Miracle-dz/UniFAR-FTUs huggingface dataset:
Exotoxin-Targeted Drug Modalities as Antibiotic Alternatives

The paradigm of antivirulence therapy dictates that bacterial pathogens are specifically disarmed but not killed by neutralizing their virulence factors. Clearance of the invading pathogen by the immune system is promoted. As compared to antibiotics, the pathogen-selective antivirulence drugs hold promise to minimize collateral damage to the beneficial microbiome. Also, selective pressure for resistance is expected to be lower because bacterial viability is not directly affected. Antivirulence drugs are being developed for stand-alone prophylactic and therapeutic treatments but also for combinatorial use with antibiotics. This Review focuses on drug modalities that target bacterial exotoxins after the secretion or release-upon-lysis. Exotoxins have a significant and sometimes the primary role as the disease-causing virulence factor, and thereby they are attractive targets for drug development. We describe the key pre-clinical and clinical trial data that have led to the approval of currently used exotoxin-targeted drugs, namely the monoclonal antibodies bezlotoxumab (toxin B/TcdB, Clostridioides difficile), raxibacumab (anthrax toxin, Bacillus anthracis), and obiltoxaximab (anthrax toxin, Bacillus anthracis), but also to challenges with some of the promising leads. We also highlight the recent developments in pre-clinical research sector to develop exotoxin-targeted drug modalities, i.e., monoclonal antibodies, antibody fragments, antibody mimetics, receptor analogs, neutralizing scaffolds, dominant-negative mutants, and small molecules. We describe how these exotoxin-targeted drug modalities work with high-resolution structural knowledge and highlight their advantages and disadvantages as antibiotic alternatives.
The Effects of Posture on the Three-Dimensional Gait Mechanics of Human Walking in Comparison to Bipedal Chimpanzees

Humans walk with an upright posture on extended limbs during stance and with a double-peaked vertical ground reaction force. Our closest living relatives, chimpanzees, are facultative bipeds that walk with a crouched posture on flexed, abducted hind limbs and with a single-peaked vertical ground reaction force. Differences in human and bipedal chimpanzee three-dimensional kinematics have been well quantified; however, it is unclear what the independent effects of using a crouched posture are on three-dimensional gait mechanics for humans, and how they compare with chimpanzees. Understanding the relationships between posture and gait mechanics, with known differences in morphology between species, can help researchers better interpret the effects of trait evolution on bipedal walking. We quantified pelvis and lower limb three-dimensional kinematics and ground reaction forces as humans adopted a series of upright and crouched postures and compared them with data from bipedal chimpanzee walking. Human crouched posture gait mechanics were more similar to bipedal chimpanzee gait than normal human walking, especially in sagittal plane hip and knee angles. However, there were persistent differences between species, as humans walked with less transverse plane pelvis rotation, less hip abduction, and greater peak horizontal ground reaction force in late stance than chimpanzees. Our results suggest that human crouched posture walking reproduces only a small subset of the characteristics of three-dimensional kinematics and ground reaction forces of chimpanzee walking, with the remaining differences likely due in large part to the distinct musculoskeletal morphologies of humans and chimpanzees. Summary Statement Differences between human crouched posture gait and bipedal chimpanzee gait illustrate the limitations of using modern day humans to infer the evolution of hominin bipedalism.
Cranial osteology of Hypoptophis (Aparallactinae: Atractaspididae: Caenophidia), with a discussion on the evolution of its fossorial adaptations

