bluuebunny/crossref_metadata_2025 huggingface dataset:
Conceptual Engineering: For What Matters
Authors: Köhler Sebastian , Veluwenkamp Herman
Published: January 2024

Conceptual engineering is the enterprise of evaluating and improving our representational devices. But how should we conduct this enterprise? One increasingly popular answer to this question proposes that conceptual engineering should proceed in terms of the functions of our representational devices. In this paper, we argue that the best way of understanding this suggestion is in terms of normative functions, where normative functions of concepts are, roughly, things that they allow us to do that matter normatively (for example, things in virtue of which we have normative reasons to have these concepts). Not only does this introduce a novel view about functions to the literature. This proposal also fits more naturally than the alternatives with conceptual engineering as a normative enterprise, and it allows functions to play all of the explanatory roles assigned to them in the conceptual engineering literature. Our discussion of the explanatory advantages of normative functions also advances the understanding of the ways in which concepts can be authoritative, what this means for conceptual engineering, and highlights the importance of political philosophy for thinking about conceptual engineering in practice. Furthermore, the paper explicates what kind of role considerations about function can and should actually play in conceptual engineering.
The Global Rise of the British Property Development Sector, 1945–1975
Authors: Kefford Alistair
Published: January 2024

In the three decades after 1945 the British property development sector exploded in size and began operating on a worldwide scale. The largest property companies in the world were British in this era and they built office blocks, shopping centres and hotels in cities all over the world. These overseas property developments overlapped firmly with the pre-existing political and economic geographies of empire, and their speculative transnational financing was made possible by allying with London’s financial sector and the world of ‘gentlemanly capitalism’. This article surveys the rise, financialization, and imperially inflected internationalization of the British property development sector in this period, showing how property companies capitalized upon post-war Britain’s developer-friendly urban renewal order, internationalist financial sector, and inherited imperial advantages even as many of the formal political structures of empire were being dismantled. In the post-war decades, the remnants of empire as a commercial world system provided Britain’s property developers with vital stepping stones towards the fully globalized forms of financialized real-estate development that shape cities around the world today.
Assessment of gamma absorbed doses and radiological risk indexes from soil radioactivity around the phosphate area in south Tunisia
Authors: Machraoui Sonia , Labidi Salam , Purushotham Mohan M
Published: January 2024

Human beings are constantly exposed to the radiations coming from the environment. This work assesses the radiological hazards of natural radioactivity in soil samples taken at four locations around the phosphate area in south Tunisia. Concentrations of primordial radionuclides were measured by gamma spectrometer using an HPGe detector. The overall mean values of 40K, 226Ra and 232Th concentrations were 264, 27 and 13 Bq kg−1, respectively. From the radioactivity measurements, radiation hazard indices specified by the United Nation Scientific Committee on the Effect of Atomic Radiation such as radium equivalent activity (Raeq), absorbed dose rates ($ {\dot{\text D}} $) and annual effective dose (AED) to the population for outdoor environment were determined. The mean values for the abovementioned parameters were 64 Bq kg−1, 33 nGy h−1 and 40 μSv y−1, respectively.
Reconstruction of organ doses for patients undergoing computed tomography examinations in Canada 1992–2019
Authors: Lee Choonsik , Moroz Brian , Thome Christopher , Gaudreau Katherine , Emami Pirouz , Little Mark P
Published: January 2024

We derived the first comprehensive organ dose library for Canadian pediatric and adult patients who underwent computed tomography (CT) scans between 1992 and 2019 to support epidemiological analysis of radiation risk. We calculated organ absorbed doses for Canadian CT patients in two steps. First, we modeled Computed Tomography Dose Index (CTDI) values by patient age, scan body part, and scan year for the scan period between 1992 and 2019 using national survey data conducted in Canada and partially the United Kingdom survey data as surrogates. Second, we converted CTDI values to organ absorbed doses using a library of organ dose conversion coefficients built in an organ dose calculation program, the National Cancer Institute dosimetry system for CT. In result, we created a library of doses delivered to 33 organs and tissues by different patient ages and genders, scan body parts and scan years. In the scan period before 2000, the organs receiving the greatest dose in the head, chest and abdomen–pelvis scans were the active marrow (3.7–15.2 mGy), lungs (54.7–62.8 mGy) and colon (54.9–68.5 mGy), respectively. We observed organ doses reduced by 24% (pediatric head and torso scans, and adult head scans) and 55% (adult torso scans) after 2000. The organ dose library will be used to analyse the risk of radiation exposure from CT scans in the Canadian CT patient cohort.
LYST-Interacting Protein 5 (LIP5) confers boad spctrum potato late blight resistance in Solanum agimoniifolium
Authors: Monino Lopez Daniel
Published: January 2024

