Miracle-dz/UniFAR-FTUs huggingface dataset:
Small-Molecule-Induced Activation of Cellular Respiration Inhibits Biofilm Formation and Triggers Metabolic Remodeling in Staphylococcus aureus

Chronic infections caused by Staphylococcus aureus are characterized by biofilm formation, suggesting that methods to control biofilm formation may be of therapeutic value. The small compound JBD1 showed biofilm inhibitory activity and increased sensitivity to aminoglycosides and respiratory activity of S. aureus. ABSTRACT Staphylococcus aureus, a major pathogen of community-acquired and nosocomial-associated infections, forms biofilms consisting of extracellular matrix-embedded cell aggregates. S. aureus biofilm formation on implanted medical devices can cause local and systemic infections due to the dispersion of cells from the biofilms. Usually, conventional antibiotic treatments are not effective against biofilm-related infections, and there is no effective treatment other than removing the contaminated devices. Therefore, the development of new therapeutic agents to combat biofilm-related infections is urgently needed. We conducted high-throughput screening of S. aureus biofilm inhibitors and obtained a small compound, JBD1. JBD1 strongly inhibits biofilm formation of S. aureus, including methicillin-resistant strains. In addition, JBD1 activated the respiratory activity of S. aureus cells and increased the sensitivity to aminoglycosides. Furthermore, it was shown that the metabolic profile of S. aureus was significantly altered in the presence of JBD1 and that metabolic remodeling was induced. Surprisingly, these JBD1-induced phenotypes were blocked by adding an excess amount of the electron carrier menaquinone to suppress respiratory activation. These results indicate that JBD1 induces biofilm inhibition and metabolic remodeling through respiratory activation. This study demonstrates that compounds that enhance the respiratory activity of S. aureus may be potential leads in the development of therapeutic agents for chronic S. aureus-biofilm-related infections. IMPORTANCE Chronic infections caused by Staphylococcus aureus are characterized by biofilm formation, suggesting that methods to control biofilm formation may be of therapeutic value. The small compound JBD1 showed biofilm inhibitory activity and increased sensitivity to aminoglycosides and respiratory activity of S. aureus. Additionally, transcriptomic and metabolomic analyses demonstrated that JBD1 induced metabolic remodeling. All JBD1-induced phenotypes were suppressed by the extracellular addition of an excess amount of menaquinone, indicating that JBD1-mediated respiratory stimulation inhibits biofilm formation and triggers metabolic remodeling in S. aureus. These findings suggest a strategy for developing new therapeutic agents for chronic S. aureus infections.
Aerobic exercise for HIV-associated neurocognitive disorders in individuals on antiretroviral therapy: A randomised controlled trial

Introduction The increasing burden of self-limiting forms of HIV-associated neurocognitive disorder (HAND) in the antiretroviral therapy era calls for adjunctive interventions. The study aimed to determine the effects of a 12-week aerobic exercise programme on HAND. Methods This is a parallel-group, randomized controlled trial with concealed allocation and intention-to-treat analysis. This study was a clinic-based programme. Seventy-three patients with HAND were enrolled in the trial. The intervention comprised a moderate-intensity aerobic exercise, 20–60 min per session, three times per week, for twelve weeks. The control group received exercise education. Prevalence of HAND constituted the primary outcome. HAND was identified and classified following the Frascati criteria. We computed the odds ratio and number needed-to-treat to estimate the treatment effect. Results There were 73 patients (38 in exercise and 35 in control arm). Individuals in the exercise arm recorded a significantly higher reduction in working memory deficit (OR = 5.14; CI = 2.6–10.4; NNT = 6) but not in attention-deficit (OR = 0.31, CI = 0.2–0.5; NNT = −5) compared to the control group at twelve-week. Reductions in attention deficit (OR = 1.55, 95 CI = 1.0–2.4; NNT = 5) and HAND prevalence (OR = 1.8, 95 CI = 1.2–2.8); NNT = 8) were significantly higher in the exercise group compared the control group at three-month. No significant between-group difference in functional independence was observed immediately after exercise (p > 0.05). Discussion The neuroprotective effects of aerobic exercise appear selective and vary with cognitive abilities impaired and aerobic capacity, with a greater change occurring with improved aerobic capacity. Conclusion Individuals with working memory and attention deficits may benefit more from moderate-intensity aerobic exercise.
A Protocol for Prolonged Surgical Anaesthesia with Recovery in Fire Salamanders Using Tricaine Mesylate (MS-222): A Case Series

