Mechanical and biochemical feedback combine to generate complex contractile oscillations in cytokinesis.

The actomyosin cortex is an active material that generates force to drive shape changes via cytoskeletal remodeling. Cytokinesis is the essential cell division event during which a cortical actomyosin ring closes to separate two daughter cells. Our active gel theory predicted that actomyosin systems controlled by a biochemical oscillator and experiencing mechanical strain would exhibit complex spatiotemporal behavior. To test whether active materials in vivo exhibit spatiotemporally complex kinetics, we imaged the C. elegans embryo with unprecedented temporal resolution and discovered that sections of the cytokinetic cortex undergo periodic phases of acceleration and deceleration. Contractile oscillations exhibited a range of periodicities, including those much longer periods than the timescale of RhoA pulses, which was shorter in cytokinesis than in any other biological context. Modifying mechanical feedback in vivo or in silico revealed that the period of contractile oscillation is prolonged as a function of the intensity of mechanical feedback. Fast local ring ingression occurs where speed oscillations have long periods, likely due to increased local stresses and, therefore, mechanical feedback. Fast ingression also occurs where material turnover is high, in vivo and in silico. We propose that downstream of initiation by pulsed RhoA activity, mechanical feedback, including but not limited to material advection, extends the timescale of contractility beyond that of biochemical input and, therefore, makes it robust to fluctuations in activation. Circumferential propagation of contractility likely allows for sustained contractility despite cytoskeletal remodeling necessary to recover from compaction. Thus, like biochemical feedback, mechanical feedback affords active materials responsiveness and robustness.

Chronic Rhinosinusitis Risk after Maxillectomy with Microvascular Reconstruction.

INTRODUCTION: Chronic rhinosinusitis (CRS) can be associated with tumors involving the maxillary sinus, but outcomes after undergoing maxillectomy with free flap reconstruction remain unclear. METHODS: A retrospective analysis of medical records was performed to evaluate evidence of CRS in patients who underwent maxillectomy with free flap reconstruction at a single tertiary care academic institution from 2013 through 2020. RESULTS: Eighty-four patients were assessed. Nineteen (22.6%) patients were diagnosed with CRS after surgery, 23 (27.4%) patients were treated for sinus symptoms, and 49 (58.3%) had radiographic evidence of sinus inflammation for more than 6 months. Risk factors for requiring sinus treatment included adjuvant or neoadjuvant chemotherapy (p = 0.002) and pre-operative use of sinus medication (p < 0.001). Radiographic evidence of sinusitis 6 months after surgery is also closely associated with sinusitis treatment (p = 0.051). CONCLUSIONS: CRS may be underdiagnosed in patients undergoing maxillectomy with microvascular reconstruction. Further evaluation into patient sinus disease and symptoms following neoplastic surgery may lead to a higher quality of life in some long-term survivors.

Extranodal marginal zone lymphoma of the larynx: A case report and scoping review.

BACKGROUND: This scoping review aims to review cases of extranodal marginal zone lymphoma (MZL) of the larynx to establish best management practices for this rare clinical entity. METHODS: In this paper, we report a case of laryngeal MZL, in accordance with CARE guidelines. We then performed a scoping review according to PRISMA-ScR criteria of published cases of MZL involving the larynx. The following data were collected for each case: age, sex, size, location(s) involved, stage, treatment, follow-up, and recurrence duration. RESULTS: Sixty-six patients with laryngeal MZL, first reported in 1990, were identified. Characterized by its low-grade histological appearance and indolent course, laryngeal MZL is generally confined to the larynx and has an excellent prognosis with radiation used as first-line therapy. CONCLUSIONS: It is imperative for clinicians to consider lymphoma in the differential diagnosis of a laryngeal tumor from any subsite, as certain pathologies may carry high risks of metastasis.

An exploration into the relationship between insomnia and repetitive negative thinking among cancer survivors.