Phytophthora infestans is a devastating pathogenic oomycete that causes potato late blight. Wild Solanum species are known to be a major source of resistance against P. infestans. In this study, we described a late blight broad spectrum resistant Solanum agrimoniifolium accession, resistant to 26 out of 27 tested P. infestans isolates. Here, we cloned the resistance gene located on the long arm of chromosome 7. Unlike most Rpi genes, the new resistance gene does not code for an NLR but for Lyst-Interacting Protein 5 (LIP5), which is an essential component of the endosomal sorting complex required for transport (ESCRT) pathway involved in the formation of multivesicular bodies (MVBs). Allele mining of LIP5 in other S. agrimoniifolium accessions identified only two amino acid polymorphisms between the proteins encoded by the resistant SaLIP5-1 and susceptible SaLIP5-2 alleles. We hypothesized that SaLIP5-1 is an effector target guarded by an NLR. Indeed, we found three different P. infestans effectors that interact with SaLIP5 in planta. Furthermore, we demonstrated that SaLIP5-1-mediated resistance requires helper NLRs (NRCs), suggesting that SaLIP5-1 is indeed guarded by an NLR. This study provides unique insights into how late blight resistance evolves among crop wild relatives and is essential for the introgression of the S. agrimoniifolium resistance into the S. tuberosum background.
Etomidate versus Ketamine as Prehospital Induction Agent in Patients with Suspected Severe Traumatic Brain Injury
Authors: Mansvelder Floor J. , Bossers Sebastiaan M. , Loer Stephan A. , Bloemers Frank W. , Van Lieshout Esther M. M. , Den Hartog Dennis , Hoogerwerf Nico , van der Naalt Joukje , Absalom Anthony R. , Peerdeman Saskia M. , Bulte Carolien S. E. , Schwarte Lothar A. , Schober Patrick ,   for the BRAIN-PROTECT collaborators
Published: January 2024

Background

Severe traumatic brain injury is a leading cause of morbidity and mortality among young people around the world. Prehospital care focuses on the prevention and treatment of secondary brain injury and commonly includes tracheal intubation after induction of general anesthesia. The choice of induction agent in this setting is controversial. This study therefore investigated the association between the chosen induction medication etomidate versus S(+)-ketamine and the 30-day mortality in patients with severe traumatic brain injury who received prehospital airway management in the Netherlands.

Methods

This study is a retrospective analysis of the prospectively collected observational data of the Brain Injury: Prehospital Registry of Outcomes, Treatments and Epidemiology of Cerebral Trauma (BRAIN-PROTECT) cohort study. Patients with suspected severe traumatic brain injury who were transported to a participating trauma center and who received etomidate or S(+)-ketamine for prehospital induction of anesthesia for advanced airway management were included. Statistical analyses were performed with multivariable logistic regression and inverse probability of treatment weighting analysis.

Results

In total, 1,457 patients were eligible for analysis. No significant association between the administered induction medication and 30-day mortality was observed in unadjusted analyses (32.9% mortality for etomidate versus 33.8% mortality for S(+)-ketamine; P = 0.716; odds ratio, 1.04; 95% CI, 0.83 to 1.32; P = 0.711), as well as after adjustment for potential confounders (odds ratio, 1.08; 95% CI, 0.67 to 1.73; P = 0.765; and risk difference 0.017; 95% CI, −0.051 to 0.084; P = 0.686). Likewise, in planned subgroup analyses for patients with confirmed traumatic brain injury and patients with isolated traumatic brain injury, no significant differences were found. Consistent results were found after multiple imputations of missing data.

Conclusions

The analysis found no evidence for an association between the use of etomidate or S(+)-ketamine as an anesthetic agent for intubation in patients with traumatic brain injury and mortality after 30 days in the prehospital setting, suggesting that the choice of induction agent may not influence the patient mortality rate in this population.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Determinants of Subjective Mental and Functional Health of Critical Illness Survivors: Comparing Pre-ICU and Post-ICU Status
Authors: Paul Nicolas , Cittadino Jonas , Krampe Henning , Denke Claudia , Spies Claudia D. , Weiss Björn
Published: January 2024

OBJECTIVES:

To compare ICU survivors’ subjective mental and functional health before ICU admission and after discharge and to assess determinants of subjective health decline or improvement.

DESIGN:

Secondary analysis of the multicenter cluster-randomized Enhanced Recovery after Intensive Care trial (ClinicalTrials.gov: NCT03671447).

SETTING:

Ten ICU clusters in Germany.

PATIENTS:

Eight hundred fifty-five patients with 1478 follow-up assessments.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

At two patient follow-ups scheduled 3 and 6 months after ICU discharge, patients rated their subjective mental and functional/physical health on two separate visual analog scales from 0 (worst) to 10 (best) in the previous week and before ICU admission. We compared pre-ICU and post-ICU subjective health and used mixed-effects regression to assess determinants of a health decline or improvement. At the first follow-up, 20% (n= 165/841) and 30% (n= 256/849) of patients reported a decline in subjective mental and functional health of at least three points, respectively; 16% (n= 133/841 andn= 137/849) outlined improvements of mental and functional health. For 65% (n= 543/841) and 54% (n= 456/849), mental and functional health did not change three points or more at the first follow-up. Multivariable mixed-effects logistic regressions revealed that the ICU length of stay was a predictor of mental (adjusted odds ratio [OR] per ICU day, 1.04; 95% CI, 1.00–1.09;p= 0.038) and functional health (adjusted OR per ICU day, 1.06; 95% CI, 1.01–1.12;p= 0.026) decline. The odds of a mental health decline decreased with age (adjusted OR per year, 0.98; 95% CI, 0.96–0.99;p= 0.003) and the odds of a functional health decline decreased with time after discharge (adjusted OR per month, 0.86; 95% CI, 0.79–0.94;p= 0.001).

