bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cdk1-mediated threonine phosphorylation of Sam68 modulates its RNA binding, alternative splicing activity and cellular functions
Authors: Malki Idir , Liepina Inara , Kogelnik Nora , Watmuff Hollie , Robinson Sue , Lightfoot Adam , Gonchar Oksana , Bottrill Andrew , Fry Andrew M , Dominguez Cyril 
Published: December 2022

Abstract
Sam68, also known as KHDRBS1, is a member of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins and its role is modulated by post-translational modifications, including serine/threonine phosphorylation, that differ at various stages of the cell cycle. However, the molecular basis and mechanisms of these modulations remain largely unknown. Here, we combined mass spectrometry, nuclear magnetic resonance spectroscopy and cell biology techniques to provide a comprehensive post-translational modification mapping of Sam68 at different stages of the cell cycle in HEK293 and HCT116 cells. We established that Sam68 is specifically phosphorylated at T33 and T317 by Cdk1, and demonstrated that these phosphorylation events reduce the binding of Sam68 to RNA, control its cellular localization and reduce its alternative splicing activity, leading to a reduction in the induction of apoptosis and an increase in the proliferation of HCT116 cells.
Insights into the molecular mechanism of translation inhibition by the ribosome-targeting antibiotic thermorubin
Authors: Paranjpe Madhura N , Marina Valeria I , Grachev Aleksandr A , Maviza Tinashe P , Tolicheva Olga A , Paleskava Alena , Osterman Ilya A , Sergiev Petr V , Konevega Andrey L , Polikanov Yury S , Gagnon Matthieu G 
Published: December 2022

Abstract
Thermorubin (THR) is an aromatic anthracenopyranone antibiotic active against both Gram-positive and Gram-negative bacteria. It is known to bind to the 70S ribosome at the intersubunit bridge B2a and was thought to inhibit factor-dependent initiation of translation and obstruct the accommodation of tRNAs into the A site. Here, we show that thermorubin causes ribosomes to stall in vivo and in vitro at internal and termination codons, thereby allowing the ribosome to initiate protein synthesis and translate at least a few codons before stalling. Our biochemical data show that THR affects multiple steps of translation elongation with a significant impact on the binding stability of the tRNA in the A site, explaining premature cessation of translation. Our high-resolution crystal and cryo-EM structures of the 70S-THR complex show that THR can co-exist with P- and A-site tRNAs, explaining how ribosomes can elongate in the presence of the drug. Remarkable is the ability of THR to arrest ribosomes at the stop codons. Our data suggest that by causing structural re-arrangements in the decoding center, THR interferes with the accommodation of tRNAs or release factors into the ribosomal A site.
DNA processing by the Kaposi's sarcoma-associated herpesvirus alkaline exonuclease SOX contributes to viral gene expression and infectious virion production
Authors: Hartenian Ella , Mendez Aaron S , Didychuk Allison L , Khosla Shivani , Glaunsinger Britt A 
Published: December 2022

Abstract
Alkaline exonucleases (AE) are present in several large DNA viruses including bacteriophage λ and herpesviruses, where they play roles in viral DNA processing during genome replication. Given the genetic conservation of AEs across viruses infecting different kingdoms of life, these enzymes likely assume central roles in the lifecycles of viruses where they have yet to be well characterized. Here, we applied a structure-guided functional analysis of the bifunctional AE in the oncogenic human gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), called SOX. In addition to identifying a preferred DNA substrate preference for SOX, we define key residues important for DNA binding and DNA processing, and how SOX activity on DNA partially overlaps with its functionally separable cleavage of mRNA. By engineering these SOX mutants into KSHV, we reveal roles for its DNase activity in viral gene expression and infectious virion production. Our results provide mechanistic insight into gammaherpesviral AE activity as well as areas of functional conservation between this mammalian virus AE and its distant relative in phage λ.
Improved genome editing by an engineered CRISPR-Cas12a
Authors: Ma Enbo , Chen Kai , Shi Honglue , Stahl Elizabeth C , Adler Ben , Trinidad Marena , Liu Junjie , Zhou Kaihong , Ye Jinjuan , Doudna Jennifer A 
Published: December 2022

