Drosophila ring chromosomes interact with sisters and homologs to produce anaphase bridges in mitosis.

Ring chromosomes are known in many eukaryotic organisms, including humans. They are typically associated with a variety of maladies, including abnormal development and lethality. Underlying these phenotypes are anaphase chromatin bridges that can lead to chromosome loss, nondisjunction and breakage. By cytological examination of ring chromosomes in Drosophila melanogaster we identified five causes for anaphase bridges produced by ring chromosomes. Catenation of sister chromatids is the most common cause and these bridges frequently resolve during anaphase, presumably by the action of topoisomerase II. Sister chromatid exchange and chromosome breakage followed by sister chromatid union also produce anaphase bridges. Mitotic recombination with the homolog was rare, but was another route to generation of anaphase bridges. Most surprising, was the discovery of homolog capture, where the ring chromosome was connected to its linear homolog in anaphase. We hypothesize that this is a remnant of mitotic pairing and that the linear chromosome is connected to the ring by multiple wraps produced through the action of topoisomerase II during establishment of homolog pairing. In support, we showed that in a ring/ring homozygote the two rings are frequently catenated in mitotic metaphase, a configuration that requires breaking and rejoining of at least one chromosome.

Efficacy of Aromatherapy Against Behavioral and Psychological Disturbances in People With Dementia: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Behavioral and psychological symptoms of dementia (BPSD) are common in people with dementia. Aromatherapy may reduce the frequency and severity of BPSD. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of aromatherapy in relieving BPSD and improving functional ability in people with dementia. DESIGN: Systematic review and meta-analysis. SETTING AND PARTICIPANTS: Patients with dementia receiving aromatherapy. METHODS: A literature search was conducted using PubMed, Embase, and Cochrane Library for RCTs published before March 2024 comparing aromatherapy with control treatments in patients with dementia. RESULTS: There were 15 trials involving 821 patients. Overall, significant reduction in BPSD was observed after 1 month of aromatherapy treatment. Among 15 trials, 9 reported the Cohen-Mansfield Agitation Inventory (CMAI) score, and 7 evaluated the Neuropsychiatric Inventory (NPI) score. The meta-analysis showed significant improvement in CMAI score (weighted mean difference [WMD] -6.31, 95% CI -9.52 to -3.11) and NPI score (WMD -8.07, 95% CI -13.53 to -2.61) in patients receiving 3 to 4 weeks of aromatherapy compared with the control group. Four of the 15 trials reported improvement in depressive mood and 3 trials reported no significant improvement in functional ability. CONCLUSIONS AND IMPLICATIONS: In conclusion, aromatherapy is a safe and viable nonpharmacologic treatment to improve BPSD in people with dementia and its combination with massage showed higher efficacy.

The prevalence of overt, occult, and no-demonstrated stress urinary incontinence and their clinical and urodynamic findings in women with advanced-stage cystoceles.

OBJECTIVES: To elucidate the prevalence of overt, occult and no demonstrated (ND) stress urinary incontinence (SUI) in women with advanced-stage cystoceles. STUDY DESIGN: Between November 2011 and January 2017, all women with ≥stage 2 cystoceles were retrospectively enrolled. Overt SUI was diagnosed before the prolapse reduction test, and occult SUI was diagnosed when urine leakage was noted after a reduction test with vaginal gauze. Otherwise, a diagnosis of ND-SUI was made. MAIN OUTCOME MEASURES: The prevalence, clinical and urodynamic findings of overt SUI, occult SUI, and ND-SUI. RESULTS: In 480 enrolled women, 62% had overt SUI, 17% had occult SUI, and 21% had ND-SUI. The occult SUI group had the most advanced prolapse. The pad weight results after prolapse reduction (37.3 ± 44.3 vs. 13.4 ± 21.9, p < 0.05), the bladder capacity (243 ± 54 vs. 273 ± 48, p < 0.001), and questionnaires regarding life quality were significantly different between the overt SUI and the occult SUI groups. Bladder oversensitivity (BO) was the most common urodynamic diagnosis (389/480, 81%), especially in overt SUI, while urodynamic stress incontinence (56/480, 12%) and detrusor overactivity (60/480, 13%) were uncommon. The cutoff value of stage 3 uterine prolapse was the strongest predictor for predicting occult SUI (sensitivity = 30.3%, specificity = 78.5%; area = 0.60, 95% CI: 0.52-0.68). CONCLUSIONS: SUI occurs in a ratio of 3:1:1 among cases with overt, occult, and no demonstrable symptoms. BO is the most common urodynamic diagnosis. Pad test with prolapse reduction remains an important tool, especially for coexistent stage 3 uterine prolapse.