CONCLUSIONS:

The majority of ICU survivors did not experience substantial changes in their subjective health status, but patients with long ICU stays were prone to subjective mental and functional health decline. Hence, post-ICU care in post-ICU clinics could focus on these patients.
Low-Dose Colchicine for the Prevention of Cardiovascular Events After Acute Coronary Syndrome
Authors: Gera Priyanka , Wasserstein David Haner , Frishman William H. , Aronow Wilbert S.
Published: January 2024

Colchicine, an established anti-inflammatory drug, is examined for its potential in mitigating adverse cardiovascular events following acute coronary syndrome (ACS). ACS, primarily triggered by plaque rupture and subsequent thrombosis, is a critical cardiovascular condition. Colchicine’s mechanism of action involves inhibiting microtubule activity, leading to immobilization of white blood cells and reducing inflammation. Clinical data from studies, including low-dose colchicine for secondary prevention of cardiovascular disease two and colchicine cardiovascular outcomes trial, support its efficacy in reducing major cardiovascular events post-ACS, though some studies report varying results. Colchicine can cause transient gastrointestinal side effects and is prescribed with caution in patients with certain medical conditions. The recent FDA approval of a low dose of colchicine reiterates its benefit in reducing cardiovascular risk. The cost-effectiveness of colchicine products (0.5 and 0.6 mg doses) are compared, suggesting the generic 0.6 mg dose of colchicine to be an alternative to branded forms of the drug.
Prostate cancer genotyping for risk stratification and precision treatment
Authors: Kumar Ashish A.
Published: January 2024

Prostate cancer (PC) is the most frequently diagnosed cancer and second leading cause of cancer-related deaths in men. It is heterogeneous, as is evident from the wide spectrum of therapeutic approaches. Most patients with PC are initially responsive to androgen deprivation therapy; however, the majority of cases are either hormone-sensitive PC or castration-resistant PC. Current therapeutic protocols follow the evolution of PC, a continuously progressive process involving a combination of widespread genomic alterations. These genomic alterations are either hereditary germline mutations, such as mutations in BRCA2, or specific only to tumor cells (somatic). Tumor-specific genomic spectra include genomic structural rearrangements, canonical androgen response genes, and many other specific genes such as TMPRSS2-ERG fusion, SPOP/FOXA1, TP53/RB1/PTEN, and BRCA2. New evidence indicates the involvement of signaling pathways including PI3K, WNT/β-catenin, SRC, and IL-6/STAT, which have been shown to promote epithelial-mesenchymal transition cancer stem cell–like features/stemness, and neuroendocrine differentiation in PC. Over the last decade, our understanding of the genotype-phenotype relationships has been enhanced considerably. The genetic background of PC related to canonical genetic alterations and signaling pathway activation genes has shed more insight into the molecular subtype and disease landscape, resulting in a more flexible role of individual therapies targeting diverse genotypes and phenotypes.
Bilateral thoracic sympathectomy for refractory coronary artery spasm—A case report
Authors: Lee Han-Hung , Chen Chao-Kun , Su Ying-Chieh , Chang Wei-Ting , Fong Yao
Published: January 2024

A 51-year-old woman was admitted because of three-degree AV block. Serial coronary angiogram revealed right coronary artery spasm, which is refractory to drug eluting stents and Nitroglycerin infusion. She underwent bilateral cardiac sympathetic denervation with video-assisted thoracoscopic surgery and was discharged on day 26 asymptomatically. Bilateral cardiac sympathetic denervation could be used for patients with symptomatic coronary artery spasm.
The Effect of Early Cultures and Dual-port Expanders on Two-stage, Prepectoral Breast Reconstruction: The 25/25 Study
Authors: Moyer Hunter R. , Sisson Kayla M.
Published: January 2024

Background:

Two-stage tissue expander to implant surgery remains the predominant technique for breast reconstruction. Unfortunately, there is a high incidence of reconstruction failure which portends a financial and emotional burden. Most failures are related to postmastectomy skin flap necrosis and infection. Recently, a dual-port tissue expander was introduced to the market, and the authors hypothesize that early cultures from the peri-implant fluid will guide antibiotic treatment and decrease reconstruction failure.

Methods:

This is a cohort study of 50 consecutive patients treated for breast cancer or genetic susceptibility via a two-stage, prepectoral technique. The first 25 patients (46 breasts) were treated with a variety of tissue expanders, and the subsequent 25 patients (47 breasts) received a dual-port expander. Routine cultures from the drain port were taken from the dual-port group at the second postoperative visit, and cultures were taken in the control group only when signs of infection were present. All other procedures and interventions were similar.

Results:

Fifty patients, totaling 93 breasts, completed the study with a mean follow-up of 145 days. There were no statistically significant demographic or pathologic differences between groups. Fifteen tissue expanders were explanted in the control group and five in the dual-port cohort (32.6% versus 10.6%, P = 0.012). All bacteria in the control group failures were either methicillin-resistant Staphylococcus aureus or Staphylococcus epidermidis, whereas failures in the dual-port group varied.

Conclusion:

Treatment of routine, early cultures from a dual-port expander led to a statistically significant decrease in tissue expander explantation.
Local Flaps to Cover Skin Necrosis after Skin-sparing Mastectomy and Prepectoral Reconstruction from PreQ-20 Trial
Authors: García-Novoa Alejandra , Acea-Nebril Benigno , López-Domínguez Carlota , Bouzón Alejandro Alberto , Díaz Carballada Carlota , Conde Iglesias Carmen , Cereijo Garea Carmen
Published: January 2024

Background:

In recent years, mastectomy has increasingly been indicated for women at high risk and those with breast cancer. Prepectoral reconstruction with polyurethane implant is an option for these patients. Nevertheless, this procedure can become complicated with exposure of the implant. The aim of this article is to describe the feasibility of local flaps to treat skin necrosis and dehiscence after prepectoral reconstruction and its impact on implant loss.