Fossoriality evolved early in snakes, and has left its signature on the cranial morphology of many extinct Mesozoic and early Caenozoic forms. Knowledge of the cranial osteology of extant snakes is indispensable for associating the crania of extinct lineages with a particular mode of life; this applies to fossorial taxa as well. In the present work, we provide a detailed description of the cranium of Hypoptophis wilsonii, a member of the subfamily Aparallactinae, using micro‐computed tomography (CT). This is also the first thorough micro‐CT‐based description of any snake assigned to this African subfamily of predominantly mildly venomous, fossorial, and elusive snakes. The cranium of Hypoptophis is adapted for a fossorial lifestyle, with increased consolidation of skull bones. Aparallactines show a tendency toward reduction of maxillary length by bringing the rear fangs forward. This development attains its pinnacle in the sister subfamily Atractaspidinae, in which the rear fang has become the “front fang” by a loss of the part of the maxilla lying ahead of the fang. These dentitional changes likely reflect adaptation to subdue prey in snug burrows. An endocast of the inner ear of Hypoptophis shows that this genus has the inner ear typical of fossorial snakes, with a large, globular sacculus. A phylogenetic analysis based on morphology recovers Hypoptophis as a sister taxon to Aparallactus. We also discuss the implications of our observations on the burrowing origin hypothesis of snakes.
Code Performance Comparison in SAC-OCDMA Systems under the Impact of Group Velocity Dispersion

In this paper, three code families for spectral amplitude coding optical code division multiple access (SAC-OCDMA) systems in terms of performance are compared to each other under the impact of group velocity dispersion (GVD). The investigated code families are m-sequence, Walsh-Hadamard and modified quadratic congruence (MQC). The performance of these codes is evaluated for three types of transmission media such as single-mode fiber (SMF), dispersion shifted fiber (DSF) and nonzero dispersion shifted fiber (NZ-DSF). Results show that in each of the three transmission media m-sequence code family offers the best performance among the investigated code sets under the impact of GVD. Systems which employ m-sequence codes can achieve longer transmission length compared to those using Walsh-Hadamard and MQC codes. In addition, a chirped fiber Bragg grating (CFBG) is designed as a compensating element to compensate the impact of GVD in a SAC-OCDMA system. Employing the designed grating in the system results in a wide opening in the eye diagram as well as improved bit error rate (BER) of the system which indicate that the impact of GVD is effectively compensated.
Arthroscopic Debridement Versus Refixation of the Acetabular Labrum Associated With Femoroacetabular Impingement: Updated Mean 7-Year Follow-up

Background: Short- and midterm follow-up studies suggest that arthroscopic labral refixation/preservation leads to superior outcomes compared with labral excision/debridement. Purpose: To update the previous early (16 months) and midterm (mean, 42 months) follow-up of this cohort, which reported better patient-reported outcome measures and lower failure rates in the repair/refixation group. Study Design: Cohort study; Level of evidence, 3. Methods: The authors identified patients who underwent labral debridement/focal labral excision during a period before the development of labral repair techniques. A consecutive group of patients within the labral debridement group thought to be repairable with the authors’ current arthroscopic techniques were compared with a group of consecutive patients who underwent labral repair/refixation. In 46 hips, the labrum was focally excised/debrided consistent with pincer- or combined pincer- and cam-type impingement; in 54 hips, the labrum was repaired/refixed. Subjective outcomes were measured with the modified Harris Hip Score (mHHS), 12-Item Short Form Health Survey (SF-12), and visual analog scale (VAS) for pain preoperatively and postoperatively. Results: The mean age was 34.0 years in the debridement group and 28.3 years in the repair/refixation group, with a mean follow-up of 7.3 years (range, 2-13.6 years). At the mean follow-up of 7.3 years, subjective outcomes were significantly improved (P < .01) for both groups compared with preoperative scores. The mHHS (P = .008), SF-12 score (P = .012), and VAS pain score (P = .002) were all significantly better for the repair/refixation group compared with the debridement group. Although most recent outcomes for both groups fell slightly at the mean follow-up of 7.3 years in comparison with the 16-month and 3.5-year follow-ups, these differences were not significant. However, the failure rate in the debridement group did get significantly worse (P = .014). Good to excellent results were 47.7% in the debridement group and 86.3% in the refixation group (P < .001), and failure rates were 30.4% (debridement) and 13% (refixation) (P = .033). There were 4 revisions in the debridement group and 3 revisions in the refixation group. Conclusion: Longer term, >7-year follow-up comparing focal labral excision/debridement with repair/refixation revealed better patient-reported outcomes and lower failure rates in the labral repair/refixation cohort. Additionally, despite an absolute decrease in patient-related outcome scoring and number of good/excellent results in both groups compared with the 3.5-year report, there was a significantly greater increase in failure rates over time for the excision/debridement group with better maintenance of good to excellent results in the repair/refixation group.
Effect of colorectal cancer screening on long‐term survival of colorectal cancer patients: Results of the Korea National Cancer Screening Program

