bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental and computational investigation of enzyme functional annotations uncovers misannotation in the EC 1.1.3.15 enzyme class
Authors: Rembeza Elzbieta , Engqvist Martin K. M.
Published: September 2021

Only a small fraction of genes deposited to databases have been experimentally characterised. The majority of proteins have their function assigned automatically, which can result in erroneous annotations. The reliability of current annotations in public databases is largely unknown; experimental attempts to validate the accuracy within individual enzyme classes are lacking. In this study we performed an overview of functional annotations to the BRENDA enzyme database. We first applied a high-throughput experimental platform to verify functional annotations to an enzyme class of S-2-hydroxyacid oxidases (EC 1.1.3.15). We chose 122 representative sequences of the class and screened them for their predicted function. Based on the experimental results, predicted domain architecture and similarity to previously characterised S-2-hydroxyacid oxidases, we inferred that at least 78% of sequences in the enzyme class are misannotated. We experimentally confirmed four alternative activities among the misannotated sequences and showed that misannotation in the enzyme class increased over time. Finally, we performed a computational analysis of annotations to all enzyme classes in the BRENDA database, and showed that nearly 18% of all sequences are annotated to an enzyme class while sharing no similarity or domain architecture to experimentally characterised representatives. We showed that even well-studied enzyme classes of industrial relevance are affected by the problem of functional misannotation.
Neighbor-enhanced diffusivity in dense, cohesive cell populations
Authors: Lee Hyun Gyu , Lee Kyoung J.
Published: September 2021

The dispersal or mixing of cells within cellular tissue is a crucial property for diverse biological processes, ranging from morphogenesis, immune action, to tumor metastasis. With the phenomenon of ‘contact inhibition of locomotion,’ it is puzzling how cells achieve such processes within a densely packed cohesive population. Here we demonstrate that a proper degree of cell-cell adhesiveness can, intriguingly, enhance the super-diffusive nature of individual cells. We systematically characterize the migration trajectories of crawling MDA-MB-231 cell lines, while they are in several different clustering modes, including freely crawling singles, cohesive doublets of two cells, quadruplets, and confluent population on two-dimensional substrate. Following data analysis and computer simulation of a simple cellular Potts model, which faithfully recapitulated all key experimental observations such as enhanced diffusivity as well as periodic rotation of cell-doublets and cell-quadruplets with mixing events, we found that proper combination of active self-propelling force and cell-cell adhesion is sufficient for generating the observed phenomena. Additionally, we found that tuning parameters for these two factors covers a variety of different collective dynamic states.
Enhancers with cooperative Notch binding sites are more resistant to regulation by the Hairless co-repressor
Authors: Kuang Yi , Pyo Anna , Eafergan Natanel , Cain Brittany , Gutzwiller Lisa M. , Axelrod Ofri , Gagliani Ellen K. , Weirauch Matthew T. , Kopan Raphael , Kovall Rhett A. , Sprinzak David , Gebelein Brian
Published: September 2021

Notch signaling controls many developmental processes by regulating gene expression. Notch-dependent enhancers recruit activation complexes consisting of the Notch intracellular domain, theCbf/Su(H)/Lag1 (CSL) transcription factor (TF), and the Mastermind co-factor via two types of DNA sites: monomeric CSL sites and cooperative dimer sites calledSu(H)pairedsites (SPS). Intriguingly, the CSL TF can also bind co-repressors to negatively regulate transcription via these same sites. Here, we tested how synthetic enhancers with monomeric CSL sites versus dimeric SPSs bindDrosophilaSu(H) complexesin vitroand mediate transcriptional outcomesin vivo. Our findings reveal that while the Su(H)/Hairless co-repressor complex similarly binds SPS and CSL sites in an additive manner, the Notch activation complex binds SPSs, but not CSL sites, in a cooperative manner. Moreover, transgenic reporters with SPSs mediate stronger, more consistent transcription and are more resistant to increased Hairless co-repressor expression compared to reporters with the same number of CSL sites. These findings support a model in which SPS containing enhancers preferentially recruit cooperative Notch activation complexes over Hairless repression complexes to ensure consistent target gene activation.
Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line
Authors: Singh Ramya , Smit Ryan B. , Wang Xin , Wang Chris , Racher Hilary , Hansen Dave
Published: September 2021

Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumour of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.
Assessment of neuropathic pain in leprosy patients with relapse or treatment failure by infrared thermography: A cross-sectional study
Authors: Tiago Liliane Marques de Pinho , Santos Diogo Fernandes dos , Antunes Douglas Eulálio , Tiago Letícia Marques Pinho , Goulart Isabela Maria Bernardes
Published: September 2021

Background

Neuropathic pain (NP) is one of the main complications of leprosy, and its management is challenging. Infrared thermography (IRT) has been shown to be effective in the evaluation of peripheral autonomic function resulting from microcirculation flow changes in painful syndromes. This study used IRT to map the skin temperature on the hands and feet of leprosy patients with NP.