Methods:

This study includes the women who met the inclusion/exclusion criteria of the PreQ-20 protocol (12), which assessed patients with exposed implant who required a local flap for its coverage. Three types of flaps were used: thoracoepigastric, lateral thoracic, and batwing.

Results:

The study included 226 skin-sparing mastectomies and immediate reconstruction using prepectoral implants (52.7% bilateral mastectomies). Some 20.9% of the patients showed complications, with wound dehiscence the most frequent. Thirteen local flaps to cover the implant were performed. All flaps presented appropriate perfusion; however, the implant cover failed in six patients (46.2%).

Conclusions:

The use of local flaps can be a low-morbidity option for preventing implant loss when skin dehiscence or necrosis occurs and delays in oncology treatments.
Multicenter Study of Rotavirus Infection, Diversity of Circulating Genotypes and Clinical Outcomes in Children ≤5 Years Old in Iran
Authors: Mansour Ghanaiee Roxana , Fallah Tina , Karimi Abdollah , Sedighi Iraj , Tariverdi Marjan , Nazari Tayebe , Nahanmoghaddam Negin , Sedighi Parinaz , Nateghian Alireza , Amirali Arezu , Monavari Seyed Hamidreza , Fallahi Mahsa , Zahraei Seyed Mohsen , Mahmoudi Sussan , Elikaei Ameneh , Alebouyeh Masoud
Published: January 2024

Background:

To determine the epidemiology of rotavirus group A (RVA) infection in symptomatic children, and analyze genotype diversity in association with clinical characteristics, geographical and seasonal changes.

Methods:

The stool samples of symptomatic children 5≥ years old were collected from 5 different hospitals during December 2020 and March 2022. Rotavirus stool antigen test was done and G and P genotypes of the positive samples were determined. Associations of the infection and genotype diversity with demographical and clinical data were assessed by statistical methods.

Results:

RVA infection was detected in 32.1% (300/934) of the patients (Ranges between 28.4% and 47.4%). An inverse association with age was detected, where the highest frequency was measured in children ≤12 months of age (175/482, 36.3%). The infection was more frequent during winter (124/284, 43.7%) and spring (64/187, 34.2%). Children who were exclusively fed with breast milk showed a lower rate of infection (72/251, 28.6%). Among the 46 characterized genotypes (17 single- and 29 mixed-genotype infections), G1P[8] and G9P[4] were more frequently detected in children <36 (67/234, 28.63%) and 36–60 (7/24, 29.16%) months of age children, respectively. A seasonal diversity in the circulating genotypes was detected in different cities. Children with G1P[8], G1P[6], and mixed-genotype infection experienced a shorter duration of hospitalization, and a higher frequency of nausea and severe diarrhea, respectively.

Conclusions:

In this study high frequency of RVA infection was detected in symptomatic children in Iran. Moreover, genotype diversity according to geographic area, seasons, age groups, and clinical features of disease was detected.
Safety and Pharmacokinetics of Lopinavir/Ritonavir Oral Solution in Preterm and Term Infants Starting Before 3 Months of Age
Authors: Bekker Adrie , Yang Jincheng , Wang Jiajia , Cotton Mark F. , Cababasay Mae , Wiesner Lubbe , Moye Jack , Browning Renee , Nakwa Firdose L. , Rabie Helena , Violari Avy , Mirochnick Mark , Cressey Tim R. , Capparelli Edmund V.
Published: January 2024

Background:

Study of liquid lopinavir/ritonavir (LPV/r) in young infants has been limited by concerns for its safety in neonates.

Methods:

International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1106 was a phase IV, prospective, trial evaluating the safety and pharmacokinetics of antiretroviral medications administered according to local guidelines to South African preterm and term infants <3 months of age. Safety evaluation through 24-week follow-up included clinical, cardiac and laboratory assessments. Pharmacokinetic data from P1106 were combined with data from International Maternal Pediatric Adolescent AIDS Clinical Trials Network studies P1030 and P1083 in a population pharmacokinetics model used to simulate LPV exposures with a weight-band dosing regimen in infants through age 6 months.

Results:

Safety and pharmacokinetics results were similar in 13/28 (46%) infants initiating LPV/r <42 weeks postmenstrual age (PMA) and in those starting ≥42 weeks PMA. LPV/r was started at a median (range) age of 47 (13–121) days. No grade 3 or higher adverse events were considered treatment related. Modeling and simulation predicted that for infants with gestational age ≥27 weeks who receive the weight-band dosing regimen, 82.6% will achieve LPV trough concentration above the target trough concentration of 1.0 µg/mL and 56.6% would exceed the observed adult lower limit of LPV exposure of 55.9 µg·h/mL through age 6 months.

Conclusions:

LPV/r oral solution was safely initiated in a relatively small sample size of infants ≥34 weeks PMA and >2 weeks of life. No serious drug-related safety signal was observed; however, adrenal function assessments were not performed. Weight-band dosing regimen in infants with gestational age ≥27 weeks is predicted to result in LPV exposures equivalent to those observed in other pediatric studies.
Immigration background as a risk factor of chronic pain and high-impact chronic pain in children and adolescents living in Spain: differences as a function of age
Authors: Roman-Juan Josep , Sánchez-Rodríguez Elisabet , Solé Ester , Castarlenas Elena , Jensen Mark P. , Miró Jordi
Published: January 2024

