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Nuclear hormone receptors (NHRs) are a family of ligand-regulated transcription factors that control key aspects of development and physiology. The regulation of NHRs by ligands derived from metabolism or diet makes them excellent pharmacological targets, and the mechanistic understanding of how NHRs interact with their ligands to regulate downstream gene networks, along with the identification of ligands for orphan NHRs, could enable innovative approaches for cellular engineering, disease modeling and regenerative medicine. We review recent discoveries in the identification of physiologic ligands for NHRs. We propose new models of ligand-receptor co-evolution, the emergence of hormonal function and models of regulation of NHR specificity and activity via one-ligand and two-ligand models as well as feedback loops. Lastly, we discuss limitations on the processes for the identification of physiologic NHR ligands and emerging new methodologies that could be used to identify the natural ligands for the remaining 17 orphan NHRs in the human genome.
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Metaboloma , Receptores Citoplasmáticos e Nucleares , Humanos , Receptores Citoplasmáticos e Nucleares/metabolismo , Ligantes , AnimaisRESUMO
Phosphorus is essential in all cells' structural, metabolic and regulatory functions. For fungal cells that import inorganic phosphate (Pi) up a steep concentration gradient, surface Pi transporters are critical capacitators of growth. Fungi must deploy Pi transporters that enable optimal Pi uptake in pH and Pi concentration ranges prevalent in their environments. Single, triple and quadruple mutants were used to characterize the four Pi transporters we identified for the human fungal pathogen Candida albicans, which must adapt to alkaline conditions during invasion of the host bloodstream and deep organs. A high-affinity Pi transporter, Pho84, was most efficient across the widest pH range while another, Pho89, showed high-affinity characteristics only within one pH unit of neutral. Two low-affinity Pi transporters, Pho87 and Fgr2, were active only in acidic conditions. Only Pho84 among the Pi transporters was clearly required in previously identified Pi-related functions including Target of Rapamycin Complex 1 signaling, oxidative stress resistance and hyphal growth. We used in vitro evolution and whole genome sequencing as an unbiased forward genetic approach to probe adaptation to prolonged Pi scarcity of two quadruple mutant lineages lacking all 4 Pi transporters. Lineage-specific genomic changes corresponded to divergent success of the two lineages in fitness recovery during Pi limitation. Initial, large-scale genomic alterations like aneuploidies and loss of heterozygosity eventually resolved, as populations gained small-scale mutations. Severity of some phenotypes linked to Pi starvation, like cell wall stress hypersensitivity, decreased in parallel to evolving populations' fitness recovery in Pi scarcity, while severity of others like membrane stress responses diverged from Pi scarcity fitness. Among preliminary candidate genes for contributors to fitness recovery, those with links to TORC1 were overrepresented. Since Pi homeostasis differs substantially between fungi and humans, adaptive processes to Pi deprivation may harbor small-molecule targets that impact fungal growth, stress resistance and virulence.
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Fungi were some of the earliest organismal systems used to explore mutational processes and its phenotypic consequences on members of a species. Yeasts that cause significant human disease were quickly incorporated into these investigations to define the genetic and phenotypic drivers of virulence. Among Candida species, Candida albicans has emerged as a model for studying genomic processes of evolution because of its clinical relevance, relatively small genome, and ability to tolerate complex chromosomal changes. Here, we describe major recent findings that used evolution of strains from defined genetic backgrounds to delineate mutational and adaptative processes and include how nascent exploration into naturally occurring variation is contributing to these conceptual frameworks. Ultimately, efforts to discern adaptive mechanisms used by C. albicans will continue to divulge new biology and can better inform treatment regimens for the increasing prevalence of fungal disease.
