competent nanobodies, reveals novel insights into CDMPR trafficking biology, and further outlines that the selection of machinery inactivation is critical for phenotype analysis.
Multisensory mental imagery of fatigue : Evidence from an fMRI study

Functional imaging experimental designs measuring fatigue, defined as a subjective lack of physical and/or mental energy characterizing a wide range of neurologic conditions, are still under development. Nineteen right‐handed healthy subjects (9 M and 10 F, mean age 43.15 ± 8.34 years) were evaluated by means of functional magnetic resonance imaging (fMRI), asking them to perform explicit, first‐person, mental imagery of fatigue‐related multisensory sensations. Short sentences designed to assess the principal manifestations of fatigue from the Multidimensional Fatigue Symptom Inventory were presented. Participants were asked to imagine the corresponding sensations (Sensory Imagery, SI). As a control, they had to imagine the visual scenes (Visual Imagery, VI) described in short phrases. The SI task (vs. VI task) differentially activated three areas: (i) the precuneus, which is involved in first‐person perspective taking; (ii) the left superior temporal sulcus, which is a multisensory integration area; and (iii) the left inferior frontal gyrus, known to be involved in mental imagery network. The SI fMRI task can be used to measure processing involved in mental imagery of fatigue‐related multisensory sensations.
2‐Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon‐like peptide 1 receptor

We report the discovery of two new 2‐aminothiophene based small molecule positive allosteric modulators (PAMs) of glucagon‐like peptide 1 receptor (GLP‐1R) for the treatment of type 2 diabetes. One of the chemotypes, (S‐1), has a molecular weight of 239 g/mol, the smallest molecule among all reported GLP‐1R PAMs. When combined with GLP‐1 peptide, S‐1 increased the GLP‐1R activity in a dose‐dependent manner in a cell‐based assay. When combined with the peptide agonist of vasoactive intestinal polypeptide receptor 1 (VIPR1), S‐1 showed no specific activity on VIPR1, another class B GPCR present in the same HEK293‐CREB cell line. Insulin secretion studies found S‐1 combined with GLP‐1 increased insulin secretion by 1.5‐fold at 5 μM. In a mechanistic study, evidence is provided that the synergistic effect of S‐1 with GLP‐1 may be partly due to the enhanced impact on CREB based phosphorylation. Given the favorable profile of these chemotypes, the work reported herein suggests that 2‐aminothiophene derivatives are a new and promising class of GLP‐1R PAMs.
Determination of the Microinjected Cytosolic Concentration by Using Mathematical Models of Fluid Dynamics

The precise determination of the intracellular concentration of a drug is a major challenge in drug discovery. Microinjection is a very effective technique for the introduction of macromolecules into single cells. However, due to the large number of parameters that need to be adjusted and the complex physical mechanisms involved, there are currently no means by which the concentration of a microinjected intracellular compound could be theoretically estimated. In this paper, we present a method for the theoretical estimation of intracellular drug concentration, based on the framework of classical fluid mechanism theory — specifically, the modified Bernoulli equation. We introduce into Bernoulli’s classical equation the effect of friction due to the non-laminar regimes of the injected fluid. We also study the compatibility of our theoretical estimation model with variations in injection time and concentration of the compound inside the microinjection needle. Finally, microinjected calcium concentrations estimated with the theoretical model were compared with those determined experimentally in several cell types, by using a Fura-2-based Ca2+ imaging technique.
Enzyme Inhibition Properties and Molecular Docking Studies of 4‐Sulfonate Containing Aryl α‐Hydroxyphosphonates Based Hybrid Molecules

In this study, a series of new hybrid molecules containing two important functional groups on the same skeleton were designed. 4‐Hydroxybenzaldehyde and its two different derivatives were converted into their respective sulphonates by interacting with tosylchloride and methanesulfonyl chloride. Then, the desired molecules were synthesized by adding diethoxyphosphonate to the aldehyde group. Also, novel synthesis of hybrid compounds (4a–c and 5a–c) were tested toward some metabolic enzymes like carbonic anhydrase I and II isoenzymes (hCA I and hCA II) and acetylcholinesterase (AChE) enzyme. The synthesis of hybrid compounds (4a–c and 5a–c) showed Ki values of in range of 25.084±4.73‐69.853±15.19 nM against hCA I, 32.325±1.67–82.761±22.73 nM against hCA II and 1.699±0.25 and 3.500±0.91 nM against AChE. For these compounds, compound 4c showed maximum inhibition effect against hCA I and hCA II isoenzymes and compound 5b showed maximum inhibition effect against AChE enzyme. By performing docking studies of the most active compounds for their binding modes and interactions were determined.
Impaired auxin signaling increases vein and stomatal density but reduces hydraulic efficiency and ultimately net photosynthesis.