The number of people immigrating from one country to another is increasing worldwide. Research has shown that immigration background is associated with chronic pain and pain disability in adults. However, research in this issue in children and adolescents has yielded inconsistent results. The aims of this study were to examine (1) the association between immigration background and chronic pain in children and adolescents; (2) the association between immigration background and pain interference in children and adolescents with chronic pain; and (3) the extent these associations differed as a function of sex and age. Participants of this cross-sectional study were 1115 school children and adolescents (mean age = 11.67 years; 56% girls). Participants were asked to provide sociodemographic information and respond to a survey including measures of pain (location, extension, frequency, intensity, and interference). Results showed that having an immigration background was associated with a greater prevalence of chronic pain (odds ratio [OR] = 1.91, P < 0.001) and that this association was higher in children (OR = 6.92, P < 0.001) and younger adolescents (OR = 1.66, P < 0.05) than in older adolescents. No significant association between immigration background and pain interference was identified. Children and adolescents with an immigration background, especially younger children, are at higher risk for having chronic pain. More resources should be allocated in the prevention of chronic pain in children and adolescents with an immigration background.
Description and initial validation of a novel measure of pain intensity: the Numeric Rating Scale of Underlying Pain without concurrent Analgesic use
Authors: Suri Pradeep , Heagerty Patrick J. , Timmons Andrew , Jensen Mark P.
Published: January 2024

Although many individuals with chronic pain use analgesics, the methods used in many randomized controlled trials (RCTs) do not sufficiently account for confounding by differential post-randomization analgesic use. This may lead to underestimation of average treatment effects and diminished power. We introduce (1) a new measure—the Numeric Rating Scale of Underlying Pain without concurrent Analgesic use (NRS-UP(A))—which can shift the estimand of interest in an RCT to target effects of a treatment on pain intensity in the hypothetical situation where analgesic use was not occurring at the time of outcome assessment; and (2) a new pain construct—an individuals' perceived effect of analgesic use on pain intensity (EA). The NRS-UP(A) may be used as a secondary outcome in RCTs of point treatments or nonpharmacologic treatments. Among 662 adults with back pain in primary care, participants' mean value of the NRS-UP(A) among those using analgesics was 1.2 NRS points higher than their value on the conventional pain intensity NRS, reflecting a mean EA value of −1.2 NRS points and a perceived beneficial effect of analgesics. More negative values of EA (ie, greater perceived benefit) were associated with a greater number of analgesics used but not with pain intensity, analgesic type, or opioid dose. The NRS-UP(A) and EA were significantly associated with future analgesic use 6 months later, but the conventional pain NRS was not. Future research is needed to determine whether the NRS-UP(A), used as a secondary outcome may allow pain RCTs to target alternative estimands with clinical relevance.
Nutritional deficiencies in children
Authors: Ali Farhana , Mouzaki Marialena
Published: January 2024

Purpose of review

The purpose of this review is to summarize commonly encountered nutritional deficiencies in children and their implications. Considering data suggesting that the majority of children with the United States consume unhealthy diets, the growing interest in the consumption of limiting diets, as well as the insidious clinical presentation of nutritional deficiencies, this is a timely and highly relevant review.

Recent findings

The underlying socioeconomic and medical circumstances that predispose to nutritional deficiencies in the Western world are covered. The high index of suspicion required to recognize nutritional deficiencies and the limitations of available testing are also discussed. Finally, the need for the development of accurate nutritional biomarkers is presented as a future research priority.

Nutritional deficiencies are not uncommon, even in high resource countries. Clinicians should remain vigilant and include nutritional deficiencies in the differential diagnoses of patients presenting with nonspecific symptoms.
Comamonas endophytica sp. nov., a novel indole acetic acid producing endophyte isolated from bamboo in China
Authors: Yue Jinjun , Yang Fu , Xiao Youtie , Lin Seqiao , He Zhengping , Wang Siyu , Zhao Jiayi , Yuan Jinling , Li Lubin , Liu Lei
Published: January 2024

Two novel indole acetic acid-producing strains, 5MLIRT and D4N7, were isolated from Indosasa shibataeoides in Yongzhou, Hunan province, and Phyllostachys edulis in Hangzhou, Zhejiang province, respectively. Based on their 16S rRNA sequences, strains 5MLIRT and D4N7 were closely related to Comamonas antarcticus 16-35-5T (98.4 % sequence similarity), and the results of 92-core gene phylogenetic trees showed that strains 5MLIRT and D4N7 formed a phylogenetic lineage within the clade comprising

Comamonas

species. The complete genome size of strain 5MLIRT was 4.49 Mb including two plasmids, and the DNA G+C content was 66.5 mol%. The draft genome of strain D4N7 was 4.26 Mb with 66.7 mol% G+C content. The average nucleotide identity and digital DNA–DNA hybridization values among strain 5MLIRT and species in the genus

Comamonas

were all below the species delineation threshold. The colonies of strain 5MLIRT and D4N7 were circular with regular margins, convex, pale yellow and 1.0–2.0 mm in diameter when incubated at 30 °C for 3 days. Strains 5MLIRT and D4N7 grew optimally at 30 °C, pH 7.0 and 1.0 % NaCl. The respiratory isoprenoid quinone was ubiquinone-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Polyphasic analyses indicated that strains 5MLIRT and D4N7 could be distinguished from related validly named

Comamonas

species and represent a novel species of the genus

Comamonas

, for which the name Comamonas endophytica sp. nov. is proposed. The type strain is 5MLIRT (=ACCC 62069T=GDMCC 1.2958T=JCM 35331T).
Comamonas resistens sp. nov. and Pseudomonas triclosanedens sp. nov., two members of the phylum Pseudomonadota isolated from the wastewater treatment system of a pharmaceutical factory
Authors: Yin Yiran , Han Jiayu , Wu Hao , Lu Yifei , Bao Xiangxiang , Lu Zhenmei
Published: January 2024