The objective of this study was to describe prolonged surgical anaesthesia and recovery in fire salamanders (Salamandra salamandra) using tricaine methanesulfonate (MS-222). A total of 14 salamanders were anaesthetised for electromyography wire implantation. Sodium bicarbonate buffered solutions (0.5–4 g l–1) of MS-222 were prepared (adjusted to pH 7.0). Anaesthesia was induced by partial immersion in pre-oxygenated 3 g l–1 solution for 20 min. Buprenorphine (0.5 mg kg–1) was administered subcutaneously. During microsurgery, heart rate (HR), solution pH and temperature were recorded. Reflectance pulse oximeter (SpO2) (Masimo Rad-57) was recorded in two salamanders. Anaesthetic plane and MS-222 pH stability (pH 7.6) were maintained by renewing administration of oxygenated MS-222 solution (0.5–3 g l–1) onto swabs that partially covered the body. Recovery started at the end of surgery (MS-222 0 g l–1). Postoperatively, salamanders were given oral meloxicam (0.2 mg kg–1). Mean time for loss of righting reflex during induction was 13.7 ± 2.2 min. Duration of anaesthesia and time to recovery were 111 ± 24.2 and 31 ± 10.3 min, respectively. Due to complications, two salamanders did not recover. Baseline HR was 67.4 ± 34.5 beats/min, and it decreased significantly until recovery (p ≤ 0.0001). In two salamanders, baseline SpO2 was 85.5% ± 14.5, SpO2 during surgery was 61% ± 6.4, improving to 80.5% ± 2.1 on recovery. In conclusion, prolonged recovery anaesthesia is achievable with MS-222 dilutions in salamander. Reflectance SpO2 could prove valuable during immersion anaesthesia.
A new indirect magnetic resonance imaging finding in anterior cruciate ligament injuries: Medial and lateral meniscus posterior base angle

Objectives This study aimed to define the medial meniscus posterior base angle (MMPBA) and the lateral meniscus posterior base angle (LMPBA) measured in the medial and lateral meniscus posterior horns and examine the biomechanical and morphological relationship between anterior cruciate ligament (ACL) injuries and posterior meniscus horns using these parameters. Patients and methods The retrospective study was conducted with 32 patients with ACL rupture and 40 control patients, for a total of 72 patients (40 males, 32 females; mean age: 36.3±9.9 years; range, 18 to 57 years), between January 2016 and January 2018. The posterior tibial slope (PTS) was measured in standard radiographs, and MMPBA and LMPBA values were assessed by standard knee magnetic resonance imaging. The MMPBA was defined as the angle between the line passing through the medial meniscus’ tibial side border and the line passing through the capsular side border in the sagittal section's medial meniscus posterior horn. The LMPBA was defined as the angle between the line passing through the lateral meniscus' tibial side border and the line passing through the capsular side border on the sagittal section's lateral meniscus posterior horn. Groups were compared for PTS, MMPBA, and LMPBA. Results When both groups were compared in terms of MMPBA and LMPBA, patients with ACL rupture had significantly higher base angles (p<0.001 and p=0.031, respectively). The mean MMPBA was 84. 27º±12. 59º (range, 62º to 106.1º) in patients with ACL rupture, while it was 70. 75º±7. 85º (range, 55.1º to 88.6º) in the control group. The mean LMPBA was 83. 62º±11. 4º (range, 62.3º to 105.9º) in patients with ACL rupture, while it was 76. 94º±11. 46º (range, 30.8º to 96.5º) in the control group. In the receiver operating characteristics curve analysis, the cut-off value of MMPBA was 84.5, and values above this showed a 58.5% sensitivity and a 97.6% specificity for ACL rupture, whereas for LMPBA, the cut-off value was 93.15, and values above this showed a 27.3% sensitivity and a 95.1% specificity for ACL rupture. The PTS and MMPBA were significantly correlated with each other (p=0.047). The MMPBA and LMPBA were also significantly correlated with each other (p=0.011). However, there was no significant correlation between PTS and LMPBA (p=0.56). Conclusion Medial meniscus posterior base angle and LMPBA values above 84.5º and 93.15º, respectively, are new indirect magnetic resonance imaging findings of ACL injury.
Meaningful involvement of children and young people in health technology development