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Quantitative assessment of nucleophosmin 1 (NPM1) mutation status is integral to evaluating measurable residual disease (MRD) in NPM1-mutated acute myeloid leukemia (AML) patients. In a retrospective study, leftover peripheral blood (PB) specimens (n = 40) which were collected for routine clinical diagnostic evaluations of AML disease burden were tested by both a novel automated RT-qPCR quantitative NPM1 assay (Xpert NPM1 mutation assay) and the NPM1 mutA, mutB&D MutaQuant kit. Based on a Deming regression analysis, there was a high correlation (slope = 0.92; intercept = 0.12; Pearson's r = 0.982) between the quantitative results of the Xpert NPM1 mutation assay and the NPM1 mutA, mutB&D MutaQuant kit. The Xpert test quantitative results are thus highly correlated with the comparator method and the former has potential as a useful alternative for the monitoring of AML patients with a known NPM1 mutation.
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Leucemia Mieloide Aguda , Mutação , Proteínas Nucleares , Nucleofosmina , Reação em Cadeia da Polimerase em Tempo Real , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estudos Retrospectivos , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Masculino , Feminino , Pessoa de Meia-IdadeRESUMO
Green fluorescent protein has long been a favorite protein for demonstrating protein purification in the biochemistry lab course. The protein's vivid green color helps demonstrate to students the concept(s) behind affinity or ion exchange chromatography. We designed a series of introduction to biochemistry labs utilizing a thermostable green protein (TGP-E) engineered to have unusually high thermostability. This protein allows students to proceed through purification and characterization without the need to keep protein samples on ice. The 5-week lab series begins with an introduction to molecular biology techniques during weeks 1 and 2, where site-directed mutagenesis is used introduce, a single nucleotide change that shifts the fluorescent spectra of TGP-E to either cyan (CTP-E) or yellow (YTP-E). Students identify successful mutagenesis reaction by the color of a small expression sample after induction with IPTG. Next, students purify either the TGP-E (control-typically one group volunteers), YTP-E, or CTP-E protein as a 1-week lab. During the following week's lab, students run SDS-PAGE to verify protein purity, bicinchoninic acid assay to quantify protein yield, and absorbance and fluorescence spectra to characterize their protein's fluorescent character. The final lab in the series investigates the thermostability of YTP-E and CTP-E compared with TGP-E using a fluorescence plate reader. This 5-week series of experiments provide students with experience in several key biochemistry techniques and allows the students to compare properties of mutations. At the end of the course, the students will write a research report and give a short presentation over their results.
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INTRODUCTION: Opioid analgesics are often used to manage moderate to severe pain. A significant proportion of patients taking opioids have compromised kidney function. This systematic review aimed to examine the available evidence on the safety and analgesic effect of opioid use in adults with kidney disease. METHODS: We searched eight electronic databases from inception to January 26, 2023. Published original research articles in English reporting on opioid use and pharmacokinetic data among adults with reduced renal function were included. Article screening, data extraction, and quality assessment were conducted by at least two investigators independently. This review was registered prospectively on PROSPERO (ID: CRD42020159091). RESULTS: There were 32 observational studies included, 14 of which reported on morphine use, three involved fentanyl use, two involved hydromorphone use, and 13 articles reported on other opioids including codeine, dihydrocodeine, and buprenorphine. CONCLUSION: There is limited and low-quality evidence to inform the safety and analgesic effect of opioid use in reduced renal function. Morphine remains the opioid for which there is the most evidence available on safety and analgesic effect in the context of renal disease. Greater caution and consideration of potential risks and benefits should be applied when using other opioids. Further high-quality studies examining clinical outcomes associated with the use of different opioids and opioid doses in renal disease are warranted.
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Analgésicos Opioides , Nefropatias , Humanos , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/efeitos adversos , Morfina/uso terapêutico , Morfina/efeitos adversos , Dor/tratamento farmacológicoRESUMO
With growing recognition that climate change is a significant threat to human health, allied health professionals are increasingly recognized as critical allies in addressing this threat. This article describes the approach that Rush University's College of Sciences is pursuing to better prepare health sciences students for this reality. Faculty and students enrolled across all programs of the College were surveyed regarding their levels of concern about global warming using items from the Six Americas Survey, as well as perceived importance of planetary health curricular elements adapted from the Planetary Health Report Card. Faculty were additionally asked about perceived opportunities to bring planetary health education into each of the degree programs offered by the university. A total of 37 faculty and 43 students completed the survey, collectively representing all programs in the college. Responses reflected widespread interest in expanding planetary health education, but topic priorities and optimal methods for implementation differed between programs. Although the survey process had limitations, it demonstrated the need for greater attention to planetary health across curricula and offered more efficient approaches implementing this essential content across programs.