Five strains of two novel species were isolated from the wastewater treatment systems of a pharmaceutical factory located in Zhejiang province, PR China. Strains ZM22T and Y6 were identified as belonging to a potential novel species of the genus

Comamonas

, whereas strains ZM23T, ZM24 and ZM25 were identified as belonging to a novel species of the genus

Pseudomonas

. These strains were characterized by polyphasic approaches including 16S rRNA gene analysis, multi-locus sequence analysis, average nucleotide identity (ANI), in silico DNA–DNA hybridization (isDDH), physiological and biochemical tests, as well as chemotaxonomic analysis. Genome-based phylogenetic analysis further confirmed that strains ZM22T and Y6 form a distinct clade closely related to

Comamonas testosteroni

ATCC 11996T and

Comamonas thiooxydans

DSM 17888T. Strains ZM23T, ZM24 and ZM25 were grouped as a separate clade closely related to

Pseudomonas nitroreducens

DSM 14399T and

Pseudomonas nicosulfuronedens

LAM1902T. The orthoANI and isDDH results indicated that strains ZM22T and Y6 belong to the same species. In addition, genomic DNA fingerprinting demonstrated that these strains do not originate from a single clone. The same results were observed for strains ZM23T, ZM24 and ZM25. Strains ZM22T and Y6 were resistant to multiple antibiotics, whereas strains ZM23T, ZM24 and ZM25 were able to degrade an emerging pollutant, triclosan. The phylogenetic, physiological and biochemical characteristics, as well as chemotaxonomy, allowed these strains to be distinguished from their genus, and we therefore propose the names Comamonas resistens sp. nov. (type strain ZM22=MCCC 1K08496T=KCTC 82561T) and Pseudomonas triclosanedens sp. nov. (type strain ZM23T=MCCC 1K08497T=JCM 36056T), respectively.
The phosphorylation of the movement protein TGBp1 regulates the accumulation of the Bamboo mosaic virus
Authors: Wu Wan-Chen , Chen I-Hsuan , Hou Pei-Yu , Wang Lan-Hui , Tsai Ching-Hsiu , Cheng Chi-Ping
Published: January 2024

Phosphorylation and dephosphorylation of viral movement proteins plays a crucial role in regulating virus movement. Our study focused on investigating the movement protein TGBp1 of Bamboo mosaic virus (BaMV), which is a single-stranded positive-sense RNA virus. Specifically, we examined four potential phosphorylation sites (S15, S18, T58, and S247) within the TGBp1 protein. To study the impact of phosphorylation, we introduced amino acid substitutions at the selected sites. Alanine substitutions were used to prevent phosphorylation, while aspartate substitutions were employed to mimic phosphorylation. Our findings suggest that mimicking phosphorylation at S15, S18 and T58 of TGBp1 might be linked to silencing suppressor activities. The phosphorylated form at these sites exhibits a loss of silencing suppressor activity, leading to reduced viral accumulation in the inoculated leaves. Furthermore, mimicking phosphorylation at residues S15 and S18 could diminish viral accumulation at the single-cell level, while doing so at residue T58 could influence virus movement. However, mimicking phosphorylation at residue S247 does not appear to be relevant to both functions of TGBp1. Overall, our study provides insights into the functional significance of specific phosphorylation sites in BaMV TGBp1, illuminating the regulatory mechanisms involved in virus movement and silencing suppression.
Clinical features relating to pneumococcal colony phase variation in hospitalized adults with pneumonia
Authors: Ideguchi Shuhei , Yamamoto Kazuko , Takazono Takahiro , Fukuda Yuichi , Tashiro Takahiro , Shizukuishi Sayaka , Chang Bin , Ogawa Michinaga , Izumikawa Koichi , Yanagihara Katsunori , Yatera Kazuhiro , Mukae Hiroshi
Published: January 2024

Background.

Streptococcus pneumoniae

is a major causative bacteria of pneumonia and invasive pneumococcal disease (IPD); however, the mechanisms underlying its severity and invasion remain to be defined. Pneumococcal colonies exhibit opaque and transparent opacity phase variations, which have been associated with invasive infections and nasal colonization, respectively, in animal studies. This study evaluated the relationship between the opacity of pneumococcal colonies and the clinical presentation of pneumococcal pneumonia.

Methods. This retrospective study included adult patients hospitalized with pneumococcal pneumonia between 2012 and 2019 at four tertiary medical institutions. Pneumococcal strains from lower respiratory tract specimens were determined for their serotypes and microscopic colony opacity, and the association between the opacity phase and the severity of pneumonia was evaluated. Serotypes 3 and 37 with mucoid colony phenotypes were excluded from the study because their colony morphologies were clearly different.

Results. A total of 92 patients were included. Most patients were older adults (median age: 72 years) and males (67 %), and 59 % had community-acquired pneumonia. Of the 92 patients, 41 (45 %), 12 (13 %), and 39 (42 %) patients had opaque, transparent, and mixed variants in their pneumococcal colony, respectively. The opaque and non-opaque pneumococcal variants had no statistically significant difference in patient backgrounds. Although the pneumonia severity index score did not differ between the opaque and non-opaque groups, the rate of bacteremia was significantly higher in the opaque group than in the non-opaque group. Serotype distribution was similar between the groups.