Abstract
CRISPR-Cas12a is an RNA-guided, programmable genome editing enzyme found within bacterial adaptive immune pathways. Unlike CRISPR-Cas9, Cas12a uses only a single catalytic site to both cleave target double-stranded DNA (dsDNA) (cis-activity) and indiscriminately degrade single-stranded DNA (ssDNA) (trans-activity). To investigate how the relative potency of cis- versus trans-DNase activity affects Cas12a-mediated genome editing, we first used structure-guided engineering to generate variants of Lachnospiraceae bacterium Cas12a that selectively disrupt trans-activity. The resulting engineered mutant with the biggest differential between cis- and trans-DNase activity in vitro showed minimal genome editing activity in human cells, motivating a second set of experiments using directed evolution to generate additional mutants with robust genome editing activity. Notably, these engineered and evolved mutants had enhanced ability to induce homology-directed repair (HDR) editing by 2–18-fold compared to wild-type Cas12a when using HDR donors containing mismatches with crRNA at the PAM-distal region. Finally, a site-specific reversion mutation produced improved Cas12a (iCas12a) variants with superior genome editing efficiency at genomic sites that are difficult to edit using wild-type Cas12a. This strategy establishes a pipeline for creating improved genome editing tools by combining structural insights with randomization and selection. The available structures of other CRISPR-Cas enzymes will enable this strategy to be applied to improve the efficacy of other genome-editing proteins.
Discovery and characterization of novel type I-D CRISPR-guided transposons identified among diverse Tn7-like elements in cyanobacteria
Authors: Hsieh Shan-Chi , Peters Joseph E 
Published: December 2022

AbstractCRISPR-Cas defense systems have been naturally coopted for guide RNA-directed transposition by Tn7 family bacterial transposons. We find cyanobacterial genomes are rich in Tn7-like elements, including most of the known guide RNA-directed transposons, the type V-K, I-B1, and I-B2 CRISPR-Cas based systems. We discovered and characterized an example of a type I-D CRISPR-Cas system which was naturally coopted for guide RNA-directed transposition. Multiple novel adaptations were found specific to the I-D subtype, including natural inactivation of the Cas10 nuclease. The type I-D CRISPR-Cas transposition system showed flexibility in guide RNA length requirements and could be engineered to function with ribozyme-based self-processing guide RNAs removing the requirement for Cas6 in the heterologous system. The type I-D CRISPR-Cas transposon also has naturally fused transposase proteins that are functional for cut-and-paste transposition. Multiple attributes of the type I-D system offer unique possibilities for future work in gene editing. Our bioinformatic analysis also revealed a broader understanding of the evolution of Tn7-like elements. Extensive swapping of targeting systems was identified among Tn7-like elements in cyanobacteria and multiple examples of convergent evolution, including systems targeting integration into genes required for natural transformation.
Offences against Status
Authors: Letsas George 
Published: December 2022

Abstract
Philosophical accounts of status understand it either pejoratively, as social rank, or laudatorily, as the dignity possessed by all in virtue of our shared humanity. Status is considered to be something either we all have or no one should have. This article aims to show that there is a third, neglected, sense of status. It refers to the moral rights and duties one holds in virtue of one’s social position or role. Employees, refugees, doctors, teachers and judges all hold social roles in virtue of which they have distinctive obligations, rights, privileges, powers and the like. This article aims to do two things: first, to distinguish the role-based notion of status from ideas of social rank, and to identify the various ways in which it constitutes a distinct category of moral wrongdoing; and second, to show that status, thus understood, is justified on egalitarian grounds even though, unlike dignity, not everyone has it. The moral point of status, I argue, is to regulate asymmetrical relations in which one of the parties suffers from background vulnerabilities and dependencies. Status as a moral idea vests both parties with a complex set of rights and duties, whose aim is to restore moral equality between the parties.
Complete Genome Sequences of Septoria linicola: A Resource for Studying a Damaging Flax Pathogen
Authors: Lapalu Nicolas , Simon Adeline , Demenou Boris , Paumier Delphine , Guillot Marie-Pierre , Gout Lilian , Suffert Frederic , Valade Romain 
Published: December 2022