The Korea National Cancer Screening Program (KNCSP) provides fecal immunochemical test‐based colorectal cancer (CRC) screening for people aged ≥50 years. Our study aimed to investigate the long‐term survival effects of CRC screening based on screening history and interval time since screening. The study cohort was obtained by linking three national databases, namely the Korea Central Cancer Registry, KNCSP database and Death Certificate. We included 32 509 CRC patients diagnosed in 2008 to 2009, who underwent CRC screening via the KNCSP between 2004 and 2009. The patients were followed‐up until 2019, and their survival was assessed according to their CRC screening history. Cox proportional hazards regression was used to compare time to deaths among CRC patients according to CRC screening history, after adjusting for covariates. Of the 32 509 patients, 20 022 (61.5%) patients were alive by the end of 2019. Long‐term survival was significantly higher among screened patients (68.2%) than nonscreened (57.2%) individuals. Compared to never‐screened patients, the hazard ratio (HR) for CRC‐specific death in screened patients was 0.77 (95% CI%, 0.73‐0.80). Lowest HR was observed in screened, localized CRC patients (HR, 0.48; 95% CI, 0.42‐0.56); HR for CRC‐specific death was the lowest in patients screened within 12 months of diagnosis (HR, 0.70; 95% CI, 0.66‐0.74), following which, the HRs increased with increasing time interval. CRC screening was positively associated with favorable prognosis in CRC patients aged 50 to 79 years. The effects on long‐term survival according to interval time was the best among individuals screened within 1 year before diagnosis.
Responding to safe care: Healthcare staff experiences caring for a child with intellectual disability in hospital. Implications for practice and training.

BACKGROUND Children with intellectual disability are vulnerable to adverse events in hospital due to limited staff skills and system safeguards. METHOD A systematic review of the literature explored healthcare staff (HCS) experiences in providing care for children and young persons with intellectual disability in hospital using thematic analysis. RESULTS Eleven of the 735 publications extracted identified the following themes: distress, communication, partnerships, identification, training and education and optimising care. Consistent findings suggest that HCS feel unskilled in providing care for the child with intellectual disability in hospital settings. HCS recognised the role of parents as experts of their child but also feel unsettled when challenged by them. Skills in communicating with the child, developing partnerships with parents, having identification systems to plan for reasonable adjustments was key to improving care. CONCLUSIONS Organisational advocacy, practical skills training in identification, reasonable adjustments and improved attitudes are important for HCS to provide safe and quality care.
Differential photoregulation of the nuclear and cytoplasmic CRY1 in Arabidopsis.

Arabidopsis cryptochrome 1 (CRY1) is a blue light receptor distributed in the nucleus and cytoplasm. The nuclear CRY1, but not cytoplasmic CRY1, mediates blue light inhibition of hypocotyl elongation. However, the photobiochemical mechanisms distinguishing the CRY1 protein in the two subcellular compartments remains unclear. Here we show that the nuclear CRY1, but not the cytoplasmic CRY1, is regulated by phosphorylation, polyubiquitination and 26S proteasome-dependent proteolysis in response to blue light. The blue light-dependent CRY1 degradation is observed only under high fluences of blue light. The nuclear specificity and high fluence dependency of CRY1 explain why this photochemical regulatory mechanism of CRY1 was not observed previously and it further support the hypothesis that CRY1 is a high light receptor regulating photomorphogenesis. We further show that the nuclear CRY1, but not cytoplasmic CRY1, undergoes blue light-dependent phosphorylation by PPK1 followed by polyubiquitination by the E3 ubiquitin ligase Cul4COP1/SPAs , resulting in the blue light-dependent proteolysis. Both phosphorylation and ubiquitination of nuclear CRY1 are inhibited by BIC1, demonstrating the involvement of photo-oligomerization of the nuclear CRY1. These finding reveals a photochemical mechanism that differentially regulates the physiological activity of the CRY1 photoreceptor in distinct subcellular compartments.
Hyaluronic Acid Filler Incidentally Found During Mohs Micrographic Surgery: Observations in 36 Patients Regarding Skin Depth, Degradation Size, and Estimated Persistence Time