Age-specific prevalence, clinical and urodynamic findings of detrusor underactivity and bladder outlet obstruction in female voiding dysfunction.

OBJECTIVE: Female voiding dysfunction with cystocele have been widely studied, but there are no data regarding women without cystoceles. The present study aimed to evaluate the prevalence of detrusor underactivity (DU) and bladder outlet obstruction (BOO) without cystoceles in a large sample size. METHODS: This was a retrospective cohort study. Between April 1996 and September 2018, 602 neurologically intact women with voiding dysfunction without cystoceles were enrolled. Detrusor pressure (DU) at the maximum flow rate (PdetQmax) <20 cmH2O, maximum flow rate (Qmax) <15 mL/s, and a bladder voiding efficiency <90% and BOO (PdetQmax ≥40 cmH2O and Qmax <12 mL/s) were diagnosed by urodynamic study. Otherwise, a non-DU/BOO diagnosis was made. The prevalence of DU and BOO was the primary outcome. The secondary outcomes were the analyses of the differences between these three groups in objective UDS parameters and subjective questionnaires and bladder diary parameters. RESULTS: This study included 100 (17%) women with DU, 60 (10%) with BOO, and 442 (73%) with a non-DU/BOO diagnosis. DU increased with age, but BOO decreased as age increased. The women in the DU group were older, had higher parity and pad weights, and lower PdetQmax, maximum urethral closure pressure, and functional profile length than the BOO group. The urodynamic findings did not correlate well to subjective questionnaire parameters. None of the symptoms revealed a significant difference between the groups. The retrospective design was the limitation of the study. CONCLUSION: The prevalence of DU increased with age in women with voiding dysfunction without advanced cystoceles. Conversely, BOO decreased with age. Prevalence intersected in the fourth decade. Diagnosis requires urodynamic evaluation, as subjective symptoms are inconclusive.

Metformin alters dendrite development and synaptic plasticity in rat cortical neurons.

Synaptic plasticity is crucial as it dynamically molds the strength and connectivity of neural circuits, influencing learning, memory, and the development of neurological disorders. Metformin, a widely prescribed anti-diabetic medication, has been shown to readily cross the blood-brain barrier (BBB) and the placenta. However, its prolonged impact on neuronal morphology and functions remains underexplored. In this study, we investigated the influence of metformin on dendrite development and synaptic plasticity in embryonic brains and primary rat cortical neurons. Our findings reveal a negative modulation of dendrite development by metformin, as evidenced by altered dendritic arborization, impaired dendritic spine morphology and disruptions in synaptic plasticity, suggesting a potential link between metformin exposure and aberrations in neuronal connectivity. In addition, we extend our insights to the impact of maternal metformin exposure on embryonic brains, revealing a significant inhibition of dendrite development in E18.5 rat brains. In conclusion, this study adds to the expanding knowledge base on the non-metabolic effects of metformin, emphasizing the significance of assessing its potential influence on both neuronal structure and function. There is an urgent need for further investigations into the enduring impact of prolonged metformin administration on the structural and functional aspects of neurons.

Impact of metformin on neocortical development during pregnancy: Involvement of ERK and p35/CDK5 pathways.

Metformin, the most commonly prescribed drug for the treatment of diabetes, is increasingly used during pregnancy to address various disorders such as diabetes, obesity, preeclampsia, and metabolic diseases. However, its impact on neocortex development remains unclear. Here, we investigated the direct effects of metformin on neocortex development, focusing on ERK and p35/CDK5 regulation. Using a pregnant rat model, we found that metformin treatment during pregnancy induces small for gestational age (SGA) and reduces relative cortical thickness in embryos and neonates. Additionally, we discovered that metformin inhibits neural progenitor cell proliferation in the sub-ventricular zone (SVZ)/ventricular zone (VZ) of the developing neocortex, a process possibly mediated by ERK inactivation. Furthermore, metformin induces neuronal apoptosis in the SVZ/VZ area of the developing neocortex. Moreover, metformin retards neuronal migration, cortical lamination, and differentiation, potentially through p35/CDK5 inhibition in the developing neocortex. Remarkably, compensating for p35 through in utero electroporation partially rescues metformin-impaired neuronal migration and development. In summary, our study reveals that metformin disrupts neocortex development by inhibiting neuronal progenitor proliferation, neuronal migration, cortical layering, and cortical neuron maturation, likely via ERK and p35/CDK5 inhibition. Consequently, our findings advocate for caution in metformin usage during pregnancy, given its potential adverse effects on fetal brain development.