Methodology/Principal findings

This cross-sectional study included 20 controls and 55 leprosy patients, distributed into 29 with NP (PWP) and 26 without NP (PNP). Thermal images of the hands and feet were captured with infrared camera and clinical evaluations were performed. Electroneuromyography (ENMG) was used as a complementary neurological exam. Instruments used for the NP diagnosis were visual analog pain scale (VAS), Douleur Neuropathic en 4 questions (DN4), and simplified neurological assessment protocol. The prevalence of NP was 52.7%. Pain intensity showed that 93.1% of patients with NP had moderate/severe pain. The most frequent DN4 items in individuals with NP were numbness (86.2%), tingling (86.2%) and electric shocks (82.7%). Reactional episodes type 1 were statistically significant in the PWP group. Approximately 81.3% of patients showed a predominance of multiple mononeuropathy in ENMG, 79.6% had sensory loss, and 81.4% showed some degree of disability. The average temperature in the patients’ hands and feet was slightly lower than in the controls, but without a significant difference. Compared to controls, all patients showed significant temperature asymmetry in almost all points assessed on the hands, except for two palmar points and one dorsal point. In the feet, there was significant asymmetry in all points, indicating a greater involvement of the lower limbs.

Conclusion

IRT confirmed the asymmetric pattern of leprosy neuropathy, indicating a change in the function of the autonomic nervous system, and proving to be a useful method in the approach of pain.
The role of nuclear organization in trans-splicing based expression of heat shock protein 90 in Giardia lamblia
Authors: Iyer Vinithra , Tushir Sheetal , Verma Shreekant , Majumdar Sudeshna , Gayen Srimonta , Mishra Rakesh , Tatu Utpal
Published: September 2021

Hsp90 gene of G. lamblia has a split nature comprising two ORFs separated by 777 kb on chromosome 5. The ORFs of the split gene on chromosome 5 undergo transcription to generate independent pre-mRNAs that join by a unique trans-splicing reaction that remains partially understood. The canonical cis-acting nucleotide elements such as 5’SS-GU, 3’SS-AG, polypyrimidine tract and branch point adenine are present in the independent pre-mRNAs and therefore trans-splicing of Hsp90 must be assisted by spliceosomes in vivo. Using an approach of RNA-protein pull down, we show that an RNA helicase selectively interacts with HspN pre-mRNA. Our experiments involving high resolution chromosome conformation capture technology as well as DNA FISH show that the trans-spliced genes of Giardia are in three-dimensional spatial proximity in the nucleus. Altogether our study provides a glimpse into the in vivo mechanisms involving protein factors as well as chromatin structure to facilitate the unique inter-molecular post-transcriptional stitching of split genes in G. lamblia.
Leishmania tarentolae and Leishmania infantum in humans, dogs and cats in the Pelagie archipelago, southern Italy
Authors: Iatta Roberta , Mendoza-Roldan Jairo Alfonso , Latrofa Maria Stefania , Cascio Antonio , Brianti Emanuele , Pombi Marco , Gabrielli Simona , Otranto Domenico
Published: September 2021

Visceral leishmaniasis (VL) caused by Leishmania infantum is endemic in the Mediterranean basin with most of the infected human patients remaining asymptomatic. Recently, the saurian-associated Leishmania tarentolae was detected in human blood donors and in sheltered dogs. The circulation of L. infantum and L. tarentolae was investigated in humans, dogs and cats living in the Pelagie islands (Sicily, Italy) by multiple serological and molecular testing. Human serum samples (n = 346) were tested to assess the exposure to L. infantum by immunofluorescence antibody test (IFAT), enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) and to L. tarentolae by IFAT. Meanwhile, sera from dogs (n = 149) and cats (n = 32) were tested for both Leishmania species by IFAT and all blood samples, including those of humans, by specific sets of real time-PCR for L. infantum and L. tarentolae. The agreement between serological tests performed for human samples, and between serological and molecular diagnostic techniques for both human and animal samples were also assessed.

Overall, 41 human samples (11.8%, 95% CI: 8.9–15.7) were positive to L. infantum (5.2%, 95% CI: 3.3–8.1), L. tarentolae (5.2%, 95% CI: 3.3–8.1) and to both species (1.4%, 95% CI: 0.6–3.3) by serology and/or molecular tests. A good agreement among the serological tests was determined. Both Leishmania spp. were serologically and/or molecularly detected in 39.6% dogs and 43.7% cats. In addition to L. infantum, also L. tarentolae circulates in human and animal populations, raising relevant public health implications. Further studies should investigate the potential beneficial effects of L. tarentolae in the protection against L. infantum infection.
Comparative analysis of transcriptomic profiles among ascidians, zebrafish, and mice: Insights from tissue-specific gene expression
Authors: Matsubara Shin , Osugi Tomohiro , Shiraishi Akira , Wada Azumi , Satake Honoo
Published: September 2021