BACKGROUND Although its clinical effect is reported to last up to 2 years, how long hyaluronic acid filler (HAF) histologically persists in the skin is unknown. OBJECTIVE To determine the approximate persistence time of HAF in the skin and to correlate persistence time with HAF histological appearance, size, depth, and location. METHODS Retrospective review of patient data and available frozen sections from 2003 to 2021 in which HAF was identified in 36 Mohs micrographic surgery patients. RESULTS Incidental HAF histologically persisted in the skin for as long as 10.75 years in 1 patient and 3 years or more in 36.8% (7/19) of the patients who remembered the time of implantation. HAF is more apparent in frozen sections stained with toluidine blue than those stained with hematoxylin and eosin. Although HAF volume tended to be less with time, fragmentation was present both early at 3 months and at 3 years or more. There was no correlation of persistence time with anatomic location or depth. In 90.3% of the cases (28/31), HAF was located in the subcutaneous fat. There was no granulomatous or giant cell response at any time period. CONCLUSION Hyaluronic acid filler may be seen histopathologically in the skin, usually in the subcutaneous fat, up to 10.75 years after implantation.
Systems Approach to Biosafety and Risk Assessment of Engineered Nanomaterials

The need for nanomaterials biosafety and risk assessment is an offshoot of the widespread use of nanoscale particle (NP)-derived materials in over 300 nanotechnology-based products already in commerce, including over 70 healthcare-related products (WWICS, 2006). Rapid advances in material sciences research and the advent of new and highly sophisticated nanofabrication technologies have yielded a vast array of products with poorly established life-cycle risks to health and safety and with potential adverse impact on the environment. As a result, regulatory agencies in the United States and Europe have taken preliminary steps to regulate NP-based products, including pharmaceuticals and cosmetics, fine chemicals, DNA vaccine and gene therapy delivery systems, next generation antibiotics, and immune modulators, for associated potential health, safety, and environmental risks. However, much of the current literature on NP safety and risk assessment grapples with fundamental disagreements in the classification schema for nanomaterials; the lack of a common analytical framework to capture the physiochemical and biological properties constituting risk assessment parameters such as hazard, dose, exposure, and risk; and relatively poor data on occupational safety and health related to the process engineering and manufacture of NP-derived products. Most of all, conventional toxicological principles based on mass per unit volume of the test material to determine dose-response relationship for toxicity and safety assessment may not hold for nanotechnology-derived products. Based on the author's extensive support to U.S. regulatory agencies in the design and development of novel risk assessment paradigms for new chemical compounds with limited or no published toxicity literature, as well as combinatorial chemicals risk assessment strategies where conventional toxicological methods often yield unpredictable dose-response relationships, the author has developed a conceptual framework for an integrated life cycle analysis (LCA) to perform hazard/safety assessment for NP-based products similar to the Safety Data Sheet (SDS) development process. The proposed framework allows systematic capture of safety data unique across the product development life cycle to perform hazard and safety assessment. This approach is better suited to assist development of occupational safety and health guidelines during NP process engineering and manufacturing activities.
Interactive Effects on Motor Performance of Mindfulness, Performance Under Pressure, Self-Talk, and Motor Task Characteristics