Auxins are known to regulate xylem development in plants, however, their effects on water transport efficiency are poorly known. Here we used tomato plants of the diageotropica mutant (dgt), which has impaired function of a Cyclophilin 1 cis/trans isomerase involved in auxin signaling, and its corresponding wild type (WT) to explore its effects on plant hydraulics and leaf gas exchange. The xylem conduits of dgt showed a reduced hydraulically-weighted vessel diameter (Dh) (24-43%) and conduit number (25-58%) in petioles and stems, resulting in lower theoretical hydraulic conductivities (Kt); on the other hand, no changes in root Dh and Kt were observed. The measured stem and leaf hydraulic conductances of dgt agreed with the Kt values and were lower (up to 81%) as well; however, despite dgt and WT showed similar root Dh and Kt, the measured root hydraulic conductance of dgt was 75% lower. The dgt mutation increased the vein and stomata density, which could potentially increase photosynthesis. Nevertheless, even presenting the same photosynthetic capacity of WT plants, the dgt showed a photosynthetic rate c. 25% lower, coupled with a stomatal conductance reduction of 52%. These results clearly demonstrate that increases in Dv and Ds only result in higher leaf gas exchange when accompanied by higher hydraulic efficiency.
Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

Background and Objectives KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. Results We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. Discussion These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.
Consensus paper of the WFSBP task force on cannabis, cannabinoids and psychosis

Abstract Objectives The liberalisation of cannabis laws, the increasing availability and potency of cannabis has renewed concern about the risk of psychosis with cannabis. Methods The objective of the WFSBP task force was to review the literature about this relationship. Results Converging lines of evidence suggest that exposure to cannabis increases the risk for psychoses ranging from transient psychotic states to chronic recurrent psychosis. The greater the dose, and the earlier the age of exposure, the greater the risk. For some psychosis outcomes, the evidence supports some of the criteria of causality. However, alternate explanations including reverse causality and confounders cannot be conclusively excluded. Furthermore, cannabis is neither necessary nor sufficient to cause psychosis. More likely it is one of the multiple causal components. In those with established psychosis, cannabis has a negative impact on the course and expression of the illness. Emerging evidence also suggests alterations in the endocannabinoid system in psychotic disorders. Conclusions Given that exposure to cannabis and cannabinoids is modifiable, delaying or eliminating exposure to cannabis or cannabinoids, could potentially impact the rates of psychosis related to cannabis, especially in those who are at high risk for developing the disorder.
Managing Increased Cognitive Load in a Guided Search

In the Sternberg item recognition task and its variants, an individual’s mean reaction time increases with the number of items to be retained in the memory set. An increase in reaction time has also been seen when a secondary task was added. The usual interpretation for this increased reaction time is that adding cognitive load makes tasks more difficult. In a series of three experiments, we manipulated cognitive load through increases in the memory set or through a second task. In each experiment, high cognitive load was associated with higher mean response times but a reduced slope, based on the target position in a series of probes. Thus, in a Sternberg task with multiple word targets and multiple word probes, participants searched more efficiently per probe under high load than under low load. This pattern was replicated with the addition of a working memory task requiring participants to calculate a cumulative price based on the price per target word item. By considering both initial response times and reaction time slopes in large memory sets, this study provides a challenge to the traditional interpretation of cognitive load effects on search performance.
Safe and Appropriate Minimally Invasive and Robotic Esophagectomy in a Community Cancer Center