Tissue/organ-specific genes (TSGs) are important not only for understanding organ development and function, but also for investigating the evolutionary lineages of organs in animals. Here, we investigate the TSGs of 9 adult tissues of an ascidian, Ciona intestinalis Type A (Ciona robusta), which lies in the important position of being the sister group of vertebrates. RNA-seq and qRT-PCR identified the Ciona TSGs in each tissue, and BLAST searches identified their homologs in zebrafish and mice. Tissue distributions of the vertebrate homologs were analyzed and clustered using public RNA-seq data for 12 zebrafish and 30 mouse tissues. Among the vertebrate homologs of the Ciona TSGs in the neural complex, 48% and 63% showed high expression in the zebrafish and mouse brain, respectively, suggesting that the central nervous system is evolutionarily conserved in chordates. In contrast, vertebrate homologs of Ciona TSGs in the ovary, pharynx, and intestine were not consistently highly expressed in the corresponding tissues of vertebrates, suggesting that these organs have evolved in Ciona-specific lineages. Intriguingly, more TSG homologs of the Ciona stomach were highly expressed in the vertebrate liver (17–29%) and intestine (22–33%) than in the mouse stomach (5%). Expression profiles for these genes suggest that the biological roles of the Ciona stomach are distinct from those of their vertebrate counterparts. Collectively, Ciona tissues were categorized into 3 groups: i) high similarity to the corresponding vertebrate tissues (neural complex and heart), ii) low similarity to the corresponding vertebrate tissues (ovary, pharynx, and intestine), and iii) low similarity to the corresponding vertebrate tissues, but high similarity to other vertebrate tissues (stomach, endostyle, and siphons). The present study provides transcriptomic catalogs of adult ascidian tissues and significant insights into the evolutionary lineages of the brain, heart, and digestive tract of chordates.
Intolerance of uncertainty and decisions about delayed, probabilistic rewards: A replication and extension of Luhmann, C. C., Ishida, K., & Hajcak, G. (2011)
Authors: Ciria Luis F. , Quintero María J. , López Francisco J. , Luque David , Cobos Pedro L. , Morís Joaquín
Published: September 2021

Intolerance of Uncertainty (IU) is thought to lead to maladaptive behaviours and dysfunctional decision making, both in the clinical and healthy population. The seminal study reported by Luhmann and collaborators in 2011 [1] showed that IU was negatively associated with choosing a delayed, but more probable and valuable, reward over choosing an immediate, but less probable and valuable, reward. These findings have been widely disseminated across the field of personality and individual differences because of their relevance for the understanding of the role of IU in the development and maintenance of anxiety-related disorders. Given their importance it would be desirable to have replications of this study, but none have been carried out so far. The current study has been designed to replicate and extend Luhmann et al.’s results. Our sample will include 266 healthy participants (more than five times the sample size used by Luhmann et al.) to detect with a power of 95% the effect size that can be detected with a power of 33% in the original study. To increase our chances of getting such a sample size, the experiment will be conducted online, To increase our chances of getting such a sample size, the experiment will be conducted online, adding check trials to the original decision-making task to monitor participants’ engagement. Additionally, we will explore the role of impulsivity in the relationship between IU and willingness to wait. This study will add empirical evidence about the role of IU in decision making and, in case of replication of Luhmann et al.’s results, will support the hypothesis that high-IU individuals may engage in inefficient or costly behaviour in exchange for less time enduring an uncertain situation.
Altered smell and taste: Anosmia, parosmia and the impact of long Covid-19
Authors: Burges Watson Duika L. , Campbell Miglena , Hopkins Claire , Smith Barry , Kelly Chris , Deary Vincent
Published: September 2021

Background

Qualitative olfactory (smell) dysfunctions are a common side effect of post-viral illness and known to impact quality of life and health status. Evidence is emerging that taste and smell loss are common symptoms of Covid-19 that may emerge and persist long after initial infection. The aim of the present study was to document the impact of post Covid-19 alterations to taste and smell.

Methods

We conducted exploratory thematic analysis of user-generated text from 9000 users of the AbScent Covid-19 Smell and Taste Loss moderated Facebook support group from March 24 to 30th September 2020.

Results

Participants reported difficulty explaining and managing an altered sense of taste and smell; a lack of interpersonal and professional explanation or support; altered eating; appetite loss, weight change; loss of pleasure in food, eating and social engagement; altered intimacy and an altered relationship to self and others.

