Auxin signaling is essential for organogenesis but not for cell survival in the liverwort Marchantia polymorpha.

Auxin plays pleiotropic roles in plant development via gene regulation upon its perception by the receptors TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALING F-BOX (TIR1/AFBs). This auxin-regulated transcriptional control mechanism originated in the common ancestor of land plants. Although the complete loss of TIR1/AFBs causes embryonic lethality in Arabidopsis thaliana, it is unclear whether the requirement for TIR1-mediated auxin perception in cell viability can be generalized. The model liverwort Marchantia polymorpha has a minimal auxin signaling system with only a single TIR1/AFB, MpTIR1. Here we show by genetic, biochemical, and transcriptomic analyses that MpTIR1 functions as an evolutionarily conserved auxin receptor. Null mutants and conditionally knocked-out mutants of MpTIR1 were viable but incapable of forming any organs and grew as cell masses. Principal component analysis performed using transcriptomes at various developmental stages indicated that MpTIR1 is involved in the developmental transition from spores to organized thalli, during which apical notches containing stem cells are established. In Mptir1 cells, stem cell- and differentiation-related genes were up- and downregulated, respectively. Our findings suggest that, in M. polymorpha, auxin signaling is dispensable for cell division but is essential for three-dimensional patterning of the plant body by establishing pluripotent stem cells for organogenesis, a derived trait of land plants.

The renaissance and enlightenment of Marchantia as a model system.

The liverwort Marchantia polymorpha has been utilized as a model for biological studies since the 18th century. In the past few decades, there has been a Renaissance in its utilization in genomic and genetic approaches to investigating physiological, developmental, and evolutionary aspects of land plant biology. The reasons for its adoption are similar to those of other genetic models, e.g. simple cultivation, ready access via its worldwide distribution, ease of crossing, facile genetics, and more recently, efficient transformation, genome editing, and genomic resources. The haploid gametophyte dominant life cycle of M. polymorpha is conducive to forward genetic approaches. The lack of ancient whole-genome duplications within liverworts facilitates reverse genetic approaches, and possibly related to this genomic stability, liverworts possess sex chromosomes that evolved in the ancestral liverwort. As a representative of one of the three bryophyte lineages, its phylogenetic position allows comparative approaches to provide insights into ancestral land plants. Given the karyotype and genome stability within liverworts, the resources developed for M. polymorpha have facilitated the development of related species as models for biological processes lacking in M. polymorpha.

Histone methyltransferase SUV420H1/KMT5B contributes to poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a high rate of recurrence and poor prognosis, even after curative surgery. Multikinase inhibitors have been applied for HCC patients, but their effect has been restricted. This study aims to clarify the clinical impact of SUV420H1/KMT5B, one of the methyltransferases for histone H4 at lysine 20, and elucidate the novel mechanisms of HCC progression. We retrospectively investigated SUV420H1 expression using HCC clinical tissue samples employing immunohistochemical analysis (n = 350). We then performed loss-of-function analysis of SUV420H1 with cell cycle analysis, migration assay, invasion assay and RNA sequence for Gene Ontology (GO) pathway analysis in vitro, and animal experiments with xenograft mice in vivo. The SUV420H1-high-score group (n = 154) had significantly poorer prognosis for both 5-year overall and 2-year/5-year disease-free survival than the SUV420H1-low-score group (n = 196) (p < 0.001 and p < 0.05, respectively). The SUV420H1-high-score group had pathologically larger tumor size, more tumors, poorer differentiation, and more positive vascular invasion than the SUV420H1-low-score group. Multivariate analysis demonstrated that SUV420H1 high score was the poorest independent factor for overall survival. SUV420H1 knockdown could suppress cell cycle from G1 to S phase and cell invasion. GO pathway analysis showed that SUV420H1 contributed to cell proliferation, cell invasion, and/or metastasis. Overexpression of SUV420H1 clinically contributed to poor prognosis in HCC, and the inhibition of SUV420H1 could repress tumor progression and invasion both in vitro and in vivo; thus, further analyses of SUV420H1 are necessary for the discovery of future molecularly targeted drugs.