OBJECTIVE: Insomnia and repetitive negative thinking (RNT) are both prevalent among cancer survivors, yet little work has investigated their interrelationship. To explore the hypothesis that RNT and insomnia are related, we conducted secondary analyses on data from a pilot clinical trial of cognitive behavioral therapy for insomnia (CBT-I) for cancer survivors. METHODS: This study analyzed survey data from 40 cancer survivors with insomnia who participated in a pilot randomized trial of CBT-I. Correlations and linear regression models were used to determine associations between aspects of RNT and related constructs (fear of cancer recurrence [FCR], cancer-specific rumination, worry, and intolerance of uncertainty) and sleep (insomnia and sleep quality), while accounting for psychiatric symptoms such as anxiety and depression. Treatment-related change in RNT was examined using a series of linear mixed models. RESULTS: Evidence for an association between RNT and insomnia among cancer survivors emerged. Higher levels of FCR and cancer-related rumination were correlated with more severe insomnia symptoms and worse sleep quality. Notably, FCR levels predicted insomnia, even after controlling for anxiety and depression. Results identified potential benefits and limitations of CBT-I in addressing RNT that should be examined more thoroughly in future research. CONCLUSIONS: RNT is a potential target to consider in insomnia treatment for cancer survivors.

A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Newly identified nematodes from the Great Salt Lake are associated with microbialites and specially adapted to hypersaline conditions.

Extreme environments enable the study of simplified food-webs and serve as models for evolutionary bottlenecks and early Earth ecology. We investigated the biodiversity of invertebrate meiofauna in the benthic zone of the Great Salt Lake (GSL), Utah, USA, one of the most hypersaline lake systems in the world. The hypersaline bays within the GSL are currently thought to support only two multicellular animals: brine fly larvae and brine shrimp. Here, we report the presence, habitat, and microbial interactions of novel free-living nematodes. Nematode diversity drops dramatically along a salinity gradient from a freshwater river into the south arm of the lake. In Gilbert Bay, nematodes primarily inhabit reef-like organosedimentary structures built by bacteria called microbialites. These structures likely provide a protective barrier to UV and aridity, and bacterial associations within them may support life in hypersaline environments. Notably, sampling from Owens Lake, another terminal lake in the Great Basin that lacks microbialites, did not recover nematodes from similar salinities. Phylogenetic divergence suggests that GSL nematodes represent previously undescribed members of the family Monhysteridae-one of the dominant fauna of the abyssal zone and deep-sea hydrothermal vents. These findings update our understanding of halophile ecosystems and the habitable limit of animals.

Characterization of the Pristionchus pacificus "epigenetic toolkit" reveals the evolutionary loss of the histone methyltransferase complex PRC2.

Comparative approaches have revealed both divergent and convergent paths to achieving shared developmental outcomes. Thus, only through assembling multiple case studies can we understand biological principles. Yet, despite appreciating the conservation-or lack thereof-of developmental networks, the conservation of epigenetic mechanisms regulating these networks is poorly understood. The nematode Pristionchus pacificus has emerged as a model system of plasticity and epigenetic regulation as it exhibits a bacterivorous or omnivorous morph depending on its environment. Here, we determined the "epigenetic toolkit" available to P. pacificus as a resource for future functional work on plasticity, and as a comparison with Caenorhabditis elegans to investigate the conservation of epigenetic mechanisms. Broadly, we observed a similar cast of genes with putative epigenetic function between C. elegans and P. pacificus. However, we also found striking differences. Most notably, the histone methyltransferase complex PRC2 appears to be missing in P. pacificus. We described the deletion/pseudogenization of the PRC2 genes mes-2 and mes-6 and concluded that both were lost in the last common ancestor of P. pacificus and a related species P. arcanus. Interestingly, we observed the enzymatic product of PRC2 (H3K27me3) by mass spectrometry and immunofluorescence, suggesting that a currently unknown methyltransferase has been co-opted for heterochromatin silencing. Altogether, we have provided an inventory of epigenetic genes in P. pacificus to compare with C. elegans. This inventory will enable reverse-genetic experiments related to plasticity and has revealed the first loss of PRC2 in a multicellular organism.

