bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro inhibition of human cytochrome P450 enzymes by licoisoflavone B from Glycyrrhiza uralensis Fisch. ex DC
Authors: Chen Luying , Nikolic Dejan , Li Guannan , Liu Jialin , van Breemen Richard B
Published: August 2023

Glycyrrhiza uralensis Fisch. ex DC, one of the 3 pharmacopeial species of licorice and widely used in dietary supplements, can inhibit certain cytochrome P450 (CYP) enzymes. Thereby, G. uralensis preparations have the potential to cause pharmacokinetic drug interactions when consumed along with prescription medicines. One compound (1.34 mg dry weight) responsible for inhibiting CYP2B6, CYP2C8, and CYP2C9 was isolated using bioactivity-guided fractionation from 250 g dried roots, stolons, and rhizomes. The enzyme kinetics and mechanisms of inhibition were determined using human liver microsomes, recombinant enzymes, and UHPLC-MS/MS-based assays. Identified as licoisoflavone B, this compound displayed reversible inhibition of CYP2C8 with an IC50 value of 7.4 ± 1.1 µM and reversible inhibition of CYP2C9 with an IC50 value of 4.9 ± 0.4 µM. The enzyme kinetics indicated that the mechanism of inhibition was competitive for recombinant CYP2C8, with a Ki value of 7.0 ± 0.7 μM, and mixed-type inhibition for recombinant CYP2C9, with a Ki value of 1.2 ± 0.2 μM. Licoisoflavone B moderately inhibited CYP2B6 through a combination of irreversible and reversible mechanisms with an IC50 value of 16.0 ± 3.9 µM.
Ratoon Stunting Disease of Sugarcane: A Review Emphasizing Detection Strategies and Challenges
Authors: Chakraborty Moutoshi , Soda Narshone , Strachan Simon , Ngo Chuong N. , Bhuiyan Shamsul A. , Shiddiky Muhammad J. A. , Ford Rebecca
Published: August 2023

Sugarcane ( Saccharum hybrid) is an important cash crop grown in tropical and subtropical countries. Ratoon stunting disease (RSD), caused by a xylem-inhabiting bacterium, Leifsonia xyli subsp. xyli ( Lxx) is one of the most economically significant diseases globally. RSD results in severe yield losses because its highly contagious nature and lack of visually identifiable symptoms make it harder to devise an effective management strategy. The efficacy of current management practices is hindered by implementation difficulties caused by lack of resources, high cost, and difficulties in monitoring. Rapid detection of the causal pathogen in vegetative planting material is crucial for sugarcane growers to manage this disease. Several microscopic, serological, and molecular-based methods have been developed and used for detecting the RSD pathogen. Although these methods have been used across the sugarcane industry worldwide to diagnose Lxx, some lack reliability or specificity, are expensive and time-consuming to apply, and most of all, are not suitable for on-farm diagnosis. In recent decades, there has been significant progress in the development of integrated isothermal amplification-based microdevices for accurate human and plant pathogen detection. There is a significant opportunity to develop a novel diagnostic method that integrates nanobiosensing with isothermal amplification within a microdevice format for accurate Lxx detection. In this review, we summarize (i) the historical background and current knowledge of sugarcane ratoon stunting disease, including some aspects related to transmission, pathosystem, and management practices; and (ii) the drawbacks of current diagnostic methods and the potential for application of advanced diagnostics to improve disease management.
Cross-platform social media analysis regarding ACL injury and surgery
Authors: Hasley Hunter L. , Bukowiec Lainey G. , Zaifman Jay M. , Malik Martin , Batko Brian , Kissin Yair D. , Kelly Michael
Published: August 2023

Background:

Anterior cruciate ligament (ACL) injury affects a broad patient population, but there is limited knowledge on how ACL injury is discussed across social media platforms. This study aims to develop an extensive snapshot of the social media milieu for understanding who uses social media platforms, what topics users discuss, and how these platforms vary regarding ACL injury and surgery.