Comparison of Postoperative outcomes Among Patients Treated by Male Versus Female Surgeons: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare clinical outcomes of patients treated by female surgeons versus those treated by male surgeons. SUMMARY BACKGROUND DATA: It remains unclear as to whether surgical performance and outcomes differ between female and male surgeons. METHODS: We conducted a meta-analysis to compare patients' clinical outcomes-including patients' postoperative mortality, readmission, and complication rates-between female versus male surgeons. MEDLINE, Embase, CENTRAL, ICTRP, and ClinicalTrials.gov were searched from inception to September 8, 2022. The update search was conducted on July 19, 2023. We used random-effects models to synthesize data and GRADE to evaluate the certainty. RESULTS: A total of 15 retrospective cohort studies provided data on 5,448,121 participants. We found that patients treated by female surgeons experienced a lower post-operative mortality compared with patients treated by male surgeons (8 studies; adjusted odds ratio [aOR], 0.93; 95%CI, 0.88 - 0.97; I2=27%; moderate certainty of the evidence). We found a similar pattern for both elective and non-elective (emergent or urgent) surgeries, although the difference was larger for elective surgeries (test for subgroup difference P=0.003). We found no evidence that female and male surgeons differed for patient readmission (3 studies; aOR, 1.20; 95%CI, 0.83 - 1.74; I2=92%; very low certainty of the evidence) or complication rates (8 studies; aOR, 0.94; 95%CI, 0.88 - 1.01: I2=38%; very low certainty of the evidence). CONCLUSIONS: This systematic review and meta-analysis suggests that patients treated by female surgeons have a lower mortality compared with those treated by male surgeons.

Evolution of vascular plants through redeployment of ancient developmental regulators.

Vascular plants provide most of the biomass, food, and feed on earth, yet the molecular innovations that led to the evolution of their conductive tissues are unknown. Here, we reveal the evolutionary trajectory for the heterodimeric TMO5/LHW transcription factor complex, which is rate-limiting for vascular cell proliferation in Arabidopsis thaliana Both regulators have origins predating vascular tissue emergence, and even terrestrialization. We further show that TMO5 evolved its modern function, including dimerization with LHW, at the origin of land plants. A second innovation in LHW, coinciding with vascular plant emergence, conditioned obligate heterodimerization and generated the critical function in vascular development in Arabidopsis In summary, our results suggest that the division potential of vascular cells may have been an important factor contributing to the evolution of vascular plants.

Associations Between Industry Payments to Physicians for Antiplatelet Drugs and Utilization of Cardiac Procedures and Stents.

BACKGROUND: A study has shown that industry payments to physicians for drugs are associated not only with higher drug prescriptions but also with higher non-drug costs due to additional utilization of healthcare services. However, the association between industry payments to cardiologists for antiplatelet drugs and the costs and number of percutaneous coronary interventions they perform has not been investigated. OBJECTIVE: To examine the association between industry payments to cardiologists for antiplatelet drugs and the costs and number of percutaneous coronary interventions they perform. DESIGN: Using the 2016 Open Payments Database linked to the 2017 Medicare Provider Utilization and Payment Data, we examined the association between the value of industry payments related to the antiplatelet drugs prasugrel and ticagrelor and healthcare spending and volume for cardiovascular procedures, adjusted for potential cofounders. SUBJECTS: A total of 7456 cardiologists who performed diagnostic cardiac catheterizations on Medicare beneficiaries in 2017. MAIN MEASURES: Primary outcomes included (1) healthcare spending on cardiac procedures, (2) diagnostic cardiac catheterization volumes, and (3) rates of coronary stenting. Secondary outcomes were total expenditures for all drugs and for antiplatelet drugs. KEY RESULTS: Industry payments for antiplatelet drugs were associated with higher healthcare spending on cardiac procedures (adjusted difference, +$50.9 for additional $100 industry payments; 95% CI, +$25.5 to +$76.2; P < 0.001), diagnostic cardiac catheterizations (+0.1 procedures per cardiologist; 95% CI, +0.03 to +0.1; P=0.001), and stent use (+0.5 per 1000 diagnostic cardiac catheterizations per cardiologist; 95% CI, +0.2 to +0.9; P=0.002). Industry payments for antiplatelet drugs were associated with higher total costs for all drugs and antiplatelet drugs. CONCLUSIONS: Industry payments to cardiologists for antiplatelet drugs were associated with both prescribing of antiplatelet drugs and the use of cardiac procedures and stents. Further research is warranted to understand whether the observed associations are causal or reflect a greater propensity for higher volume proceduralists to have relationships with industry.