Conclusions

Our findings suggest altered taste and smell with Covid-19 may lead to severe disruption to daily living that impacts on psychological well-being, physical health, relationships and sense of self. More specifically, participants reported impacts that related to reduced desire and ability to eat and prepare food; weight gain, weight loss and nutritional insufficiency; emotional wellbeing; professional practice; intimacy and social bonding; and the disruption of people’s sense of reality and themselves. Our findings should inform further research and suggest areas for the training, assessment and treatment practices of health care professionals working with long Covid.
Electroporation safety factor of 300 nanosecond and 10 millisecond defibrillation in Langendorff-perfused rabbit hearts
Authors: Neuber Johanna U. , Pakhomov Andrei G. , Zemlin Christian W.
Published: September 2021

Aims

Recently, a new defibrillation modality using nanosecond pulses was shown to be effective at much lower energies than conventional 10 millisecond monophasic shocks in ex vivo experiments. Here we compare the safety factors of 300 nanosecond and 10 millisecond shocks to assess the safety of nanosecond defibrillation.

Methods and results

The safety factor, i.e. the ratio of median effective doses (ED50) for electroporative damage and defibrillation, was assessed for nanosecond and conventional (millisecond) defibrillation shocks in Langendorff-perfused New Zealand white rabbit hearts. In order to allow for multiple shock applications in a single heart, a pair of needle electrodes was used to apply shocks of varying voltage. Propidium iodide (PI) staining at the surface of the heart showed that nanosecond shocks had a slightly lower safety factor (6.50) than millisecond shocks (8.69), p = 0.02; while PI staining cross-sections in the electrode plane showed no significant difference (5.38 for 300 ns shocks and 6.29 for 10 ms shocks, p = 0.22).

Conclusions

In Langendorff-perfused rabbit hearts, nanosecond defibrillation has a similar safety factor as millisecond defibrillation, between 5 and 9, suggesting that nanosecond defibrillation can be performed safely.
What contributes to good outcomes? The perspective of young people on short-term psychoanalytic psychotherapy for depressed adolescents
Authors: Housby Harriet , Thackeray Lisa , Midgley Nick
Published: September 2021

Depression is the fourth leading cause of adolescent illness and disability worldwide. A growing evidence base demonstrates that Short Term Psychoanalytic Psychotherapy [STPP] is an efficacious treatment for moderate to severe adolescent depression. However, with research in its infancy, key factors contributing to efficacy are unknown. Service users’ lived experiences provide valuable insight in this area. This study aimed to elucidate what adolescents value in treatment by inductively exploring lived experiences of STPP. Five adolescents with the largest reduction in depressive symptoms scores between baseline and end of treatment, who had taken part in a large-scale randomized controlled trial, were sampled. In-depth interviews carried out soon after the end of therapy were analysed using Interpretative Phenomenological Analysis. Three superordinate themes were identified: “Therapy as a Transformational Process”, “Explorative and Exposing: The Therapeutic Space” and “Being Heard and Working Together: The Therapeutic Relationship”. Adolescents valued a process of collaborative exploration with the therapist which when it was achieved was felt to facilitate a deep-rooted transformation in self-perception. Additionally, they described how an adjustment was needed to the particular frame of a psychoanalytic therapy. However, not all participants with a good treatment outcome experienced therapy in this way, suggesting a potential gap between the quantitative assessment of outcomes, and the way young people experience and understand the change process. Clinical implications and directions for research are discussed.
Survey of dermatophytes in stray dogs and cats with and without skin lesions in Puerto Rico and confirmed with MALDI-TOF MS
Authors: Hernandez-Bures Andrea , Pieper Jason B. , Bidot Willie A. , O’Dell Miranda , Sander William E. , Maddox Carol W.
Published: September 2021

Dermatophytosis is a common and highly contagious zoonotic skin disease in companion animals. This disease is a major concern in geographical areas that contain large numbers of stray animal populations. Numerous surveys on dermatophytosis among stray animal populations worldwide range between 27% to 50%. In recent years, the US territory of Puerto Rico was impacted by several natural disasters such as hurricanes, which has led to a large increase of abandonment cases and an increase in the stray animal population. Due to this, large low-cost spay/neuter clinics and trap-neuter-release programs have become a more common practice on the island. During these events, veterinary staff are exposed to multiple animals with no health history, and therefore, zoonotic diseases are of concern. The aim of this study was to provide information regarding the presence of dermatophyte species in symptomatic and asymptomatic stray dogs and cats in a region of Puerto Rico. Hair samples were collected from 99 stray animals with and without dermatological clinical signs. The hair samples were cultured on plates containing rapid sporulation medium and dermatophyte test medium. All cultures were evaluated microscopically to confirm the presence of dermatophytes. Then, all dermatophytes were further evaluated with MALDI-TOF MS to compare both diagnostic tests. A total of 19 animals (19%) were positive for dermatophyte growth. Of these animals, 18/19 were infected withM.canisand 1/19 withTrichophytonspp. Animals with clinical lesions were positive only 13.5% of the time compared to asymptomatic animals, who were positive in 36% of the sample population. All 19 dermatophytes (100%) diagnosed with microscopic evaluation were confirmed with MALDI-TOF MS. Our results indicate that there is a prevalence of 19% of dermatophytosis among the stray dog and cat population of the southeastern coast of the island.
Interventions to mitigate indoor air pollution: A cost-benefit analysis
Authors: Irfan Muhammad , Cameron Michael P. , Hassan Gazi
Published: September 2021