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Currículo , Humanos , Mudança Climática , Avaliação das Necessidades , Docentes , Feminino , MasculinoRESUMO
Idiopathic intracranial hypertension is defined by headaches and a decline in visual acuity due to increased intracranial pressure. Treatment options historically included weight loss, acetazolamide, and/or cerebrospinal fluid diversion surgery. Recent understanding of the contributions of dural venous sinus hypertension and stenosis has led to venous sinus stenting as a treatment option.
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Pseudotumor Cerebral , Humanos , Acetazolamida/uso terapêutico , Cavidades Cranianas/cirurgia , Hipertensão Intracraniana/terapia , Pseudotumor Cerebral/cirurgia , Pseudotumor Cerebral/terapia , StentsRESUMO
Background: Significant psychological impact and prevalence of posttraumatic stress disorder (PTSD) have been well documented in patients sustaining anterior cruciate ligament injury. Purpose: To examine PTSD symptomatology in baseball players after sustaining elbow ulnar collateral ligament (UCL) injury. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Male baseball players of various competition levels (high school through Minor League Baseball [MiLB]) who underwent surgery for a UCL injury between April 2019 and June 2022 participated in the study. Before surgery, patients completed the Impact of Event Scale-Revised (IES-R) to assess PTSD symptomatology. Subgroup analysis was conducted according to level of play and player position. Results: A total of 104 male baseball players with a mean age of 19.4 years (range, 15-29 years) were included in the study; 32 players (30.8%) were in high school, 65 (62.5%) were in college, and 7 (6.7%) were in MiLB. There were 64 (61.5%) pitchers, 18 (17.3%) position players, and 22 (21.2%) 2-way players (both pitching and playing on the field). A total of 30 (28.8%) patients scored high enough on the IES-R to support PTSD as a probable diagnosis, and another 22 patients (21.2%) scored high enough to support PTSD as a clinical concern. Nineteen patients (18.3%) had potentially severe PTSD. Only 4 players (3.8%) were completely asymptomatic. Subgroup analysis revealed college players as significantly more symptomatic than high school players (P = .02), and 2-way players were found to be significantly less susceptible to developing symptoms of PTSD compared with pitchers (P = .04). Conclusion: Nearly 30% of baseball players who sustained a UCL injury qualified for a probable diagnosis of PTSD based on the IES-R. Pitchers and college athletes were at increased risk for PTSD after UCL injury compared with 2-way players and high school athletes, respectively.
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BACKGROUND: Unilateral cranial nerve (CN) VI, or abducens nerve, palsy is rare in children and has not been reported in association with Chiari malformation type 1 (CM1) in the absence of other classic CM1 symptoms. OBSERVATIONS: A 3-year-old male presented with acute incomitant esotropia consistent with a unilateral, left CN VI palsy and no additional neurological symptoms. Imaging demonstrated CM1 without hydrocephalus or papilledema, as well as an anterior inferior cerebellar artery (AICA) vessel loop in the immediate vicinity of the left abducens nerve. Given the high risk of a skull base approach for direct microvascular decompression of the abducens nerve and the absence of other classic Chiari symptoms, the patient was initially observed. However, as his palsy progressed, he underwent posterior fossa decompression with duraplasty (PFDD), with the aim of restoring global cerebrospinal fluid dynamics and decreasing possible AICA compression of the left abducens nerve. Postoperatively, his symptoms completely resolved. LESSONS: In this first reported case of CM1 presenting as a unilateral abducens palsy in a young child, possibly caused by neurovascular compression, the patient's symptoms resolved after indirect surgical decompression via PFDD.