Neonatal congenital mesoblastic nephroma that caused respiratory oncologic emergency early after birth: a case report.

BACKGROUND: Congenital mesoblastic nephromas mainly present as asymptomatic abdominal masses, but some present hematuria, hypertension or hypercalcemia. Neonatal dyspnea in an early-birth neonate due to rapid tumor growth is reported here for the first time. CASE PRESENTATION: A renal tumor and polyhydramnios were detected by ultrasonography of a male fetus at 32 weeks and 3 days of gestation. The mother had abdominal distension due to the polyhydramnios and signs of imminent premature birth. Amniocentesis was performed and the signs of imminent preterm birth subsided, but growth of the renal tumor was noted as a potential cause of respiratory dysfunction. Cesarean section was performed at 36 weeks and 2 days of gestation. His birthweight was 2638 g and his 1 and 5 min APGAR scores were 2 and 4 points, respectively. There was no spontaneous breathing at birth and he had remarkable abdominal distention. He underwent cardiopulmonary resuscitation. After circulation stabilized, emergency surgery was performed because of progressive hypoxemia and respiratory acidosis. Laparotomy revealed a huge tumor arising from the right kidney and right nephrectomy was performed. Histopathological examination led to diagnosis of congenital mesoblastic nephroma. The respiratory condition and circulatory dynamics stabilized after the pressure on the thorax from the tumor was relieved by surgery. The postoperative course was uneventful. No recurrence or complications have been observed in the 36 months since the surgery. CONCLUSIONS: Congenital mesoblastic nephroma can rapidly increase in size from the fetal period and may cause respiratory oncologic emergency, although there is relatively good prognosis.

Changes in oral function, swallowing function, and quality of life in patients with head and neck cancer: a prospective cohort study.

BACKGROUND: Head and neck cancer (HNC) treatment can cause oral morbidities, such as oral dryness and dysphagia, affecting the patient's quality of life (QOL). The relationship between oral functions and QOL in patients with early-stage HNC remains poorly studied. This study aimed to evaluate changes in the QOL of patients with early-stage HNC and identify factors that affect the QOL of these patients. METHODS: In this prospective cohort study, 37 patients who underwent early-stage (Stage I/Stage II) HNC treatment were evaluated for their oral function, swallowing function, and the QOL score at baseline (BL) and 12 months after surgical treatment (12 M). The participants were divided into two groups: patients who returned to the BL QOL score at 12 M (RE; n = 26) and those who did not (NR; n = 11). RESULTS: In total, 29.7% (11/37) patients with early-stage HNC did not return to the BL QOL score at 12 M. There was no significant difference between the RE and NR groups regarding the oral and swallowing function. Moreover, oral and swallowing function of all patients returned to the BL at 12 M. The NR group showed lower QOL scores than the RE group in the global health status, and "sticky saliva" parameters in the questionnaires. CONCLUSION: Restoration of the oral function is insufficient to improve the QOL of patients with early-stage HNC. The treatment of these patients should instead consider several factors that affect their QOL.

Incidence, predisposing conditions and outcomes of cutaneous mucormycosis: A national database study.