Globally, around three billion people depend upon solid fuels such as firewood, dry animal dung, crop residues, or coal, and use traditional stoves for cooking and heating purposes. This solid fuel combustion causes indoor air pollution (IAP) and severely impairs health and the environment, especially in developing countries like Pakistan. A number of alternative household energy strategies can be adopted to mitigate IAP, such as using liquefied petroleum gas (LPG), natural gas, biogas, electric stoves, or improved cook stoves (ICS). In this study, we estimate the benefit-cost ratios and net present value of these interventions over a ten-year period in Pakistan. Annual costs include both fixed and operating costs, whereas benefits cover health, productivity gains, time savings, and fuel savings. We find that LPG has the highest benefit-cost ratio, followed by natural gas, while ICS has the lowest benefit-cost ratio. Electric stoves and biogas have moderate benefit-cost ratios that nevertheless exceed one. To maximize the return on cleaner burning technology, the government of Pakistan should consider encouraging the adoption of LPG, piped natural gas, and electric stoves as means to reduce IAP and adopt clean technologies.
Epidemic management with admissible and robust invariant sets
Authors: Esterhuizen Willem , Lévine Jean , Streif Stefan
Published: September 2021

We present a detailed set-based analysis of the well-known SIR and SEIR epidemic models subjected to hard caps on the proportion of infective individuals, and bounds on the allowable intervention strategies, such as social distancing, quarantining and vaccination. We describe the admissible and maximal robust positively invariant (MRPI) sets of these two models via the theory of barriers. We show how the sets may be used in the management of epidemics, for both perfect and imperfect/uncertain models, detailing how intervention strategies may be specified such that the hard infection cap is never breached, regardless of the basic reproduction number. The results are clarified with detailed examples.
Somatostatin analog therapy effectiveness on the progression of polycystic kidney and liver disease: A systematic review and meta-analysis of randomized clinical trials
Authors: Suwabe Tatsuya , Barrera Francisco J. , Rodriguez-Gutierrez Rene , Ubara Yoshifumi , Hogan Marie C.
Published: September 2021

Background

Uncertainty underlies the effectiveness of somatostatin analogues for slowing the progression of polycystic kidney or liver disease.

Methods

Eligible studies included randomized controlled trials (RCTs) evaluating somatostatin analog as therapy for patients with polycystic kidney disease (PKD) or polycystic liver disease (PLD) compared to placebo or standard therapy. Two reviewers independently screened studies identified from databases (MEDLINE, EMBASE, Cochrane Database), clinical trial registries, and references from pertinent articles and clinical practice guidelines. Outcome measurements were changes in total liver volume (TLV), total kidney volume (TKV), and estimated glomerular filtration rate (eGFR).

Results

Of 264 nonduplicate studies screened, 10 RCTs met the inclusion criteria. The body of evidence provided estimates warranting moderate confidence. Meta-analysis of 7 RCTs including a total of 652 patients showed that somatostatin analogs are associated with a lower %TLV growth rate compared to control (mean difference, -6.37%; 95% CI -7.90 to -4.84, p<0.00001), and with a lower %TKV growth rate compared to control (mean difference, -3.66%; 95% CI -5.35 to -1.97, p<0.0001). However, it was not associated with a difference in eGFR decline (mean difference, -0.96 mL/min./1.73m2; 95% CI -2.38 to 0.46, p = 0.19).

Conclusions

Current body of evidence suggests that somatostatin analogs therapy slows the increase rate of TLV and TKV in patients with PKD or PLD compared to control within a 3-year follow-up period. It does not seem to have an effect on the change in eGFR. Somatostatin analogs therapy can be a promising treatment for ADPKD or ADPLD, and we need to continue to research its effectiveness for ADPKD or ADPLD.
Risk prediction models for intensive care unit-acquired weakness in intensive care unit patients: A systematic review
Authors: Zhang Wei , Tang Yun , Liu Huan , Yuan Li ping , Wang Chu chu , Chen Shu fan , Huang Jin , Xiao Xin yuan
Published: September 2021

Background and objectives

Intensive care unit-acquired weakness (ICU-AW) commonly occurs among intensive care unit (ICU) patients and seriously affects the survival rate and long-term quality of life for patients. In this systematic review, we synthesized the findings of previous studies in order to analyze predictors of ICU-AW and evaluate the discrimination and validity of ICU-AW risk prediction models for ICU patients.

Methods

We searched seven databases published in English and Chinese language to identify studies regarding ICU-AW risk prediction models. Two reviewers independently screened the literature, evaluated the quality of the included literature, extracted data, and performed a systematic review.