Conclusions. Opaque pneumococcal variants may cause pneumonia and invasive diseases in humans. This study could help elucidate IPD, and opacity assessment may serve as a predictor for IPD.
Increased extra-axial cerebrospinal fluid and benign external hydrocephalus in early autism
Authors: Ben-Arie Gal , Shelef Ilan , Meiri Gal , Menashe Idan , Dinstein Ilan , Arazi Ayelet
Published: January 2024

Previous studies have reported that some children with Autism Spectrum Disorder (ASD) below the age of 3-years-old exhibit increased extra-axial cerebrospinal fluid (EA-CSF) volumes, suggesting that transient early CSF circulation abnormalities may characterize a unique etiology in a sub-group of ASD children. Specifically, this sub-group was proposed to exhibit an EA-CSF to total brain volume (TBV) ratio >0.14. It is unknown whether such findings may correspond to an early radiological diagnosis of Benign external hydrocephalus (BEH), which is defined as an enlargement of CSF volumes within the subarachnoid space (SAS) during the first two years of life.

Here we examined a retrospective clinical sample extracted from the National Autism Database of Israel. In 2020, ∼14% of ASD children in the database (n= 102) had completed clinical brain MRI scans at different ages before or after ASD diagnosis. Scans of 83 ASD children fulfilled quality control criteria and were compared to those of 53 age and sex matched typicality developing (TD) children who were referred to the same clinical center for similar clinical reasons. EA-CSF volume and total brain volume (TBV) were quantified from T2-weighted scans using manual labeling and compared across groups.

The results revealed that ASD children scanned before the age of 2-years-old (i.e., before ASD diagnosis) exhibited significantly larger EA-CSF volumes when compared to controls (t(49)=2.89, p=0.006, Cohen’s d=0.82). No significant differences were apparent across groups at older ages. Of those scanned before the age of 2-years-old, ∼16% of the ASD children, and none of the control children, exhibited EA-CSF/TBV ratios >0.14, thereby replicating previous findings from prospective research samples. In addition, retrospective examination of the neuroradiology assessments revealed a BEH prevalence of 33% in the ASD children scanned before the age of 2-years-old, with 80% of these children exhibiting EA-CSF/TBV ratios >0.11.

These findings reveal a clear relationship between quantitative EA-CSF volume analyses and qualitative BEH radiological findings, which characterize a considerable sub-group of ASD children. Accumulating evidence, therefore, suggests that BEH diagnosis in conjunction with a high EA-CSF/TBV ratio by the age of 2-years-old may be indicative of a specific ASD etiology that warrants further research and may offer unique opportunities for intervention.
Deletion of absent in melanoma (AIM) 2 gene alters bone morphology
Authors: Gong Zhenwei , Dixit Manisha , Poudel Sher Bahadur , Yildirim Gozde , Yakar Shoshanna , Muzumdar Radhika
Published: January 2024

Absent in Melanoma (AIM) 2 is a gene that is induced by interferon and acts as a cytosolic sensor for double-stranded (ds) DNA. It forms the AIM2 inflammasome, leading to the production of interleukin (IL)-1β and IL-18. Our previous research demonstrated that mice lacking AIM2 exhibit spontaneous obesity, insulin resistance, and inflammation in adipose tissue. In this study, we aimed to explore the impact of AIM2 gene deletion on bone structure in adult and aged mice. Utilizing micro-computed tomography (micro-CT), we discovered that female mice lacking AIM2 showed an increase in the total cross-sectional area at 5 months of age, accompanied by an increase in cortical thickness in the mid-diaphysis of the femur at both 5 and 15 months of age. At 15 months of age, the cortical bone mineral density (BMD) significantly decreased in AIM2 null females compared to wild-type (WT) mice. In AIM2 null mice, both trabecular bone volume and BMD at the distal metaphysis of the femur significantly decreased at 5 and 15 months of age. Similarly, micro-CT analysis of the L4 vertebra revealed significant decreases in trabecular bone volume and BMD in aged AIM2 null females compared to WT mice. Histological examination of femurs from aged mice demonstrated increased bone marrow adiposity in AIM2 null mice, accompanied by a significant increase in CD45-/CD31-/Sca1+/Pdgfa+ adipose progenitor cells, and a decrease in the ratio of CD31-/CD31+ osteogenic progenitor cells, as determined by flow cytometry of bone marrow cells. Our findings suggest that AIM2 deficiency affects bone health by promoting adipogenesis in bone marrow cells and inducing a pro-inflammatory environment, potentially contributing to the decreased bone mineral density.
Heparan sulfate selectively inhibits the collagenase activity of cathepsin K
Authors: Zhang Xiaoxiao , Luo Yin , Hao Huanmeng , Krahn Juno M. , Su Guowei , Dutcher Robert , Xu Yongmei , Liu Jian , Pedersen Lars C. , Xu Ding
Published: January 2024