BACKGROUND: The body of evidence on cutaneous mucormycosis is largely derived from case reports or single-centre databases. OBJECTIVES: Our study aimed to describe incidence, predisposing factors and inpatient outcomes of cutaneous mucormycosis in the United States. METHODS: We conducted a population-based retrospective study using the National Inpatient Sample 2016-17 data. Fifty-six discharges had a diagnosis of cutaneous mucormycosis on the International Classification of Diseases, tenth revision. Descriptive analysis was performed for the demographics, predisposing factors, length of stay (LOS), cost and inpatient mortality. The NIS represents 20% of all discharges in the United States, which allowed us to estimate the national incidence of cutaneous mucormycosis. RESULTS: An estimated total of 280 admissions occurred between 2016 and 2017, indicating 3.9 cases per million admissions across the United States. The estimated incidence rate was 0.43 cases per million people per year. Median age was 49.5 (19-59) years, 44.6% were female, and 54.9% were Caucasian. We identified haematologic malignancies (48.2%) and solid organ transplantations (10.7%), often accompanied by skin/soft tissue or post-procedural infections, were the most common predisposing conditions. Median LOS was 15 (6-31) days, median total charges were 187,030 (65,962-446,265) USD, and in-hospital mortality rate was 16.1%. CONCLUSIONS: In current clinical practice, physicians may encounter cutaneous mucormycosis most commonly in severely immunocompromised hosts with haematologic malignancies or transplantations, accompanied by skin/soft tissue or post-procedural infections. A high index of suspicion and prompt tissue sampling in at-risk groups is important to improve the outcomes.

Gemma cup and gemma development in Marchantia polymorpha.

The basal land plant Marchantia polymorpha efficiently propagates in favourable environments through clonal progeny called gemmae. Gemmae develop in cup-shaped receptacles known as gemma cups, which are formed on the gametophyte body. Anatomical studies have described the developmental processes involved over a century ago; however, little is known about the underlying molecular mechanisms. Recent studies have started to unravel the mechanism underlying genetic and hormonal regulation of gemma cup and gemma development, showing that it shares some regulatory mechanisms with several sporophytic organs in angiosperms. Further study of these specialized organs will contribute to our understanding of the core regulatory modules underlying organ development in land plants and how these became so diversified morphologically over the course of evolution.

Improving the Validity of Nurse-Based Delirium Screening: A Head-to-Head Comparison of Nursing Delirium-Screening Scale and Short Confusion Assessment Method.

BACKGROUND: As part of a multicomponent delirium prevention protocol the Confusion Assessment Method (Short-CAM) was introduced to nursing as the standard delirium screening instrument on the general medical units. Despite significant educational efforts, quality monitoring revealed poor sensitivity with the use of Short-CAM. OBJECTIVES: To compare the validity of the Nursing Delirium Screening Scale (Nu-DESC) and Short-CAM on general medical units and to explore the impact of delirium education on the successful implementation of delirium screening tools. METHODS: In this quality improvement project, both Nu-DESC and Short-CAM were scored by nurses on 2 general medical units, per standard practice. Two blinded physician-raters determined delirium diagnosis in 192 patients on these units on 8 separate days, utilizing the Diagnostic and Statistical Manual of Mental Disorders-5 criteria as the reference standard. Sensitivity and specificity of both scales were calculated. RESULTS: Thirty-five of 192 patients (18.2%) were suffering from delirium on the day of assessment. The Short-CAM scored positive for 3 (1.6%) patients and the Nu-DESC for 50 (26.0%) patients on the same day as the physician-raters assessment. Sensitivity and specificity were respectively calculated at 8.6% and 100% for the Short-CAM and 77.1% and 85.4% for the Nu-DESC. There was no statistical difference in sensitivity and specificity of the Nu-DESC on the units regardless of the level of preimplementation delirium education. CONCLUSIONS: The Nu-DESC was shown to be an easy-to-deploy delirium-screening tool on general medical units with improved sensitivity when compared to the Short-CAM.

Glycerol kinase 2 is essential for proper arrangement of crescent-like mitochondria to form the mitochondrial sheath during mouse spermatogenesis.

The mitochondrial sheath is composed of mitochondria that coil tightly around the midpiece of sperm flagellum. These mitochondria are recruited from the cytoplasm to the flagellum late in spermatogenesis. Initially, recruited mitochondria are spherical-shaped but then elongate laterally to become crescent-like in shape. Subsequently, crescent-like mitochondria elongate continuously to coil tightly around the flagellum. Recently, disorganization of the mitochondrial sheath was reported in Glycerol kinase 2 (Gk2) disrupted mice. To analyze the disorganization of the mitochondrial sheath further, we generated Gk2-deficient mice using the CRISPR/Cas9 system and observed sperm mitochondria in testis using a freeze-fracture method with scanning electron microscopy. Gk2-disrupted spermatids show abnormal localization of crescent-like mitochondria, in spite of the initial proper alignment of spherical mitochondria around the flagellum, which causes abnormal mitochondrial sheath formation leading to exposure of the outer dense fibers. These results indicate that GK2 is essential for proper arrangement of crescent-like mitochondria to form the mitochondrial sheath during mouse spermatogenesis.