Results

Ultimately, 11 studies were considered for this review. For the verification of prediction models, internal verification methods had been used in three studies, and a combination of internal and external verification had been used in one study. The value for the area under the ROC curve for eight models was 0.7–0.923. The predictor most commonly included in the models were age and the administration of corticosteroids. All the models have good applicability, but most of the models are biased due to the lack of blindness, lack of reporting, insufficient sample size, missing data, and lack of performance evaluation and calibration of the models.

Conclusions

The efficacy of most models for the risk prediction of ICU-AW among high-risk groups is good, but there was a certain bias in the development and verification of the models. Thus, ICU medical staff should select existing models based on actual clinical conditions and verify them before applying them in clinical practice. In order to provide a reliable basis for the risk prediction of ICU-AW, it is necessary that large-sample, multi-center studies be conducted in the future, in which ICU-AW risk prediction models are verified.
Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis
Authors: Takahashi Yuki , Saito Masatoshi , Usuda Haruo , Takahashi Tsukasa , Watanabe Shimpei , Hanita Takushi , Sato Shinichi , Kumagai Yusaku , Koshinami Shota , Ikeda Hideyuki , Carter Sean , Fee Erin L. , Furfaro Lucy , Chemtob Sylvain , Keelan Jeffrey , Olson David , Yaegashi Nobuo , Newnham John P. , Jobe Alan H. , Kemp Matthew W.
Published: September 2021

Background

Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks’ gestation. Despite this, there are few treatment options allowing the prevention of preterm birth and associated fetal injury. Recent studies have shown that the small, non-competitive allosteric interleukin (IL)-1 receptor inhibitor, rytvela, may be of use in resolving inflammation associated with preterm birth (PTB) and fetal injury. We aimed to use an extremely preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela in response to established intra-amniotic (IA) lipopolysaccharide (LPS) exposure. We hypothesized that rytvela would reduce LPS-induced IA inflammation in amniotic fluid (AF) and fetal tissues.

Methods

Sheep with a single fetus at 95 days gestation (estimated fetal weight 1.0 kg) had surgery to place fetal jugular and IA catheters. Animals were recovered for 48 hours before being randomized to either: i) IA administration of 2 ml saline 24 hours before 2 ml IA and 2 ml fetal intravenous (IV) administration of saline (Saline Group, n = 7); ii) IA administration of 10 mg LPS in 2 ml saline 24 hours before 2 ml IA and 2 ml fetal IV saline (LPS Group, n = 10); 3) IA administration of 10 mg LPS in 2 ml saline 24 hours before 0.3 mg/fetal kg IA and 1 mg/fetal kg fetal IV rytvela in 2 ml saline, respectively (LPS + rytvela Group, n = 7). Serial AF samples were collected for 120 h. Inflammatory responses were characterized by quantitative polymerase chain reaction (qPCR), histology, fluorescent immunohistochemistry, enzyme-linked inmmunosorbent assay (ELISA), fluorescent western blotting and blood chemistry analysis.

Results

LPS-treated animals had endotoxin and AF monocyte chemoattractant protein (MCP)-1 concentrations that were significantly higher at 24 hours (immediately prior to rytvela administration) relative to values from Saline Group animals. Following rytvela administration, the average MCP-1 concentrations in the AF were significantly lower in the LPS + rytvela Group relative to in the LPS Group. In delivery samples, the expression of IL-1β in fetal skin was significantly lower in the LPS + rytvela Group compared to the LPS Group.

Conclusion

A single dose of rytvela was associated with partial, modest inhibition in the expression of a panel of cytokines/chemokines in fetal tissues undergoing an active inflammatory response.
Hypoglycemic active principles from the leaves of Bauhinia holophylla: Comprehensive phytochemical characterization and in vivo activity profile
Authors: Saldanha Luiz Leonardo , Quintiliano Delgado Aislan , Marcourt Laurence , de Paula Camaforte Nathalia Aparecida , Ponce Vareda Priscilla Maria , Nejad Ebrahimi Samad , Vilegas Wagner , Dokkedal Anne Lígia , Queiroz Emerson Ferreira , Wolfender Jean-Luc , Bosqueiro José Roberto
Published: September 2021

Bauhinia holophylla leaves, also known as "pata-de-vaca", are traditionally used in Brazil to treat diabetes. Although the hypoglycemic activity of this medicinal plant has already been described, the active compounds responsible for the hypoglycemic activity have not yet been identified. To rapidly obtain two fractions in large amounts compatible with further in vivo assay, the hydroalcoholic extract of B. holophylla leaves was fractionated by Vacuum Liquid Chromatography and then purified by medium pressure liquid chromatography combined with an in vivo Glucose Tolerance Test in diabetic mice. This approach resulted in the identification of eleven compounds (1–11), including an original non-cyanogenic cyanoglucoside derivative. The structures of the isolated compounds were elucidated by nuclear magnetic resonance and high-resolution mass spectrometry. One of the major compounds of the leaves, lithospermoside (3), exhibited strong hypoglycemic activity in diabetic mice at the doses of 10 and 20 mg/kg b.w. and prevents body weight loss. The proton nuclear magnetic resonance (1H NMR) quantification revealed that the hydroalcoholic leaves extract contained 1.7% of lithospermoside (3) and 3.1% of flavonoids. The NMR analysis also revealed the presence of a high amount of pinitol (4) (9.5%), a known compound possessing in vivo hypoglycemic activity. The hypoglycemic properties of the hydroalcoholic leaves extract and the traditional water infusion extracts of the leaves of B. holophylla seem thus to be the result of the activity of three unrelated classes of compounds. Such results support to some extent the traditional use of Bauhinia holophylla to treat diabetes.
Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection
Authors: Pant Jyoti , Samanovic Marie , Nelson Maria T. , Keceli Mert K. , Verdi Joseph , Beverley Stephen M. , Raper Jayne
Published: September 2021

Trypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein (HDL) complex that, through the cation channel-forming protein apolipoprotein L-1 (APOL1), provides innate immunity to select kinetoplastid parasites. The immunoprotective effects of TLF have been extensively investigated in the context of its interaction with the extracellular protozoan Trypanosoma brucei brucei, to which it confers sterile immunity. We previously showed that TLF could act against an intracellular pathogen Leishmania, and here we dissected the role of TLF and its synergy with host-immune cells. Leishmania major is transmitted by Phlebotomine sand flies, which deposit the parasite intradermally into mammalian hosts, where neutrophils are the predominant phagocytes recruited to the site of infection. Once in the host, the parasites are phagocytosed and shed their surface glycoconjugates during differentiation to the mammalian-resident amastigote stage. Our data show that mice producing TLF have reduced parasite burdens when infected intradermally with metacyclic promastigotes of L. major, the infective, fly-transmitted stage. This TLF-mediated reduction in parasite burden was lost in neutrophil-depleted mice, suggesting that early recruitment of neutrophils is required for TLF-mediated killing of L. major. In vitro we find that only metacyclic promastigotes co-incubated with TLF in an acidic milieu were lysed. However, amastigotes were not killed by TLF at any pH. These findings correlated with binding experiments, revealing that labeled TLF binds specifically to the surface of metacyclic promastigotes, but not to amastigotes. Metacyclic promastigotes of L. major deficient in the synthesis of surface glycoconjugates LPG and/or PPG (lpg1- and lpg5A-/lpg5B- respectively) whose absence mimics the amastigote surface, were resistant to TLF-mediated lysis. We propose that TLF binds to the outer surface glycoconjugates of metacyclic promastigotes, whereupon it kills the parasite in the acidic phagosome of phagocytes. We hypothesize that resistance to TLF requires shedding of the surface glycoconjugates, which occurs several hours after phagocytosis by immune cells, creating a relatively short-lived but effective window for TLF to act against Leishmania.
T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy
Authors: Lustig Gila , Cele Sandile , Karim Farina , Derache Anne , Ngoepe Abigail , Khan Khadija , Gosnell Bernadett I. , Moosa Mahomed-Yunus S. , Ntshuba Ntombi , Marais Suzaan , Jeena Prakash M. , Govender Katya , Adamson John , Kløverpris Henrik , Gupta Ravindra K. , Harrichandparsad Rohen , Patel Vinod B. , Sigal Alex
Published: September 2021

HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations.
TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis
Authors: Collins Jeffrey M. , Jones Dean P. , Sharma Ashish , Khadka Manoj , Liu Ken H. , Kempker Russell R. , Prideaux Brendan , Maner-Smith Kristal , Tukvadze Nestani , Shah N. Sarita , Brust James C. M. , Sékaly Rafick-Pierre , Gandhi Neel R. , Blumberg Henry M. , Ortlund Eric A. , Ziegler Thomas R.
Published: September 2021

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates is associated with IL-1β-mediated proinflammatory eicosanoid signaling in pulmonary TB disease. These findings support host metabolic remodeling as a key driver of pathologic inflammation in human TB disease.
Amina Weira’s Anger in the Wind: A premonitory tale of intertwined subjectivities
Authors: Niang Sada
Published: September 2021

This article analyses Amina Weira’s Anger in the Wind (2016). It argues that Weira’s documentary tells the story of slowly dying men through an exploration of a failed Anthropocene mediated by subjectivity and memory. Behind an almost casual handling of the camera, Weira casts a keen sympathetic eye on the ‘environmentally embattled’ populations of her native town, Arlit. Anger in the Wind is a documentary of painful, angry, recriminatory words; it tactfully yet pointedly exposes the devastation of the local ecosystems by staging the life stories of men and women who now realize that they were seen as disposable entities, not worthy of a dignified life cycle, fit for sacrifice at the altar of western technological prowess and comfort. As much as a testimony, Anger in the Wind is a Bamako style indictment of a destructive way of inhabiting the earth and a Hyenas’ style call to collective resistance.
Clinicoradiological Evaluation and Correlation of High-Resolution Computed Tomography Findings with Type 2 Diabetes Mellitus in Coronavirus Disease-19 Patients
Authors: Thorat Sanjay Tukaram , Kaila Niyti Vinod , Mankar Parikshit Gajanan , Bajaj Radhika Ratanlal , Damle Avanti Jayant , Rane Vaibhav Vijay
Published: September 2021