Fungal genus Septoria causes diseases in a wide range of plants. Here, we report the first genome sequences of two strains of Septoria linicola, the causal agent of the pasmo disease of flax ( Linum usitatissimum). The genome of the first strain, SE15195, was fully assembled in 16 chromosomes, while 35 unitigs were obtained for a second strain, SE14017. Structural annotations predicted 13,096 and 13,085 protein-encoding genes and transposable elements content of 19.0 and 18.1% of the genome for SE15195 and SE14017, respectively. The four smaller chromosomes 13 to 16 show genomics features of potential accessory chromosomes. The assembly of these two genomes is a new resource for studying S. linicola and improving management of pasmo. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Dystrophic Calcification of the Lower Leg in a Patient with Chronic Lower Extremity Venous Insufficiency and Diabetes Mellitus: A Case Report and Literature Review
Authors: Guo Jing , Shi Weichen , Zhang Guangming , Zhu Chaojun 
Published: December 2022

ABSTRACT
Chronic lower extremity venous insufficiency can cause local dystrophy, and some patients will develop calf dystrophic calcification. In this case report, the authors describe a patient with varicose veins of both lower extremities, venous insufficiency of the lower extremities, recurring ulcers on the left leg for more than 20 years, and diabetes mellitus with dystrophic calcification of the calf. The patient’s left leg ulcer showed extensive chronic inflammation, pathological calcification, and necrosis of the subcutaneous tissue with a thickness of approximately 0.5 to 1 cm. The computed tomography, X-ray, and hematoxylin-eosin staining results confirmed calcification; the leg skin thickened because of inflammatory irritation. After 11 months of treatment, the calcified and necrotic calcification and necrotic tissue were removed, and the wound healed.
Prevention of Postoperative Cognitive Dysfunction by Minocycline in Elderly Patients after Total Knee Arthroplasty: A Randomized, Double-blind, Placebo-controlled Clinical Trial
Authors: Takazawa Tomonori , Horiuchi Tatsuo , Orihara Masaki , Nagumo Kazuhiro , Tomioka Akihiro , Ideno Yuki , Hayashi Kunihiko , Yashima Hideaki , Araki Takuya , Hatayama Kazuhisa , Terauchi Masanori , Ikeda Yoshio , Saito Shigeru 
Published: December 2022

Background
There are no effective pharmacologic interventions for preventing postoperative cognitive dysfunction in daily practice. Since the antibiotic minocycline is known to suppress postoperative neuroinflammation, this study hypothesized and investigated whether minocycline might have a preventive effect on postoperative cognitive dysfunction after noncardiac surgery.

Methods
This study included patients aged more than 60 yr undergoing total knee arthroplasty under general anesthesia. They were randomly assigned to minocycline and placebo groups, to orally receive 100 mg of minocycline or placebo twice daily from the day before surgery until the seventh day after surgery. Cognitive function was evaluated before surgery, and 1 week and 3 months after surgery, using a battery of four cognitive function tests, including Visual Verbal Learning Test, Trail Making Test, Stroop Color and Word Test, and Letter–Digit Coding Task. Additionally, 30 healthy volunteers were subjected to the same tests as the patients to examine the learning effect of repeated tests. The occurrence of postoperative cognitive dysfunction was judged from the results of the neurocognitive test battery, with consideration of the learning effect. The secondary endpoints were the effects of minocycline on postoperative delirium and postoperative pain.

Results
A total of 100 patients were randomized to the minocycline group, and 102 were randomized to the placebo group. The average age of patients was 75 yr. Evaluation showed no significant difference in the incidence of postoperative cognitive dysfunction between the minocycline and placebo groups at both 1 week (8 of 90 [8.9%] vs. 4 of 95 [4.2%]; odds ratio, 2.22 [95% CI, 0.64 to 7.65]; P = 0.240) and 3 months (15.3 of 90 [17.0%] vs. 15.3 of 95 [16.1%]; odds ratio, 1.07 [95% CI, 0.49 to 2.32]; P = 0.889) postoperatively. Missing data 3 months after surgery were corrected by the multiple imputation method. There were no differences between the two groups in postoperative delirium and postoperative pain.

Conclusions
Minocycline is likely to have no preventive effect on postoperative cognitive dysfunction.

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Do Cultures from Percutaneously Drained Intra-abdominal Abscesses Change Treatment: A Retrospective Review
Authors: Esposito Andrew C. , Zhang Yuqi , Nagarkatti Nupur , Laird William D. , Coppersmith Nathan A. , Reddy Vikram , Leeds Ira , Mongiu Anne , Longo Walter , Hao Ritche M. , Pantel Haddon 
Published: December 2022

BACKGROUND:
Routinely obtaining intraoperative cultures for abdominal infections is not a currently recommended evidence-based practice. Yet, cultures are frequently sent from these infections when they are managed by image-guided percutaneous drains.