Effects of increased functional residual capacity on finger-floor distance in healthy young adults.

[Purpose] To investigate the effect of increased functional residual capacity on the finger-floor distance and to assess spinal curvature in the sagittal plane using the Spinal Mouse in healthy young participants. [Participants and Methods] Thirty-nine healthy volunteers (age=21.2 ± 0.8 years) participated in this study. The finger-floor distance was used to measure trunk flexion and was recorded at the resting expiration level and at 2 different functional residual capacity levels: 1,000 and 2,000 ml air inhaled at the resting expiration level. Spinal curvature morphology was evaluated using the Spinal Mouse in the sagittal plane when flexion was completed under the 2 increased functional residual capacity and resting expiration level conditions during finger-floor distance measurement. Finger-floor distance and spinal curvature were assessed according to functional residual capacity using one-way repeated measures analysis of variance and post-hoc analysis. [Results] Significant effects and differences were found for the finger-floor distance under all conditions. No significant effect was found for spinal curvature. [Conclusion] An increase in functional residual capacity may decrease trunk flexion. This correlation might also be observed in patients with chronic obstructive pulmonary disease.

Evolution of nuclear auxin signaling: lessons from genetic studies with basal land plants.

Auxin plays critical roles in growth and development through the regulation of cell differentiation, cell expansion, and pattern formation. The auxin signal is mainly conveyed through a so-called nuclear auxin pathway involving the receptor TIR1/AFB, the transcriptional co-repressor AUX/IAA, and the transcription factor ARF with direct DNA-binding ability. Recent progress in sequence information and molecular genetics in basal plants has provided many insights into the evolutionary origin of the nuclear auxin pathway and its pleiotropic roles in land plant development. In this review, we summarize the latest knowledge of the nuclear auxin pathway gained from studies using basal plants, including charophycean green algae and two major model bryophytes, Marchantia polymorpha and Physcomitrella patens. In addition, we discuss the functional implication of the increase in genetic complexity of the nuclear auxin pathway during land plant evolution.

Auxin Produced by the Indole-3-Pyruvic Acid Pathway Regulates Development and Gemmae Dormancy in the Liverwort Marchantia polymorpha.

The plant hormone auxin (indole-3-acetic acid [IAA]) has previously been suggested to regulate diverse forms of dormancy in both seed plants and liverworts. Here, we use loss- and gain-of-function alleles for auxin synthesis- and signaling-related genes, as well as pharmacological approaches, to study how auxin regulates development and dormancy in the gametophyte generation of the liverwort Marchantia polymorpha. We found that M. polymorpha possess the smallest known toolkit for the indole-3-pyruvic acid (IPyA) pathway in any land plant and that this auxin synthesis pathway mainly is active in meristematic regions of the thallus. Previously a Trp-independent auxin synthesis pathway has been suggested to produce a majority of IAA in bryophytes. Our results indicate that the Trp-dependent IPyA pathway produces IAA that is essential for proper development of the gametophyte thallus of M. polymorpha. Furthermore, we show that dormancy of gemmae is positively regulated by auxin synthesized by the IPyA pathway in the apex of the thallus. Our results indicate that auxin synthesis, transport, and signaling, in addition to its role in growth and development, have a critical role in regulation of gemmae dormancy in M. polymorpha.

Auxin-Mediated Transcriptional System with a Minimal Set of Components Is Critical for Morphogenesis through the Life Cycle in Marchantia polymorpha.