Abstract The anatomical, physiological, and developmental changes which arise as children mature through childhood and adolescence support the need to develop new health technologies that meet the specific requirements of children and young people (CYP). Failing to involve CYP during the development of technology increases the risk that the outcome falls short of their expectations and needs, leading to rejection of novel interventions. Through participation in health technology development, CYP and their families can provide context, insight, personal experience and tacit knowledge to ensure that the end-product is usable, acceptable, and can be integrated into its intended environment. A nuanced, balanced understanding of the methods that can be used to facilitate participation will support researchers in choosing an effective approach to involving CYP in health technology development. Methodological approaches include patient and public involvement and engagement, co-design, and experienced based co-design. These methods can be used in isolation or in combination, to facilitate meaningful involvement of CYP and encourage the development of impactful solutions, in consideration of the context, stakeholders, and objectives of the project. We provide the rationale and justification for involving CYP in health technology design and development, an explanation of the methods supporting meaningful involvement, and case studies exemplifying real world application of these methods with positive outputs.
Information gaps in persuasion knowledge: The discourse regarding the Covid-19 vaccination

Persuasion knowledge is personal knowledge about persuasion attempts that has an effect on the way people respond to these attempts. Persuasion attempts are made to effectively handling the Covid-19 pandemic, which is dependent on high public compliance with vaccination programs. Drawing on the idea of persuasion knowledge, we aimed at elaborating the various categories of perceived information gaps experienced by vaccine hesitants during the Covid-19 vaccination campaign. At the beginning of 2021 we conducted 20 in-depth interviews with Israelis who had decided not to be vaccinated against Covid-19. Analysis of the interviews revealed three main categories of information gaps experienced by the interviewees: missing information, manipulated information, and discrepant information. We analyzed how these are associated with distrust and may impair the persuasion efforts of governments and health authorities. Perceived information gaps, as part of persuasion knowledge, may increase negative responses, and therefore constitute an important factor in persuasion campaigns.
An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases

Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown, with a dearth of accurate preclinical models. To address this, we generated 8 GBM patient-derived xenograft (PDX) models of acquired radiation therapy–selected (RTS) resistance compared with same-patient, treatment-naive (radiation-sensitive, unselected; RTU) PDXs. These likely unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy. Indeed, while whole-exome sequencing showed retention of major genomic alterations in the RTS lines, we did detect a chromosome 12q14 amplification that was associated with clinical GBM recurrence in 2 RTS models. A potentially novel bioinformatics pipeline was applied to analyze phenotypic, transcriptomic, and kinomic alterations, which identified long noncoding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair pathways in our RTS models, which correlated with several lncRNAs. Global kinomic profiling separated RTU and RTS models, but pairwise analyses indicated that there are multiple molecular routes to acquired radiation resistance. RTS model–specific kinases were identified and targeted with clinically relevant small molecule inhibitors. This cohort of in vivo RTS patient-derived models will enable future preclinical therapeutic testing to help overcome the treatment resistance seen in patients with GBM.
Automated closed volume reduction process for apheresis stem cell grafts: From development to clinical implementation