OBJECTIVE:
Determine the utility of cultures from percutaneously drained intra-abdominal abscesses.

DESIGN:
Retrospective chart review.

SETTING:
Single university-affiliated institution.

PATIENTS:
Inpatients with intra-abdominal abscess secondary to diverticulitis or appendicitis between 2013 and 2021 managed with image-guided percutaneous drain, excluding those with active chemotherapy, HIV, or solid organ transplant.

MAIN OUTCOME MEASURES:
Frequency culture data from percutaneous drains changed antimicrobial therapy.

RESULTS:
There were 221 patients meeting inclusion criteria. Of these, 56% were admitted for diverticulitis and 44% for appendicitis. Patients were 54% female, had a median age of 62 (18-93), and 14% were active smokers. The median length of hospitalization was 8 days (range, 1-78) and the median antibiotics course was 8 days (range, 1-22). Culture data from percutaneous drains altered antimicrobial therapy in 7% (16/221) of patients. A culture was obtained from 95% of drains, with 79% of cultures with growth. Cultures grew multiple bacteria in 63% and mixed variety without speciation in 13%. The most common pathogen was Bacteroides family at 33% of all bacteria. The most common empiric antibiotic regimen was ceftriaxone and metronidazole, used in 33% and 40% of patients, respectively. Female sex (p = 0.027) and presence of bacteria with any antibiotic resistance (p < 0.01) were associated with higher likelihood of cultures influencing antimicrobial therapy.

LIMITATIONS:
Retrospective and single institution’s microbiome.

CONCLUSIONS:
Microbiology data from image-guided percutaneous drains of abdominal abscesses altered antimicrobial therapy in 7% of patients, which is lower than previously published literature on cultures obtained surgically. Given this low rate, similar to recommendation on cultures obtained intraoperatively, routinely culturing material from drains placed in abdominal abscess is not recommended. See Video Abstract at http://links.lww.com/DCR/C64.
Clinical Outcomes of Preloaded Descemet Membrane Endothelial Keratoplasty With Endothelium Inward: A 24-Month Comparative Analysis Between Fuchs Endothelial Corneal Dystrophy and Bullous Keratopathy
Authors: Viola Pietro , Neri Enrico , Testa Valeria , Parekh Mohit , Cian Roberto , Grassetto Andrea , Romano Vito 
Published: December 2022

Purpose:The aim of this study was to compare long-term clinical outcomes of preloaded Descemet membrane endothelial keratoplasty (DMEK) between Fuchs endothelial corneal dystrophy (FECD) and bullous keratopathy (BK).Methods:In this single-center retrospective clinical case series, 71 eyes of 64 patients indicated with FECD (62%) or BK (38%) (with or without cataract) were treated with preloaded DMEK grafts between March 2018 and February 2020. Standard DMEK peeling, followed by manual folding of the tissue with endothelium-inward orientation and storing in a preloaded fashion inside a 2.2-mm intraocular lens cartridge. All tissues were delivered using a bimanual pull-through technique, followed by air tamponade. Graft unfolding time, endothelial cell loss, corrected distance visual acuity, central corneal thickness, rebubbling rate, and intraoperative and postoperative complications at 1, 3, 6, 12, and 24 months were recorded.Results:The mean intraoperative graft unfolding time in FECD did not differ from the BK group (P= 0.6061). Cystoid macular edema did not differ in either group (P= 0.6866). The rebubbling rate was found to be significantly higher in FECD compared with the BK group (P= 0.0423). Corrected distance visual acuity significantly improved at the first month after surgery (P= 0.0012), with no differences between FECD and BK at 24 months (P= 0.2578). Central corneal thickness was stable postoperatively and showed no differences between the groups (P= 0.3693). Significantly higher endothelial cell counts were observed in the FECD group at 24 months (P= 0.0002).Conclusions:Preloaded DMEK with “endothelium-in” offers acceptable intraoperative time, rebubbling rate, and clinical outcomes in both FECD and BK groups. Patients with FECD show better postoperative clinical outcomes even if the rebubbling rate is relatively high.
Extending health care access via telemedicine in public libraries
Authors: DeGuzman Pamela B. , Garth Jennifer L. , Sanjay Kamya , Compton Rebekah M. 
Published: December 2022

ABSTRACT

Background:
Despite the potential for telemedicine in public libraries to expand health care access to those living a long distance from care and in broadband poor areas, there are few libraries that collaborate with providers to extend access.