The plant hormone auxin regulates many aspects of plant growth and development. Recent progress in Arabidopsis provided a scheme that auxin receptors, TIR1/AFBs, target transcriptional co-repressors, AUX/IAAs, for degradation, allowing ARFs to regulate transcription of auxin responsive genes. The mechanism of auxin-mediated transcriptional regulation is considered to have evolved around the time plants adapted to land. However, little is known about the role of auxin-mediated transcription in basal land plant lineages. We focused on the liverwort Marchantia polymorpha, which belongs to the earliest diverging lineage of land plants. M. polymorpha has only a single TIR1/AFB (MpTIR1), a single AUX/IAA (MpIAA), and three ARFs (MpARF1, MpARF2, and MpARF3) in the genome. Expression of a dominant allele of MpIAA with mutations in its putative degron sequence conferred an auxin resistant phenotype and repressed auxin-dependent expression of the auxin response reporter proGH3:GUS. We next established a system for DEX-inducible auxin-response repression by expressing the putatively stabilized MpIAA protein fused with the glucocorticoid receptor domain (MpIAA(mDII)-GR). Repression of auxin responses in (pro)MpIAA:MpIAA(mDII)-GR plants caused severe defects in various developmental processes, including gemmaling development, dorsiventrality, organogenesis, and tropic responses. Transient transactivation assays showed that the three MpARFs had different transcriptional activities, each corresponding to their phylogenetic classifications. Moreover, MpIAA and MpARF proteins interacted with each other with different affinities. This study provides evidence that pleiotropic auxin responses can be achieved by a minimal set of auxin signaling factors and suggests that the transcriptional regulation mediated by TIR1/AFB, AUX/IAA, and three types of ARFs might have been a key invention to establish body plans of land plants. We propose that M. polymorpha is a good model to investigate the principles and the evolution of auxin-mediated transcriptional regulation and its roles in land plant morphogenesis.

The Roles of the Sole Activator-Type Auxin Response Factor in Pattern Formation of Marchantia polymorpha.

Cell division patterning is important to determine body shape in plants. Nuclear auxin signaling mediated by AUXIN RESPONSE FACTOR (ARF) transcription factors affects plant growth and development through regulation of cell division, elongation and differentiation. The evolutionary origin of the ARF-mediated pathway dates back to at least the common ancestor of bryophytes and other land plants. The liverwort Marchantia polymorpha has three phylogenetically distinct ARFs: MpARF1, the sole 'activator' ARF; and MpARF2 and MpARF3, two 'repressor' ARFs. Genetic screens for auxin-resistant mutants revealed that loss of MpARF1 function conferred auxin insensitivity. Mparf1 mutants showed reduced auxin-inducible gene expression and various developmental defects, including thallus twisting and gemma malformation. We further investigated the role of MpARF1 in gemma development, which is traceable at the cellular level. In wild-type plants, a gemma initial first undergoes several transverse divisions to generate a single-celled stalk and a gemma proper, followed by rather synchronous longitudinal divisions in the latter. Mparf1 mutants often contained multicelled stalks and showed defects in the execution and timing of the longitudinal divisions. While wild-type gemmae finally generate two meristem notches, Mparf1 gemmae displayed various numbers of ectopic meristems. These results suggest that MpARF1 regulates formative cell divisions and axis formation through auxin responses. The mechanism for activator ARF regulation of pattern formation may be shared in land plants and therefore important for the general acquisition of three-dimensional body plans.

CRISPR/Cas9-Mediated Rapid Generation of Multiple Mouse Lines Identified Ccdc63 as Essential for Spermiogenesis.

Spermatozoa are flagellated cells whose role in fertilization is dependent on their ability to move towards an oocyte. The structure of the sperm flagella is highly conserved across species, and much of what is known about this structure is derived from studies utilizing animal models. One group of proteins essential for the movement of the flagella are the dyneins. Using the advanced technology of CRISPR/Cas9 we have targeted three dynein group members; Dnaic1, Wdr63 and Ccdc63 in mice. All three of these genes are expressed strongly in the testis. We generated mice with amino acid substitutions in Dnaic1 to analyze two specific phosphorylation events at S124 and S127, and generated simple knockouts of Wdr63 and Ccdc63. We found that the targeted phosphorylation sites in Dnaic1 were not essential for male fertility. Similarly, Wdr63 was not essential for male fertility; however, Ccdc63 removal resulted in sterile male mice due to shortened flagella. This study demonstrates the versatility of the CRISPR/Cas9 system to generate animal models of a highly complex system by introducing point mutations and simple knockouts in a fast and efficient manner.