Analysis of the Technical Accuracy of a Patient-Specific Stereotaxy Platform for Brain Biopsy.

The use of stereotactic frames is a common practice in neurosurgical interventions such as brain biopsy and deep brain stimulation. However, conventional stereotactic frames have been shown to require modification and adaptation regarding patient and surgeon comfort as well as the increasing demand for individualized medical treatment. To meet these requirements for carrying out state-of-the-art neurosurgery, a 3D print-based, patient-specific stereotactic system was developed and examined for technical accuracy. Sixteen patient-specific frames, each with two target points, were additively manufactured from PA12 using the Multi Jet Fusion process. The 32 target points aim to maximize the variability of biopsy targets and depths for tissue sample retrieval in the brain. Following manufacturing, the frames were measured three-dimensionally using an optical scanner. The frames underwent an autoclave sterilization process prior to rescanning. The scan-generated models were compared with the planned CAD models and the deviation of the planned target points in the XY-plane, Z-direction and in the resulting direction were determined. Significantly lower (p < 0.01) deviations were observed when comparing CAD vs. print and print vs. sterile in the Z-direction (0.17 mm and 0.06 mm, respectively) than in the XY-plane (0.46 mm and 0.16 mm, respectively). The resulting target point deviation (0.51 mm) and the XY-plane (0.46 mm) are significantly higher (p < 0.01) in the CAD vs. print comparison than in the print vs. sterile comparison (0.18 mm and 0.16 mm, respectively). On average, the results from the 32 target positions examined exceeded the clinically required accuracy for a brain biopsy (2 mm) by more than four times. The patient-specific stereotaxic frames meet the requirements of modern neurosurgical navigation and make no compromises when it comes to accuracy. In addition, the material is suitable for autoclave sterilization due to resistance to distortion.

Septins throughout phylogeny are predicted to have a transmembrane domain, which in Caenorhabditis elegans is functionally important.

Septins, a conserved family of filament-forming proteins, contribute to eukaryotic cell division, polarity, and membrane trafficking. Septins are thought to act in these processes by scaffolding other proteins to the plasma membrane. The mechanisms by which septins associate with the plasma membrane are not well understood but can involve two polybasic domains and/or an amphipathic helix. We discovered that the genomes of organisms throughout phylogeny, but not most commonly used model organisms, encode one or more septins predicted to have transmembrane domains. The nematode Caenorhabditis elegans, which was thought to express only two septin proteins, UNC-59 and UNC-61, translates multiple isoforms of UNC-61, and one isoform, UNC-61a, is predicted to contain a transmembrane domain. UNC-61a localizes specifically to the apical membrane of the C. elegans vulva and is important for maintaining vulval morphology. UNC-61a partially compensates for the loss of the other two UNC-61 isoforms, UNC-61b and UNC-61c. The UNC-61a transmembrane domain is sufficient to localize a fluorophore to membranes in mammalian cells, and its deletion from UNC-61a recapitulates the phenotypes of unc-61a null animals. The localization and loss-of-function phenotypes of UNC-61a and its transmembrane domain suggest roles in cell polarity and secretion and help explain the cellular and tissue biological underpinnings of C. elegans septin null alleles' enigmatically hypomorphic phenotypes. Together, our findings reveal a novel mechanism of septin-membrane association with profound implications for the dynamics and regulation of this association.

Mechanical positive feedback and biochemical negative feedback combine to generate complex contractile oscillations in cytokinesis.