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INTRODUCTION: Non-traumatic headache is a common complaint seen in the emergency department (ED), accounting for 2.3% of ED visits per year in the United States (Munoz-Ceron et al., 2019). When approaching the workup and management of headache, an emergency medicine physician is tasked with generating a deadly differential by means of a thorough history and physical exam to determine the next best steps. CASE: A 21-year-old male presented to the emergency department with a debilitating new-onset headache, preceded by an isolated vertiginous event 3 days prior. He was found to have a normal neurologic examination. A non-contrast CT scan of the head revealed a large hypodensity within the left cerebellum with a subsequent MRA of the brain and neck notable for a left vertebral artery dissection, complicated by an ischemic cerebellar stroke. DISCUSSION: With an estimated incidence of 1-5 per 100,000, vertebral artery dissection is a rare cause of stroke within the general population and carries with it a high degree of morbidity and mortality (Rodallec et al., 2008). Vertebral artery dissection is a result of blood penetrating the intimal wall of the artery to form an intramural hematoma. Diagnosis can be difficult in cases presenting subacutely but a thorough history evaluating for red flags and using simple but highly sensitive exams such as the bedside HINTS exam can increase pretest probability of stroke. Clinical syndromes, red flags, and time from onset of symptoms should guide imaging modalities such as CT, CTA, MRI, and MRA in detection of small ischemic changes, intimal flaps, and luminal thromboses. CONCLUSION: Vertebral artery dissection should remain high on the differential for an emergency medicine physician when history is suggestive of a new onset headache, preceded by vertiginous symptoms. An absence of recent trauma and a normal neurologic examination does not eliminate the diagnosis.
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Cefaleia , Dissecação da Artéria Vertebral , Humanos , Dissecação da Artéria Vertebral/complicações , Dissecação da Artéria Vertebral/diagnóstico , Dissecação da Artéria Vertebral/diagnóstico por imagem , Masculino , Adulto Jovem , Cefaleia/etiologia , Tomografia Computadorizada por Raios X , Serviço Hospitalar de Emergência , Angiografia por Ressonância Magnética , Diagnóstico DiferencialRESUMO
VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10-8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.
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Diabetes Mellitus , Pré-Eclâmpsia , Feminino , Humanos , Recém-Nascido , Gravidez , Número de Gestações , Ocitocina/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Proteômica , Receptores de Ocitocina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: The aim of this study is to gauge the current social climate in neurosurgical residency training and attitudes regarding sexual orientation and gender identity. METHODS: We conducted a cross-sectional study through a 35-question questionnaire distributed to roughly 1700 residents at all U.S. neurosurgical residency programs. RESULTS: A total of 107 responses were obtained. Seventeen residents (16%) identified as being an LGBTQ+ individual. The majority (76%) of LGBTQ+ residents were concerned about how their sexual orientation would be perceived while applying to programs, and 47% endorsed purposefully concealing sexual orientation at work for fear of rejection or reprisal. More than half (56%) of those surveyed have witnessed homophobic/transphobic remarks by patients. While at work, 29% of LGBTQ+ individuals stated they are uncomfortable being open with their sexual orientation, and 3 LGBTQ+ individuals admitted being the target of direct homophobic/transphobic comments. CONCLUSIONS: This is the first study to our knowledge that has been conducted assessing the presence, perception, and treatment of LGBTQ+ trainees in neurosurgical residency. Our study outlines the challenges LGBTQ+ individuals face when applying to neurosurgical programs, which involves the perception of their sexual orientation, their witnessed instances of homophobic and transphobic comments by coworkers and patients, and their hesitation with discussing their social lives compared with their non-LGBTQ+ peers at work for fear of judgment or reprisal. Ongoing research is needed to address these issues to obtain workplace respect and fairness in this population and thus create an accepting atmosphere and achieve social justice in neurosurgery training.