Collection of HPC by apheresis (HPC‐A) can sometimes result in higher collection volumes, increasing the dimethyl sulfoxide (DMSO) volume infused into patients and the space requirements in liquid nitrogen freezers. Volume reduction prior to the addition of cryoprotectant is an efficient means to reduce the DMSO load infused into patients and to optimize freezer storage space.
Investigating the role of residential migration history on the relationship between attachment and sense of belonging: A SEM approach

Abstract With the rate of both domestic and international migration steadily increasing, the psychological impact of residential migration remains largely unexplored. Attachment, the emotional bond we establish with those close to us, and sense of belonging, the feeling of connectedness to a community, may be vulnerable to frequent migration. This study investigates the association between individuals' early attachment style, sense of belonging, and migration history. A large international sample (N = 465) aged between 18 and 50 years old (M = 21.85; SD = 4.48), completed a survey on early attachment primary attachment style questionnaire (PASQ), sense of belonging (SOBI), and migration. Results comparing non‐movers (n = 240) to domestic movers (n = 52), international movers (n = 109), and domestic−international movers (n = 64), indicate important group differences related to early attachment and its relationship to one's sense of belonging. Moreover, insecure attachment was associated with increased migration early in life and, more in general, predictive of a negative sense of belonging later in life. Implications for both research and practice are discussed.
COVID-19: Challenges of Viral Variants.

The COVID-19 pandemic has been accompanied by SARS-CoV-2 evolution and emergence of viral variants that have far exceeded initial expectations. Five major variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) have emerged, each having both unique and overlapping amino acid substitutions that have affected transmissibility, disease severity, and susceptibility to natural or vaccine-induced immune responses and monoclonal antibodies. Several of the more recent variants appear to have evolved properties of immune evasion, particularly in cases of prolonged infection. Tracking of existing variants and surveillance for new variants are critical for an effective pandemic response. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
On the biquadratic theta series.

0.1. The theory of generalized theta series was initiated by T. Kubota in the 1960s (see [K]). This theta series is an automorphic function of an w-fold cover of GL2 over an algebraic number field k containing «-th roots of unity. If n = 2, this becomes to be the classical theta series. If n = 3 and k = Q(J/^3), one has a complete result (see [PJ). A modern formulation and fundamental results of the theory for the case of GLr (r ;> 2) are given in [KP].
Stable carbon isotope values of syndepositional carbonate spherules and micrite record spatial and temporal changes in photosynthesis intensity

Marine and lacustrine carbonate minerals preserve carbon cycle information, and their stable carbon isotope values (δ13C) are frequently used to infer and reconstruct paleoenvironmental changes. However, multiple processes can influence the δ13C values of bulk carbonates, confounding the interpretation of these values in terms of conditions at the time of mineral precipitation. Co‐existing carbonate forms may represent different environmental conditions, yet few studies have analyzed δ13C values of syndepositional carbonate grains of varying morphologies to investigate their origins. Here, we combine stable isotope analyses, metagenomics, and geochemical modeling to interpret δ13C values of syndepositional carbonate spherules (>500 μm) and fine‐grained micrite (<63 μm) from a ~1600‐year‐long sediment record of a hypersaline lake located on the coral atoll of Kiritimati, Republic of Kiribati (1.9°N, 157.4°W). Petrographic, mineralogic, and stable isotope results suggest that both carbonate fractions precipitate in situ with minor diagenetic alterations. The δ13C values of spherules are high compared to the syndepositional micrite and cannot be explained by mineral differences or external perturbations, suggesting a role for local biological processes. We use geochemical modeling to test the hypothesis that the spherules form in the surface microbial mat during peak diurnal photosynthesis when the δ13C value of dissolved inorganic carbon is elevated. In contrast, we hypothesize that the micrite may precipitate more continuously in the water as well as in sub‐surface, heterotrophic layers of the microbial mat. Both metagenome and geochemical model results support a critical role for photosynthesis in influencing carbonate δ13C values. The down‐core spherule–micrite offset in δ13C values also aligns with total organic carbon values, suggesting that the difference in the δ13C values of spherules and micrite may be a more robust, inorganic indicator of variability in productivity and local biological processes through time than the δ13C values of individual carbonate forms.
Duplex Labeling and Manipulation of Neuronal Proteins Using Sequential CRISPR/Cas9 Gene Editing