Objectives Minimally invasive esophagectomy is a technically challenging procedure that been associated with better outcomes at high-volume tertiary care centers. Louisiana is one of the most impoverished states, and travel to a “destination center” is not an option for many patients. We hypothesize that patients can obtain excellent surgical outcomes following MIE in a comprehensive community cancer center. Methods We identified all patients who underwent totally robotic MIE by a single surgeon at our center from July 2018 to November 2020. All cases were performed using totally robotic Ivor Lewis technique with intrathoracic isoperistaltic esophagogastrostomy. Incidence, demographics, treatment, and outcomes were compared before and after first 10 cases using Student’s t-test. Results We identified 21 patients: 16 male and 5 female. Mean age 65 (49-85). 19 patients underwent MIE for malignancy; 18 of these received neoadjuvant therapy. OR time decreased following the first 10 cases (502 vs. 408 minutes, P = 0.0127). Average lymph node harvest was 14 (4-23 nodes). Positive margin rate was 0%. Mean length of stay trended towards a decrease after the first 10 cases (11 vs. 9 days, P = NS). There were no leaks or strictures. Thirty-day readmission was five patients. Ninety-day mortality was 0%. Conclusion These outcomes rival those of high-volume referral centers and demonstrate that totally robotic MIE can be performed with excellent outcomes in community center. These data call into question the need for all patients to travel to “destination centers” to receive complex oncologic surgery.
Variable Stiffness Shoes for Knee Osteoarthritis: An Evaluation of 3-Dimensional Gait Mechanics and Medial Joint Contact Forces.

The study aim was to quantify the impact of a commercially available variable stiffness shoe (VSS) on 3-dimensional ankle, knee, and hip mechanics and estimated knee contact forces compared with a control shoe. Fourteen participants (10 females) with knee osteoarthritis completed gait analysis after providing informed consent. Shoe conditions tested were control shoe (New Balance MW411v2) and VSS (Abeo SMART3400). An OpenSim musculoskeletal model with static optimization was used to estimate knee contact forces. There were no differences in joint kinematics or in the knee adduction or flexion moments (P = .06; P = .2). There were increases in the knee internal and external rotation (P = .02; P = .03) and hip adduction and internal rotation moments for VSS versus control (P = .03; P = .02). The estimated contact forces were not different between shoes (total P = .3, medial P = .1, and lateral P = .8), but contact force changes were correlated with changes in the knee adduction moment (medial r2 = .61; P < .007). High variability in knee flexion moment changes and increases in the internal rotation moment combined with small decreases in the knee adduction moment did not lead to decreases in estimated contact forces. These results suggest that evaluation of VSS using only the knee adduction moment may not adequately capture its impact on osteoarthritis.
Life and Death Decisions and COVID‐19: Investigating and Modeling the Effect of Framing, Experience, and Context on Preference Reversals in the Asian Disease Problem

Abstract Prior research in judgment and decision making (JDM) has investigated the effect of problem framing on human preferences. Furthermore, research in JDM documented the absence of such reversal of preferences when making decisions from experience. However, little is known about the effect of context on preferences under the combined influence of problem framing and problem format. Also, little is known about how cognitive models would account for human choices in different problem frames and types (general/specific) in the experience format. One of the primary objectives of this research is to investigate the presence of preference reversals under the influence of problem framing (gain/loss), problem format (experience/description), and problem type (general/specific). Another objective of this research is to develop cognitive models to account for human choices across different problem frames and types in the experience format. A total of 320 participants from India were randomly assigned to one of eight between‐subjects conditions that differed in problem frame, format, and type. Results revealed preference reversals in the description condition; however, they were absent in the experience condition. Moreover, preference reversals were less pronounced in the general problem framing compared to the specific problem framing. Furthermore, specific problems influenced risk‐seeking behavior among participants. We developed cognitive and heuristics models using instance‐based learning theory and natural mean heuristic. Results reveal models’ dependency on recent and frequent observations during information sampling. These experience‐based cognitive models could help build artificial intelligence models with fewer preference reversals.
Yaws recurrence in children at continued risk of infection