Contractile force generation by the cortical actomyosin cytoskeleton is essential for a multitude of biological processes. The actomyosin cortex behaves as an active material that drives local and large-scale shape changes via cytoskeletal remodeling in response to biochemical cues and feedback loops. Cytokinesis is the essential cell division event during which a cortical actomyosin ring generates contractile force to change cell shape and separate two daughter cells. Our recent work with active gel theory predicts that actomyosin systems under the control of a biochemical oscillator and experiencing mechanical strain will exhibit complex spatiotemporal behavior, but cytokinetic contractility was thought to be kinetically simple. To test whether active materials in vivo exhibit spatiotemporally complex kinetics, we used 4-dimensional imaging with unprecedented temporal resolution and discovered sections of the cytokinetic cortex undergo periodic phases of acceleration and deceleration. Quantification of ingression speed oscillations revealed wide ranges of oscillation period and amplitude. In the cytokinetic ring, activity of the master regulator RhoA pulsed with a timescale of approximately 20 seconds, shorter than that reported for any other biological context. Contractility oscillated with 20-second periodicity and with much longer periods. A combination of in vivo and in silico approaches to modify mechanical feedback revealed that the period of contractile oscillation is prolonged as a function of the intensity of mechanical feedback. Effective local ring ingression is characterized by slower speed oscillations, likely due to increased local stresses and therefore mechanical feedback. Fast ingression also occurs where material turnover is high, in vivo and in silico . We propose that downstream of initiation by pulsed RhoA activity, mechanical positive feedback, including but not limited to material advection, extends the timescale of contractility beyond that of biochemical input and therefore makes it robust to fluctuations in activation. Circumferential propagation of contractility likely allows sustained contractility despite cytoskeletal remodeling necessary to recover from compaction. Our work demonstrates that while biochemical feedback loops afford systems responsiveness and robustness, mechanical feedback must also be considered to describe and understand the behaviors of active materials in vivo .

New era for myelofibrosis treatment with novel agents beyond Janus kinase-inhibitor monotherapy: Focus on clinical development of BCL-XL /BCL-2 inhibition with navitoclax.

Myelofibrosis is a heterogeneous myeloproliferative neoplasm characterized by chronic inflammation, progressive bone marrow failure, and hepatosplenic extramedullary hematopoiesis. Treatments like Janus kinase inhibitor monotherapy (e.g., ruxolitinib) provide significant spleen and symptom relief but demonstrate limited ability to lead to a durable disease modification. There is an urgent unmet medical need for treatments with a novel mechanism of action that can modify the underlying pathophysiology and affect the disease course of myelofibrosis. This review highlights the role of B-cell lymphoma (BCL) protein BCL-extra large (BCL-XL ) in disease pathogenesis and the potential role that navitoclax, a BCL-extra large/BCL-2 inhibitor, may have in myelofibrosis treatment.

Post-remission cytopenia management in patients with AML treated with venetoclax in combination with hypomethylating agents: Pre- versus post-VIALE-A real-world experience from a predominantly US community setting.

BACKGROUND: This retrospective cohort study used an electronic health record-derived, de-identified, US patient-level database to better understand the real-world treatment experience, in a predominantly community setting (80.3% of patients), of venetoclax+hypomethylating agents (HMAs) in routine clinical care, pre- and post-VIALE-A, to determine whether the post-remission cytopenia management insight from VIALE-A was reflected in real-world clinical practice. METHODS: Patients with newly diagnosed acute myeloid leukemia (AML; N = 498), who initiated venetoclax+HMA ≤30 days from AML diagnosis from June 1, 2018, to March 31, 2021, were stratified into pre-(n = 330) and post-(n = 168) VIALE-A cohorts. RESULTS: More patients in the post-(61%) versus pre-(45%) VIALE-A cohort had their first biopsy by 28 ± 14 days post-treatment initiation. Patients underwent bone marrow (BM) assessment earlier in the post- versus pre-VIALE-A cohort, and first identification of response was also earlier (2.5 vs 5.1 months, respectively). More venetoclax schedule modifications post-remission occurred among post-(82.1%) versus pre-(73.8%) VIALE-A responders; the most common reason for modification was treatment toxicities, specifically cytopenia. Treatment survival outcomes were comparable with or without venetoclax schedule modifications. CONCLUSIONS: Findings suggest that venetoclax schedule modifications can be used to manage cytopenia events without adversely affecting outcomes. Opportunities remain to improve earlier BM assessment to determine venetoclax schedule modifications, providing the best chance for optimal treatment outcomes.