Cathepsin K (CtsK) is a cysteine protease with potent collagenase activity. CtsK is highly expressed by bone-resorbing osteoclasts and plays an essential role in bone remodeling. Although CtsK is known to bind heparan sulfate (HS), the structural details of the interaction, and how HS ultimately regulates the biological functions of CtsK, remains largely unknown. In this report, we determined that CtsK preferably binds to larger HS oligosaccharides, such as dodecasaccharides (12mer), and that the12mer can induce monomeric CtsK to form a stable dimer in solution. Interestingly, while HS has no effect on the peptidase activity of CtsK, it greatly inhibits the collagenase activity of CtsK in a manner dependent on sulfation level. By forming a complex with CtsK, HS was able to preserve the full peptidase activity of CtsK for prolonged periods, likely by stabilizing its active conformation. Crystal structures of Ctsk with a bound 12mer, alone and in the presence of the endogenous inhibitor cystatin-C reveal the location of HS binding is remote from the active site. Mutagenesis based on these complex structures identified 6 basic residues of Ctsk that play essential roles in mediating HS-binding. At last, we show that HS 12mers can effectively block osteoclast resorption of bonein vitro. Combined, we have shown that HS can function as a multifaceted regulator of CtsK and that HS-based oligosaccharide might be explored as a new class of selective CtsK inhibitor in many diseases that involve exaggerated bone resorption.
Intestinal flow rates, absorption of felodipine from the small intestine and attributes of chyme collected at midgut from Labradors
Authors: Diebold Steffen M. ,   In memory of Mia Wilsson-Rahmberg
Published: January 2024

The objectives of the present study were (1) to investigate gastrointestinal hydrodynamics of Labradors as a model for human midgut (2) to examine various attributes of intestinal fluids in vivo and (3) to study the influence of hydrodynamics on the dissolution and absorption of a poorly soluble drug from various suspensions.

Gastrointestinal flow rates were determined volumetrically using an aspiration method. Isotonic saline and 20 % glucose solutions were used to alter gastrointestinal hydrodynamics. Felodipine, a BCS class II substance, was suspended in these fluids. Osmolality, pH, bile acid concentration and drug solubility in various chyme samples were determined. Blood plasma levels of felodipine were recorded while gastrointestinal dissolution was ongoing.

Fluid recovery at midgut fistula was significantly higher (>100 %) for glucose 20 % than for isotonic saline solutions (70 %). After administration of 200 ml glucose 20 % the (overall) grand median of differential gastrointestinal flow rates (DFR) was 8.3 ml/min.. Individual spike flow ranged from 20 up to 60 ml/min. Corresponding flow rates after administration of 200 ml isotonic saline were 35.0 ml/min. for the grand median including individual spike flows beyond 100 ml/min.. Within and between-dog variability in flow rate data was similar. In general, glucose solutions released more evenly. Following oral administration of glucose solution 20 % osmolality of intestinal fluids decreased within 40 min. from about 1000 mOsm. towards more physiological values of about 350 mOsm.. Saturation solubility of felodipine (Cs) in jejunal chyme after administration of either solution (saline or glucose) was determined to be about 10 (µg/ml) on average (median),exposing high variability with time! The intestinal solubility varied greatly within the course of an experiment. However, a strong correlation was observed between the aspirated fluid volume and the dissolved amount of felodipine confirming the well known relationship of Noyes, Whitney, Nernst and Brunner in-vivo. Grand median of pH in jejunal chyme of labradors was determined to be 6.68. Median values range from 4.38-7.62. The pharmacokinetic data showed a slight trend to differences based on particle size and on fluid administered.
Reprogramming of 3D genome structure underlying HSPC development in zebrafish
Authors: He Min , Li Xiaoli , Xu Bingxiang , Lu Yibo , Liu Huakai , An Ziyang , Zhang Wenqing , Li Feifei
Published: January 2024

Development of hematopoietic stem and progenitor cells (HSPC) is a multi-staged complex process that conserved between zebrafish and mammals; however, the mechanism underlying HSPC development is not fully understood. Chromatin conformation plays important roles in transcriptional regulation and cell fate decision, its dynamic and role in HSPC development is poorly investigated. Here, we performed chromatin structure and multi-omics dissection across different stages of HSPC developmental trajectory in zebrafish. Chromatin organization of zebrafish HSPC resemble mammalian cells with similar hierarchical structure and characteristics. We revealed the multi-scale reorganization of 3D genome and its influence on transcriptional regulation and transition of cell function during HSPC development. Nascent HSPC is featured by loose conformation with obscure structure at all layers. Notably, PU.1 was identified as a potential factor mediating formation of promoter-involved loops and regulating gene expression as well as HSPC function. Our results provided a global view of chromatin structure dynamics associated with development of zebrafish HSPC and discovered key transcription factor involved in HSPC chromatin interactions, which will provide new insights into the epigenetic regulatory mechanisms underlying vertebrate HSPC fate decision.
Cytochrome P450 Enzyme Design by Constraining Catalytic Pocket in Diffusion model
Authors: Wang Qian , Liu Xiaonan , Zhang Hejian , Chu Huanyu , Shi Chao , Zhang Lei , Liu Pi , Li Jing , Zhu Xiaoxi , Liu Yuwan , Chen Zhangxin , Huang Rong , Bai Jie , Chang Hong , Liu Tian , Chang Zhenzhan , Cheng Jian , Jiang Huifeng
Published: January 2024

Although cytochrome P450 enzymes are the most versatile biocatalysts in nature, there is insufficient comprehension of the molecular mechanism underlying their functional innovation process. Here, by combining ancestral sequence reconstruction, reverse mutation assay and structure analysis, we identified five founder residues in the catalytic pocket of flavone 6-hydroxylase (F6H) and proposed a “three-point fixation” model to elucidate the functional innovation mechanisms of P450s in nature. According to this design principle of catalytic pocket, we further developed a de novo diffusion model (P450Diffusion) to generate artificial P450s. Ultimately, among the 17 non-natural P450s we generated, ten designs exhibited significant F6H activity and six exhibited a 1.3- to 3.5-fold increase in catalytic capacity compared to the natural CYP706X1. This work not only explores the design principle of catalytic pockets of P450s, but also provides an insight into the artificial design of P450 enzymes with desired functions.