Metformin inhibits nerve growth factor-induced sympathetic neuron differentiation through p35/CDK5 inhibition.

The authors' previous research has shown the pivotal roles of cyclin-dependent kinase 5 (CDK5) and its regulatory protein p35 in nerve growth factor (NGF)-induced differentiation of sympathetic neurons in PC12 cells. During the process of differentiation, neurons are susceptible to environmental influences, including the effects of drugs. Metformin is commonly used in the treatment of diabetes and its associated symptoms, particularly in diabetic neuropathy, which is characterized by dysregulation of the sympathetic neurons. However, the impacts of metformin on sympathetic neuronal differentiation remain unknown. In this study, we investigated the impact of metformin on NGF-induced sympathetic neuronal differentiation using rat pheochromocytoma PC12 cells as a model. We examined the regulation of TrkA-p35/CDK5 signaling in NGF-induced PC12 differentiation. Our results demonstrate that metformin reduces NGF-induced PC12 differentiation by inactivating the TrkA receptor, subsequently inhibiting ERK and EGR1. Inhibition of this cascade ultimately leads to the downregulation of p35/CDK5 in PC12 cells. Furthermore, metformin inhibits the activation of the presynaptic protein Synapsin-I, a substrate of CDK5, in PC12 differentiation. In addition, metformin alters axonal and synaptic bouton formation by inhibiting p35 at both the axons and axon terminals in fully differentiated PC12 cells. In summary, our study elucidates that metformin inhibits sympathetic neuronal differentiation in PC12 cells by disrupting TrkA/ERK/EGR1 and p35/CDK5 signaling. This research contributes to uncovering a novel signaling mechanism in drug response during sympathetic neuronal differentiation, enhancing our understanding of the intricate molecular processes governing this critical aspect of neurodevelopment.NEW & NOTEWORTHY This study unveils a novel mechanism influenced by metformin during sympathetic neuronal differentiation. By elucidating its inhibitory effects from the nerve growth factor (NGF) receptor, TrkA, to the p35/CDK5 signaling pathways, we advance our understanding of metformin's mechanisms of action and emphasize its potential significance in the context of drug responses during sympathetic neuronal differentiation.

Fast Multichannel Inverse Design through Augmented Partial Factorization.

Computer-automated design and discovery have led to high-performance nanophotonic devices with diverse functionalities. However, massively multichannel systems such as metasurfaces controlling many incident angles and photonic-circuit components coupling many waveguide modes still present a challenge. Conventional methods require Min forward simulations and Min adjoint simulations-2Min simulations in total-to compute the objective function and its gradient for a design involving the response to Min input channels. Here, we develop a formalism that uses the recently proposed augmented partial factorization method to obtain both the objective function and its gradient for a massively multichannel system in a single or a few simulations, achieving over 2 orders of magnitude speedup and reduced memory usage. We use this method to inverse design a metasurface beam splitter that separates the incident light to the target diffraction orders for all incident angles of interest, a key component of the dot projector for 3D sensing. This formalism enables efficient inverse design for a wide range of multichannel optical systems.

Total Laryngectomy for Respiratory Complications From Advanced Duchenne Muscular Dystrophy.

Due to respiratory weakness, late-stage Duchenne muscular dystrophy (DMD) patients may suffer from chronic aspiration, which is sometimes treated using tracheostomy. However, definitive laryngectomy has not been described in the literature as an aspiration prevention modality in DMD, especially in patients with contraindications to tracheostomy. A case is presented for a patient with advanced stage Duchenne muscular dystrophy suffering from chronic aspiration pneumonia and excessive oral secretions who became ventilator dependent. A tracheostomy was placed, but was noted to have excessive secretions and high cuff pressures, which have been known to be associated with worsened swallow dysfunction as well as tracheoinnominate fistula. The patient therefore was considered for total laryngectomy, which he underwent successfully. Post-operatively, the patient was noted to have improved subjective quality of life, engaged in an oral diet, and had less secretions surrounding his tracheostoma post-operatively. Aspiration prevention surgeries are done to improve quality of life by improving oral intake, decreasing the need for frequent suctioning, and can sometimes allow for speech. It is important to consider quality of life for DMD patients as more of these patients are living into their 30s with the aid of mechanical ventilation. Laryngectomy is a surgery that can definitively correct chronic aspiration while allowing for oral intake. Laryngoscope, 134:3677-3678, 2024.