Caenorhabditis elegans septins contribute to the development and structure of the oogenic germline.

Oocytes must be exceptionally large cells in order to support embryonic development. Throughout animal phylogeny, a specialized cell called a syncytium, wherein many nuclei share a continuous cytoplasm, achieves oogenesis. The syncytial nature of germline architecture is key to its function and depends on conserved components of the cortical cytoskeleton. Septins form non-polar cytoskeletal polymers that associate with membranes. In the syncytial germline of the nematode Caenorhabditis elegans, septins are highly enriched on the cortex and generally required for fertility, but the role of septins in the germline is poorly understood. We report that the C. elegans septins, UNC-59 and UNC-61, are important for germline extension during development, the maintenance of its syncytial architecture, and production of oocytes. While much of our findings substantiate the idea that the two C. elegans septins act together, we also found evidence that they have distinct functions. Loss of UNC-61 perturbed germline extension during germline development, while the loss of UNC-59 function severely affected germline architecture in adult hermaphrodites. Consultation of clustering results from a large-scale high-throughput screen suggested that septins are involved in germ cell proliferation and/or differentiation. In sum, our findings implicate a conserved cytoskeletal component in the complex architecture of a germline syncytium.

A temperate Earth-sized planet with tidal heating transiting an M6 star.

Temperate Earth-sized exoplanets around late-M dwarfs offer a rare opportunity to explore under which conditions planets can develop hospitable climate conditions. The small stellar radius amplifies the atmospheric transit signature, making even compact secondary atmospheres dominated by N2 or CO2 amenable to characterization with existing instrumentation1. Yet, despite large planet search efforts2, detection of low-temperature Earth-sized planets around late-M dwarfs has remained rare and the TRAPPIST-1 system, a resonance chain of rocky planets with seemingly identical compositions, has not yet shown any evidence of volatiles in the system3. Here we report the discovery of a temperate Earth-sized planet orbiting the cool M6 dwarf LP 791-18. The newly discovered planet, LP 791-18d, has a radius of 1.03 ± 0.04 R⊕ and an equilibrium temperature of 300-400 K, with the permanent night side plausibly allowing for water condensation. LP 791-18d is part of a coplanar system4 and provides a so-far unique opportunity to investigate a temperate exo-Earth in a system with a sub-Neptune that retained its gas or volatile envelope. On the basis of observations of transit timing variations, we find a mass of 7.1 ± 0.7 M⊕ for the sub-Neptune LP 791-18c and a mass of [Formula: see text] for the exo-Earth LP 791-18d. The gravitational interaction with the sub-Neptune prevents the complete circularization of LP 791-18d's orbit, resulting in continued tidal heating of LP 791-18d's interior and probably strong volcanic activity at the surface5,6.

Histone 4 lysine 5/12 acetylation enables developmental plasticity of Pristionchus mouth form.

Development can be altered to match phenotypes with the environment, and the genetic mechanisms that direct such alternative phenotypes are beginning to be elucidated. Yet, the rules that govern environmental sensitivity vs. invariant development, and potential epigenetic memory, remain unknown. Here, we show that plasticity of nematode mouth forms is determined by histone 4 lysine 5 and 12 acetylation (H4K5/12ac). Acetylation in early larval stages provides a permissive chromatin state, which is susceptible to induction during the critical window of environmental sensitivity. As development proceeds deacetylation shuts off switch gene expression to end the critical period. Inhibiting deacetylase enzymes leads to fixation of prior developmental trajectories, demonstrating that histone modifications in juveniles can carry environmental information to adults. Finally, we provide evidence that this regulation was derived from an ancient mechanism of licensing developmental speed. Altogether, our results show that H4K5/12ac enables epigenetic regulation of developmental plasticity that can be stored and erased by acetylation and deacetylation, respectively.