High mindfulness individuals have been found to perform better on motor tasks under various conditions, but it is unknown whether mindfulness and performance relate when performing under pressure or using different types of self-talk with different motor tasks. In this study, 46 male participants (Mage = 21.4, SD = 1.72 years) with high mindfulness (n = 23) and low mindfulness (n = 23) performed dart-throwing and two-hand coordination tasks under pressure and non-pressure conditions and when using instructional and unrelated self-talk. First, on the two-hand coordination task, a three-way mixed ANOVA found: (a) a significant 3-way interaction in which a significantly poorer performance occurred under pressure (vs. without pressure), with low (vs. high) mindfulness and when using unrelated (vs. instructional) self-talk and (b) a significant interaction in which, both under pressure and not, both high and low mindfulness participants performed comparably when using instructional (vs. unrelated) self-talk. Second, on the dart-throwing task, mindfulness interacted with self-talk such that both high and low mindfulness participants performed better when using instructional self-talk, and pressure interacted with self-talk such that participants using instructional (vs. unrelated) self-talk performed better in both pressure and non-pressure conditions. We concluded that instructional self-talk was a useful cognitive strategy, perhaps particularly in pressure conditions and regardless of the degree of mindfulness, and its effectiveness extended to two different motor tasks. We discussed the theoretical implications of these findings, in terms of attention theory, self-talk, and motor control; and we highlighted our study’s limitations and practical applications and gave recommendations for future research.
Prevalence of relapsing fever spirochete Borrelia miyamotoi in Ixodes ricinus ticks from eastern Slovakia

Borrelia miyamotoi, recurrent fever borrelia, pathogenic to humans, has been found recently in Ixodes ricinus ticks. There is still little information about its circulation in nature and potential local impact on human health as well as the occurrence in natural localities. In our study, a total of 1609 ticks (745 nymphs, 358 females and 506 males) collected from different localities in eastern Slovakia were analysed using a polymerase chain reaction targeting a gene encoding glycerophosphodiester phosphodiesterase (glpQ), which is specific to the Borrelia species in the relapsing fever group. B. miyamotoi was found in 3 nymphs, 6 females and 9 males of quested I. ricinus ticks. Although no human case of infection with B. miyamotoi has been reported in Slovakia yet, its presence needs to be studied to obtain knowledge regarding the prevalence and the distribution of this human pathogen in questing ticks and to increase medical healthcare awareness.
Reward Weakened Inhibition of Return (IOR) in the Near Depth Plane

In attentional orienting, researchers have proposed that reward history is a component of attentional control, as the reward value might enhance the spatial attention process to achieve more efficient goal-directed behavior and to improve target-detection performance. Although the effect of reward–induced motivation on attentional orienting has been studied in two–dimensional (2-D) space, the specific mechanisms underlying the influence of reward on inhibition of return (IOR) of attentional orienting in three-dimensional space (3-D) remain unclear. In the present study, by incorporating the Posner spatial-cueing paradigm into a virtual 3-D environment, we aimed to investigate the influence of reward on IOR in 3-D space. The results showed the following: (1) IOR size in the rewarded conditions was smaller than IOR size in the unrewarded condition in the near depth plane, resulting in an IOR difference with or without reward. (2) Reward weakened IOR in the near depth plane because the response to the uncued location was delayed, not because the response to the cued location was accelerated. The present study indicated that the different depth planes of the target location in 3-D space could influence the interaction between reward and IOR, and reward weakened IOR in the near depth plane.
Understanding the evolution of viviparity using intraspecific variation in reproductive mode and transitional forms of pregnancy

How innovations such as vision, flight and pregnancy evolve is a central question in evolutionary biology. Examination of transitional (intermediate) forms of these traits can help address this question, but these intermediate phenotypes are very rare in extant species. Here we explore the biology and evolution of transitional forms of pregnancy that are midway between the ancestral state of oviparity (egg‐laying) and the derived state, viviparity (live birth). Transitional forms of pregnancy occur in only three vertebrates, all of which are lizard species that also display intraspecific variation in reproductive phenotype. In these lizards (Lerista bougainvillii, Saiphos equalis, and Zootoca vivipara), geographic variation of three reproductive forms occurs within a single species: oviparity, viviparity, and a transitional form of pregnancy. This phenomenon offers the valuable prospect of watching ‘evolution in action’. In these species, it is possible to conduct comparative research using different reproductive forms that are not confounded by speciation, and are of relatively recent origin. We identify major proximate and ultimate questions that can be addressed in these species, and the genetic and genomic tools that can help us understand how transitional forms of pregnancy are produced, despite predicted fitness costs. We argue that these taxa represent an excellent prospect for understanding the major evolutionary shift between egg‐laying and live birth, which is a fundamental innovation in the history of animals.