Background In yaws-endemic areas, children with Treponema pallidum subsp. pertenue infection may suffer recurrent episodes due to either reinfection or relapse. However, the possibility of infection with other cutaneous ulcer causative agents and difficulties in interpreting standard laboratory results challenges the estimation of yaws recurrence rates. Methods We estimated the rates of yaws recurrences in the Lihir Island (Papua New Guinea) using two approaches: passive surveillance based on a retrospective screening of electronic medical records of cutaneous ulcers diagnosed using serological testing between 2005 and 2016, and active surveillance conducted during a cross-sectional prevalence study which included PCR analyses of ulcers of all suspected cases of yaws. The risk of recurrent infection was assessed based on data from the passive surveillance analysis and using two Cox regression models (crude and multivariate), stratified by year of index episode. Data gathered from the active surveillance was used to characterize the recurrences and no hypothesis testing was performed. Results The electronic medical records included 6,125 patients (7,889 ulcer episodes) with documented serological results of cutaneous ulcers of which1,486 were diagnosed with yaws. Overall, 1,246/6,125 patients (20.3%) presented more than once with a cutaneous ulcer, and 103/1,486 (6.7%) patients had multiple episodes of yaws. The risk of yaws recurrence significantly increased with age and was higher in patients with ≥3 recurrent episodes. In the active surveillance, we identified 50 individuals with recurrent cutaneous ulcer that had PCR results available for both the index and recurrent episode. Of 12 individuals with T. pallidum in the index ulcer, 8 (66%) had T. pallidum in subsequent assessments, relapse related to macrolide-resistance was identified in two of these cases. Conclusions Our results confirm the need for active follow-up of yaws patients after treatment, particularly children and individuals with a history of recurrence.
Belastungsvorgaben nach distaler Femurfraktur - eine aktuelle Literaturübersicht

Zusammenfassung Die Inzidenz der distalen Femurfraktur steigt gerade auch bei geriatrischen Patienten deutlich an. Grundsätzliches Ziel der Behandlung dieser Verletzung ist eine frühzeitige Mobilisation der Patienten zur Prävention immobilisationsassoziierter Begleiterkrankungen. Vor dem Hintergrund einer steigenden Anzahl an Therapieoptionen, wie der Doppelplattenosteosynthese, Nagel-Platte-Kombinationen sowie dem distalen Femurersatz, gewinnen Überlegungen zur möglichen Belastung nach der Versorgung einen neuen Stellenwert. Ziel dieser Arbeit war es daher, die bestehende Literatur der vergangenen 9 Jahre hinsichtlich Belastungsvorgaben und klinischer Ergebnisse der verschiedenen Therapieoptionen aufzuarbeiten und mit dem eigenen Vorgehen abzugleichen. Abstract The incidence of distal femur fractures increases in the geriatric patient. The primary treatment goal in these fractures is early mobilisation to prevent secondary injuries associated with immobility. In light of the increasing spectrum of therapeutic options for postoperative fracture treatment, including double plating, nail-plate combination and distal femur replacement as postoperative treatments, weight-bearing recommendations are becoming increasingly important. The aim of this study was thus to analyse the weight-bearing recommendations and associated therapy results within the literature of the past 9 years and compare the recommendations to our own approach.
Theory‐based nutrition education intervention through male involvement improves the dietary diversity practice and nutritional status of pregnant women in rural Illu Aba Bor Zone, Southwest Ethiopia: A quasi‐experimental study

Abstract Maternal undernutrition is a major public health problem that disproportionately affects women in low‐income countries. Despite attempts to address maternal nutritional needs, Ethiopia still has a high rate of undernutrition. Hence, this study aimed to evaluate the effect of theory‐based nutrition education through male engagement on dietary practice and the nutritional status of pregnant women. A pretest−posttest quasi‐experimental study was conducted among 403 pregnant women selected from 22 kebeles of Illu Aba Bor zone, Southwest Ethiopia from July to December 2019. A pre‐tested, structured interviewer‐administered questionnaire was used for data collection. A qualitative 24‐h dietary recall was used to assess dietary diversity, and the Mid‐Upper Arm Circumference was used to assess nutritional status. The intervention effect was evaluated using difference‐in‐difference, generalized estimating equation, and linear mixed‐effects models. The mean dietary diversity score differed significantly between the couple group, women‐alone and the control group (p < 0.001). According to the multivariable generalized estimating equations model, couples were 3.9 times; adjusted odds ratio (AOR) = 3.91, 95% CI: (2.57, 6.88) and women alone were 2.8 times; AOR = 2.86, 95% CI: (2.17, 3.88) more likely to consume a diverse diet than the control group. The nutritional status of the women in the couple group improved significantly by the end of the intervention (p < 0.001). This study showed that involving males in nutrition education intervention was effective in improving the dietary diversity practice and nutritional status of pregnant women. The findings imply the need for targeting couples in designing nutrition education interventions.