Preliminary feasibility of integrating tobacco treatment into SUD peer recovery coaching: a mixed-methods study of peer recovery coaches.

BACKGROUND: Individuals with substance use disorder (SUD) have high prevalence of cigarette smoking and difficulty quitting. Peer recovery coaches (PRCs; individuals with lived SUD experience) facilitate SUD behavior change in recoverees but it is unknown if/how they address tobacco treatment in SUD recovery coaching. We assessed PRC's tobacco-related practices and attitudes about tobacco treatment in SUD recovery. METHODS: The Tobacco use In Peer-recovery Study (TIPS) was a cross-sectional mixed-methods pilot survey (January-March 2022) of the 26 PRCs employed by a Massachusetts-based healthcare system's 12 SUD treatment clinics/programs. PRCs completed a quantitative survey (n = 23/26; 88%) and a telephone-based qualitative interview (n = 20/26; 77%). RESULTS: One-third of PRCs reported current smoking, 50% reported former smoking, and 18% never smoked. Among PRCs, 61% reported accompanying recoverees outdoors to smoke, 26% smoked with recoverees, 17% had provided cigarettes to recoverees, 32% used smoking to help build peer-relationships, and 74% rated smoking as socially acceptable in SUD treatment. PRCs reported regularly talking to recoverees about tobacco treatment (65%), believed they should have a role in helping recoverees quit smoking (52%), and were interested in tobacco treatment training (65%). A majority of both nonsmoking and current smoking PRCs (73% vs. 57%) regularly talked to recoverees about quitting smoking. CONCLUSION: PRCs' attitudes about integrating tobacco treatment into SUD recovery coaching were generally positive and PRCs reported they could have a role in helping recoverees with tobacco treatment. Barriers to integrating tobacco treatment into SUD recovery include use of cigarettes as a peer-recovery tool and high prevalence and social acceptability of smoking in SUD recovery.

The supply of multiple ecosystem services requires biodiversity across spatial scales.

The impact of local biodiversity loss on ecosystem functioning is well established, but the role of larger-scale biodiversity dynamics in the delivery of ecosystem services remains poorly understood. Here we address this gap using a comprehensive dataset describing the supply of 16 cultural, regulating and provisioning ecosystem services in 150 European agricultural grassland plots, and detailed multi-scale data on land use and plant diversity. After controlling for land-use and abiotic factors, we show that both plot-level and surrounding plant diversity play an important role in the supply of cultural and aboveground regulating ecosystem services. In contrast, provisioning and belowground regulating ecosystem services are more strongly driven by field-level management and abiotic factors. Structural equation models revealed that surrounding plant diversity promotes ecosystem services both directly, probably by fostering the spill-over of ecosystem service providers from surrounding areas, and indirectly, by maintaining plot-level diversity. By influencing the ecosystem services that local stakeholders prioritized, biodiversity at different scales was also shown to positively influence a wide range of stakeholder groups. These results provide a comprehensive picture of which ecosystem services rely most strongly on biodiversity, and the respective scales of biodiversity that drive these services. This key information is required for the upscaling of biodiversity-ecosystem service relationships, and the informed management of biodiversity within agricultural landscapes.

Reconstruction of the Anterior Skull Base Using the Nasoseptal Flap: A Review.

The nasoseptal flap is a workhorse reconstructive option for anterior skull base defects during endonasal surgery. This paper highlights the versatility of the nasoseptal flap. After providing a brief historical perspective, this review will focus on the relevant primary literature published in the last ten years. We will touch upon new applications of the flap, how the flap has been modified to expand its reach and robustness, and some of the current limitations. We will conclude by discussing what the future holds for improving upon the design and use of the nasoseptal flap in anterior skull base reconstruction.