Abstract CRISPR/Cas9-mediated knock-in methods enable the labeling of individual endogenous proteins to faithfully determine their spatiotemporal distribution in cells. However, reliable multiplexing of knock-in events in neurons remains challenging because of cross talk between editing events. To overcome this, we developed conditional activation of knock-in expression (CAKE), allowing efficient, flexible, and accurate multiplex genome editing. To diminish cross talk, CAKE is based on sequential, recombinase-driven guide RNA (gRNA) expression to control the timing of genomic integration of each donor sequence. We show that CAKE is broadly applicable in rat neurons to co-label various endogenous proteins, including cytoskeletal proteins, synaptic scaffolds, ion channels and neurotransmitter receptor subunits. To take full advantage of CAKE, we resolved the nanoscale co-distribution of endogenous synaptic proteins using super-resolution microscopy, demonstrating that their co-organization correlates with synapse size. Finally, we introduced inducible dimerization modules, providing acute control over synaptic receptor dynamics in living neurons. These experiments highlight the potential of CAKE to reveal new biological insight. Altogether, CAKE is a versatile method for multiplex protein labeling that enables the detection, localization, and manipulation of endogenous proteins in neurons.
Opioid agonist treatment and risk of death or rehospitalization following injection drug use–associated bacterial and fungal infections: A cohort study in New South Wales, Australia

Background Injecting-related bacterial and fungal infections are associated with significant morbidity and mortality among people who inject drugs (PWID), and they are increasing in incidence. Following hospitalization with an injecting-related infection, use of opioid agonist treatment (OAT; methadone or buprenorphine) may be associated with reduced risk of death or rehospitalization with an injecting-related infection. Methods and findings Data came from the Opioid Agonist Treatment Safety (OATS) study, an administrative linkage cohort including all people in New South Wales, Australia, who accessed OAT between July 1, 2001 and June 28, 2018. Included participants survived a hospitalization with injecting-related infections (i.e., skin and soft-tissue infection, sepsis/bacteremia, endocarditis, osteomyelitis, septic arthritis, or epidural/brain abscess). Outcomes were all-cause death and rehospitalization for injecting-related infections. OAT exposure was classified as time varying by days on or off treatment, following hospital discharge. We used separate Cox proportional hazards models to assess associations between each outcome and OAT exposure. The study included 8,943 participants (mean age 39 years, standard deviation [SD] 11 years; 34% women). The most common infections during participants’ index hospitalizations were skin and soft tissue (7,021; 79%), sepsis/bacteremia (1,207; 14%), and endocarditis (431; 5%). During median 6.56 years follow-up, 1,481 (17%) participants died; use of OAT was associated with lower hazard of death (adjusted hazard ratio [aHR] 0.63, 95% confidence interval [CI] 0.57 to 0.70). During median 3.41 years follow-up, 3,653 (41%) were rehospitalized for injecting-related infections; use of OAT was associated with lower hazard of these rehospitalizations (aHR 0.89, 95% CI 0.84 to 0.96). Study limitations include the use of routinely collected administrative data, which lacks information on other risk factors for injecting-related infections including injecting practices, injection stimulant use, housing status, and access to harm reduction services (e.g., needle exchange and supervised injecting sites); we also lacked information on OAT medication dosages. Conclusions Following hospitalizations with injection drug use–associated bacterial and fungal infections, use of OAT is associated with lower risks of death and recurrent injecting-related infections among people with opioid use disorder.