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Internato e Residência , Neurocirurgia , Minorias Sexuais e de Gênero , Humanos , Minorias Sexuais e de Gênero/psicologia , Masculino , Feminino , Estados Unidos , Estudos Transversais , Neurocirurgia/educação , Inquéritos e Questionários , Adulto , Atitude do Pessoal de Saúde , Comportamento Sexual/psicologiaRESUMO
The genetic background between strains of a single species and within a single strain lineage can significantly impact the expression of biological traits. This genetic variation may also reshape epigenetic mechanisms of cell identity and environmental responses that are controlled by interconnected transcriptional networks and chromatin-modifying enzymes. Histone deacetylases, including sirtuins, are critical regulators of chromatin state and have been directly implicated in governing the phenotypic transition between the 'sterile' white state and the mating-competent opaque state in Candida albicans, a common fungal commensal and pathogen of humans. Here, we found that a previously ambiguous role for the sirtuin SIR2 in C. albicans phenotypic switching is likely linked to the genetic background of mutant strains produced in the RM lineage of SC5314. SIR2 mutants in a specific lineage of BWP17 displayed increased frequencies of switching to the opaque state compared to the wild-type. Loss of SIR2 in other SC5314-derived backgrounds, including newly constructed BWP17 sir2Δ/Δ mutants, failed to recapitulate the increased white-opaque switching frequencies observed in the original BWP17 sir2Δ/Δ mutant background. Whole-genome sequencing revealed the presence of multiple imbalanced chromosomes and large loss of heterozygosity tracts that likely interact with SIR2 to increase phenotypic switching in this BWP17 sir2Δ/Δ mutant lineage. These genomic changes are not found in other SC5314-derived sir2Δ/Δ mutants that do not display increased opaque cell formation. Thus, complex karyotypes can emerge during strain construction that modify mutant phenotypes and highlight the importance of validating strain background when interpreting phenotypes.
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Candida albicans , Cromatina , Humanos , Candida albicans/genética , Epigênese Genética , Redes Reguladoras de Genes , FenótipoRESUMO
Ovarian cancers (OVCAs) and endometrial cancers (EMCAs) with CCNE1-amplification are often resistant to standard of care treatment and represent an unmet clinical need. Previously, synthetic-lethal screening identified loss of the CDK1 regulator, PKMYT1, as synthetically lethal with CCNE1-amplification. We hypothesized that CCNE1-amplification associated replication stress will be more effectively targeted by combining the PKMYT1 inhibitor, lunresertib (RP-6306), with the ATR inhibitor, camonsertib (RP-3500/RG6526). Low dose combination RP-6306 with RP-3500 synergistically increased cytotoxicity more in CCNE1 amplified compared to non-amplified cells. Combination treatment produced durable antitumor activity and increased survival in CCNE1 amplified patient-derived and cell line-derived xenografts. Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is a novel therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs.
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BACKGROUND: There is a known shortage of nursing faculty in academia. Understanding factors influencing the shortage will help to develop strategies to reduce it. PURPOSE: The purpose was to identify the underlying factors influencing the decisions of current and former nursing faculty to leave or consider leaving their teaching roles. METHODS: A cross-sectional state-level survey was distributed to licensed registered nurses and advanced practice registered nurses. The survey covered demographics, employment status, compensation, tenure, mentorship experiences, and significant factors affecting their decision-making. RESULTS: Of 496 nursing faculty responses (221 current, 275 former), low compensation, unrealistic workload, retirement, lack of appreciation, and personal/family issues were noted as significant reasons for leaving or considering departure. CONCLUSIONS: The study gives voice to various factors influencing nursing faculty's intention to leave and emphasizes the need to address issues of compensation, workload, and mentorship to mitigate faculty shortages.