Dinaciclib inhibits the growth of acute myeloid leukemia cells through either cell cycle-related or ERK1/STAT3/MYC pathways.

Although immature differentiation and uncontrolled proliferation of hematopoietic stem cells are thought to be the primary mechanisms of acute myeloid leukemia (AML), the pathophysiology in most cases remains unclear. Dinaciclib, a selective small molecule targeting multiple cyclin-dependent kinases (CDKs), is currently being evaluated in oncological clinical trials. Despite the proven anticancer potential of dinaciclib, the differential molecular mechanisms by which it inhibits the growth of different AML cell lines remain unclear. In the current study, we treated HL-60 and KG-1 AML cell lines with dinaciclib and investigated the potential mechanisms of dinaciclib-induced AML cell growth inhibition using flow cytometry and western blotting assays. Data from HL-60 and KG-1 AML cells were validated using human primary AML cells. The results showed that the growth inhibitory effect of dinaciclib was more sensitive in HL-60 cells (IC50: 8.46 nM) than in KG-1 cells (IC50: 14.37 nM). The protein decline in Cyclin A/B and CDK1 and cell cycle arrest in the G2/M phase were more profound in HL-60 cells, corresponding to its growth inhibition. Although the growth inhibition of KG-1 cells by dinaciclib was still pronounced, the cell cycle-associated proteins were relatively insensitive. In addition to cell cycle regulation, the activation/expression of ERK1/STAT3/MYC signaling was significantly reduced by dinaciclib in KG-1 cells compared with that in HL-60 cells. Regarding the results of primary AML cells, we observed ERK1/STAT3/MYC inhibition and cell cycle regulation in different patients. These findings suggest that the cell cycle-associated and ERK1/STAT3/MYC signaling pathways might be two distinct mechanisms by which dinaciclib inhibits AML cells, which could facilitate the development of combination therapy for AML in the future.

Fast multi-source nanophotonic simulations using augmented partial factorization.

Numerical solutions of Maxwell's equations are indispensable for nanophotonics and electromagnetics but are constrained when it comes to large systems, especially multi-channel ones such as disordered media, aperiodic metasurfaces and densely packed photonic circuits where the many inputs require many large-scale simulations. Conventionally, before extracting the quantities of interest, Maxwell's equations are first solved on every element of a discretization basis set that contains much more information than is typically needed. Furthermore, such simulations are often performed one input at a time, which can be slow and repetitive. Here we propose to bypass the full-basis solutions and directly compute the quantities of interest while also eliminating the repetition over inputs. We do so by augmenting the Maxwell operator with all the input source profiles and all the output projection profiles, followed by a single partial factorization that yields the entire generalized scattering matrix via the Schur complement, with no approximation beyond discretization. This method applies to any linear partial differential equation. Benchmarks show that this approach is 1,000-30,000,000 times faster than existing methods for two-dimensional systems with about 10,000,000 variables. As examples, we demonstrate simulations of entangled photon backscattering from disorder and high-numerical-aperture metalenses that are thousands of wavelengths wide.

Novel Changes in Resident Education during a Pandemic: Strategies and Approaches to Maximize Residency Education and Safety

Abstract Introduction The COVID-19 pandemic has led to a reduction in surgical and clinical volume, which has altered the traditional training experience of the otolaryngology resident. Objective To describe the strategies we utilized to maximize resident education as well as ensure patient and staff safety during the pandemic. Methods We developed a system that emphasized three key elements. First and foremost, patient care remained the core priority. Next, clinical duties were restructured to avoid unnecessary exposure of residents. The third component was ensuring continuation of resident education and maximizing learning experiences. Results To implement these key elements, our residency divided up our five hospitals into three functional groups based on geographical location and clinical volume. Each team works for three days at their assigned location before being replaced by the next three-person team at our two busiest sites. Resident teams are kept completely separate from each other, so that they do not interact with those working at other sites. Conclusions Despite the daily challenges encountered as we navigate through the COVID-19 pandemic, our otolaryngology residency program has been able to establish a suitable balance between maintenance of resident safety and well-being without compromise to patient care.