BACKGROUND Type 2 diabetes mellitus (T2DM) has emerged as the leading comorbidity in patients with coronavirus disease 2019 (COVID-19). However, data obtained on the correlation between the incidences of T2DM with COVID-19 are limited. We wanted to assess the severity of patients with T2DM and COVID-19, and study the correlation between the high-resolution computed tomography (HRCT) findings and hyperglycaemia with disease severity. METHODS This cross-sectional study included 100 patients with a history of diabetes and diagnosed COVID-19 positive. Data were collected using a semi-structured questionnaire. P < 0.05 was considered statistically significant. RESULTS The mean age was 58.81 ± 11.43 years with male preponderance (71 %). The difference was statistically significant in mean glycated haemoglobin (HbA1c) (7.32 ± 1.39 %, P < 0.001), mean high - density lipoprotein (HDL ; 39.78 ± 6.76 mmol / L), low - density lipoprotein (LDL; 63.23 ± 13.36 mmol / L), and triglyceride (TG; 140.70 ± 43.57 mg / dL) levels (P < 0.05) in different CT severity score. Mean HbA1c (P < 0.001), LDL, and CT severity scores (P = 0.034 and P < 0.001) were highly significant in patients who died than the discharged patients. A significant positive correlation was seen between CT severity score with HbA1c, LDL, and TG levels and chances of death (P < 0.001) rates, and also between the patients who died and HbA1c (P < 0.001) and LDL (P = 0.034) levels and CT severity score (P < 0.001). CONCLUSIONS Ideal management of the metabolic equilibrium of glucose was crucial in assuring an improved clinical outcome. Increased surveillance was warranted for diabetic COVID-19 patients. KEY WORDS COVID-19, Glycated Haemoglobin A, Hyperglycaemia, Severe Acute Respiratory Syndrome Coronavirus 2
Management of Air Emphysema with Cyanosis Following Dental Treatment - A Case Report with Scientific Reasoning
Authors: Tabassum Nafeesa , Akhter Fatema , Alfirm Ghada , Alhumaidan Yara , Haque Tahsinul
Published: September 2021

Air emphysema as a consequence of dental procedures is a rare but dangerous state if not diagnosed and treated timely. It can occur incidentally or iatrogenically in many dental procedures such as restorations, endodontic and periodontal treatments, surgical and non-surgical tooth extraction, and use of air or water sprays and syringes.1-6 Subcutaneous emphysema of dental origin most commonly occurs after surgical extraction of an impacted mandibular third molar.7 Several studies have reported that the use of high speed hand-piece during surgical extraction led to escape of air into the subcutaneous tissues. 7-10 Wilson (1983) reported subcutaneous emphysema in the eyelids after extraction of the maxillary molar teeth due to vigorous irrigation combined with air and water spray for 10 seconds.6 Subcutaneous emphysema in the cheek after extraction of the maxillary third molar without using high speed hand-piece is not a common phenomenon. In the present case, we demonstrate air emphysema in the cheek associated with hematoma after extraction of the impacted right maxillary 3rd molar. Since it was a soft tissue impaction, no hand-piece was used during the tooth removal. The purpose of this case report is to create awareness among the dental surgeons about the simple extraction procedures that may lead to air emphysema associated with hematoma.
The Goldbach Comet
Authors: Feliksiak Jan , Feliksiak Monica U.
Published: September 2021

The number of solutions to the Goldbach conjecture problemis presented here in graphical form, up to n = 150,000. The dots indicating the number of solutions for a particular even number n,create a picture which is often called the Goldbach comet. For further details regarding the graph, please refer to the paper by J. Feliksiak: https://doi.org/10.14293/S2199-1006.1.SOR-.PPIU46T.v1.
Grounded in a More Credible World
Authors: Kruse Zack
Published: September 2021

Easily Ditko’s most well-known creation, Spider-Man is critical to any discussion about Ditko’s work. This chapter focuses on Ditko’s role as writer on the series and the trajectory that he set the character on: a psychological epic not seen in other superhero comics of the period. Ditko puts Spider-Man through his paces, demanding that, like Dr. Strange, he searches his interior in a quest to find and create himself, transitioning from lonely nebbish to confident individualist. Ditko’s interest in Objectivist epistemology takes an increasingly important role with Spider-Man, setting the stage for the superheroes that would follow his departure from Marvel Comics. Among those more grounded and transparently philosophical characters was the Blue Beetle. Ditko created his version of Blue Beetle, and as this chapter argues, uses him to pick up where he left of with Peter Parker, completing the psychological quest that began in Amazing Fantasy #15.