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Docentes de Enfermagem , Intenção , Humanos , Docentes de Enfermagem/estatística & dados numéricos , Docentes de Enfermagem/psicologia , Docentes de Enfermagem/provisão & distribuição , Estudos Transversais , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Pesquisa em Educação em Enfermagem , Inquéritos e Questionários , Reorganização de Recursos Humanos/estatística & dados numéricos , Carga de Trabalho/estatística & dados numéricos , Mentores/estatística & dados numéricosRESUMO
BACKGROUND: Postoperative hospital length of stay (LOS) is longer in patients with diabetes than in patients without diabetes. Stress hyperglycemia (SH) in patients without a history of diabetes has been associated with adverse postoperative outcomes. The effect of SH on postoperative LOS is uncertain. The aim of this study is to compare postoperative LOS in patients with SH to patients with diabetic hyperglycemia (DH) following noncardiac surgery. METHODS: We carried out a retrospective cohort study of inpatients with at least two glucose measurements ≥180 mg/dL. Two groups were compared. Patients with SH had no preoperative history of diabetes. Patients were considered to have DH if they had an established preoperative diagnosis of diabetes mellitus or a preoperative hemoglobin A1c (HbA1c) ≥6.5%. The primary outcome measure was hospital LOS. RESULTS: We included 270 patients with postoperative hyperglycemia-82 in the SH group and 188 in the DH group. In a linear regression analysis, hospital LOS was longer in the SH group than in the DH group (10.4 vs 7.3 days; P = .03). Within the SH group, we found no association between LOS and prompt treatment of hyperglycemia within 12 hours (P = .43), insulin dose per day (P = .89), or overall mean glucose (P = .13). CONCLUSIONS: Postoperative LOS was even longer in patients with SH than in patients with DH, representing a potential target for quality improvement efforts. We did not, however, find evidence that improved treatment of SH was associated with reduction in LOS.
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Hiperglicemia , Tempo de Internação , Humanos , Estudos Retrospectivos , Masculino , Tempo de Internação/estatística & dados numéricos , Feminino , Pessoa de Meia-Idade , Hiperglicemia/sangue , Hiperglicemia/epidemiologia , Idoso , Glicemia/análise , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Período Pós-Operatório , Hemoglobinas Glicadas/análise , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Estudos de CoortesRESUMO
Phosphorus is essential in all cells' structural, metabolic and regulatory functions. For fungal cells that import inorganic phosphate (Pi) up a steep concentration gradient, surface Pi transporters are critical capacitators of growth. Fungi must deploy Pi transporters that enable optimal Pi uptake in pH and Pi concentration ranges prevalent in their environments. Single, triple and quadruple mutants were used to characterize the four Pi transporters we identified for the human fungal pathogen Candida albicans, which must adapt to alkaline conditions during invasion of the host bloodstream and deep organs. A high-affinity Pi transporter, Pho84, was most efficient across the widest pH range while another, Pho89, showed high-affinity characteristics only within one pH unit of neutral. Two low-affinity Pi transporters, Pho87 and Fgr2, were active only in acidic conditions. Only Pho84 among the Pi transporters was clearly required in previously identified Pi-related functions including Target of Rapamycin Complex 1 signaling and hyphal growth. We used in vitro evolution and whole genome sequencing as an unbiased forward genetic approach to probe adaptation to prolonged Pi scarcity of two quadruple mutant lineages lacking all 4 Pi transporters. Lineage-specific genomic changes corresponded to divergent success of the two lineages in fitness recovery during Pi limitation. In this process, initial, large-scale genomic alterations like aneuploidies and loss of heterozygosity were eventually lost as populations presumably gained small-scale mutations. Severity of some phenotypes linked to Pi starvation, like cell wall stress hypersensitivity, decreased in parallel to evolving populations' fitness recovery in Pi scarcity, while that of others like membrane stress responses diverged from these fitness phenotypes. C. albicans therefore has diverse options to reconfigure Pi management during prolonged scarcity. Since Pi homeostasis differs substantially between fungi and humans, adaptive processes to Pi deprivation may harbor small-molecule targets that impact fungal growth and virulence.