Purpose:
To explore licensed health care providers' perspectives on telemedicine in public libraries as a method of improving equitable access to care for populations lacking the ability to connect to telemedicine from home.

Methods:
We used a two-phase explanatory sequential mixed methods design with a quantitative strand followed by a qualitative strand. Surveys were analyzed descriptively. Interviews were analyzed thematically using descriptive content analysis.

Results:
Of the 50 survey respondents, 13 were physicians and 36 were nurse practitioners (NPs); 12 NPs were interviewed. NPs were overwhelmingly supportive of telemedicine in public libraires, describing how connecting at-risk populations to a video visit (VV) allowed for a more thorough and accurate assessment than a phone call. Although several NPs were concerned with privacy, others considered a library to be more private than the home. Interviews revealed how chronic illness management may be the ideal visit type for public library-based telemedicine.

Conclusions:
Given the importance of expanding access sites for telemedicine, NPs should consider partnering with libraries in their catchment areas where broadband access is sparse and patients must travel long distances to care.

Implications:
Managing chronic illnesses using telemedicine in public libraries may be an important approach toward reducing health disparities in populations who live in long distances from care and do not have home-based internet access.
Frailty as tested by the Liver Frailty Index in out-patient patients with cirrhosis in China: a cross-sectional study
Authors: Siyu Li , Yuan Yuan , Ran An , Minyan Li 
Published: December 2022

Background
Early identification and prevention of frailty are very important for patients with cirrhosis.

Methods
The study was the first to use Liver Frailty Index in out-patient patients with cirrhosis in China, and to analyze the influencing factors.

Result
This study included 387 patients with cirrhosis. Frailty was diagnosed using the Liver Frailty Index. Multiple Logistic regression model were used to analyze influencing factors of frailty in out-patient patients with cirrhosis. Frailty was diagnosed in 9.6% of patients and prefrailty was diagnosed in 54.8% of patients. Age, sex, BMI, education level, monthly economic income, number of unplanned hospital admissions in the past year, cause of cirrhosis, Child-Pugh classification of cirrhosis, nutritional risk, physical activity, gait speed and Activity of Daily Living (ADL) Scale in the frailty, prefrailty and no frailty of groups were statistically significant. Age (OR, 1.103; CI, 0.064–0.132), BMI (OR, 0.817; CI, −0.302 to −0.104), education level (OR, 4.321; CI, 0.754–2.173), physical activity (OR, 3.580; CI, 0.534–2.016) and gait speed (OR, 0.001; CI, −8.188 to −4.972) were influential factors of frailty in out-patient patients with cirrhosis.

Conclusion
Out-patient patients with cirrhosis have a high incidence of frailty and prefrailty. Elderly, reduced gait speed, no physical activity and low culture level are risk factors for frailty and prefrailty, and we should be identification and intervention early.
Prevalence of Stress and Anxiety Among Nursing Students
Authors: Vo Thi Nhi , Chiu Hsiao-Yean , Chuang Yeu-Hui , Huang Hui-Chuan 
Published: December 2022

Background:
There is variability in the reported prevalence of stress and anxiety among nursing students across studies, and few studies have investigated the pooled prevalence of stress and anxiety of these students.

Purpose:
To investigate the prevalence and associated factors related to stress and anxiety among nursing students.

Methods:
Various electronic databases were searched up to October 26, 2022. A random-effects model and a moderator analysis were used to examine the overall prevalence and related factors. Begg's test was adopted to examine publication bias.

Results:
In total, 121 studies were included in the meta-analysis. Most nursing students experienced moderate stress (42.1%) and mild to moderate anxiety (19.4%-25.1%). Third- and fourth-year nursing students had severe stress levels compared with those in the first and second years (29.0% vs 15.1%).

Conclusions:
Nurse educators should design appropriate curricula to strengthen student knowledge and provide regular assessments and supportive interventions to reduce stress and anxiety.