Methods:

We utilized a qualitative, descriptive design with quantitative statistical analysis including Kruskal-Wallis tests and Fisher’s Exact tests with post hoc analyses to examine new posts across Facebook, Instagram, Twitter, and TikTok using ACL-specific search terms from August 2021 to January 2022. Posts were analyzed by authorship, content characterization, and engagement.

Results:

Across social media sites, 760 posts were examined involving ACL surgery and injury. There was statistically significant difference among the platforms when comparing categories of authorship (P<0.001). There were statistically significant differences where physicians (P<0.001) and patients (P<0.001) posted, with physicians representing 20.6% and 19.5% of posts on Facebook and Twitter, respectively. TikTok displayed the highest patient authorship (83.5%) and greatest content engagement. There were also significant differences among platforms regarding content characterization (P<0.001).

Conclusions:

This study breaks down a snapshot of social media revolving around ACL injury and surgery demonstrating differences in authorship, content, and engagement of posts across platforms. These findings demonstrate the frequent use of social media by patients to address unmet clinical needs and can help surgeons and patients connect on the same platforms.

Level of Evidence:

Level IV.
The Role of Thoracic Tilt in Identifying Thoracic Compensation and Predicting Proximal Junctional Kyphosis in Degenerative Lumbar Scoliosis
Authors: Qiu Weipeng , Zhou Siyu , Han Gengyu , Chen Zimu , Chen Ze , Ding Linyao , Sun Zhuoran , Li Weishi
Published: August 2023

Study Design.

A retrospective cohort study of consecutive patients.

Objective.

To investigate the clinical value of thoracic tilt (TT) in characterizing thoracic compensation and predicting proximal junctional kyphosis (PJK) in degenerative lumbar scoliosis (DLS).

Summary of Background Data.

Thoracic compensation has been shown to be associated with the development of PJK, while thoracic shape and morphology in patients with DLS remain understudied.

Methods.

Patients with DLS who underwent long-segment fusion were divided into a PJK group and a non-PJK group. Asymptomatic elderly volunteers were recruited as healthy controls. Thoracic parameters were measured in both cohorts, including the TT, T1-L1 pelvic angle (TLPA), T12 slope, thoracic kyphosis (TK, T4-T12), global thoracic kyphosis (GTK, T1-T12), and thoracolumbar kyphosis (TLK, T10-L2). Multivariate logistic regression was used to assess the association between TT and the development of PJK, adjusting for confounders. Multivariate linear regression was used to establish the predictive formula for TT.

Results.

A total of 126 patients with DLS were enrolled, of which 37 (29.4%) developed PJK. Compared with 110 healthy controls, DLS patients had significantly greater TT, TLPA, T12 slope, and TLK as well as smaller TK and GTK (allP<0.001). Preoperatively, the PJK group showed significantly greater TT (P=0.013), TLPA (P<0.001), and TLK (P=0.034) than the non-PJK group. No significant differences were found in TK and GTK before surgery. Postoperatively, the PJK group showed significantly greater TT (P<0.001), TLPA (P<0.001), TLK (P<0.001), and proximal junctional angle (P<0.001). Multivariate logistic regression analysis showed that greater postoperative TT was associated with the development of PJK. Multivariate linear regression analysis suggested that the regression formula was postoperative TT=0.675×T12slope+0.412×TK+0.158×TLK−4.808 (R2=0.643,P<0.001).

Conclusions.

The novel sagittal parameter TT can be used for the evaluation of thoracic compensation. Greater preoperative TT might represent a decompensated state of TK. Rebalancing the TT in a sagittal neutral position might help to prevent PJK in patients with DLS.
Effect of Lumbar Fusion and Pelvic Fixation Rigidity on Hip Joint Stress
Authors: Kozaki Takuhei , Lundberg Hannah J. , Mell Steven P. , Samartzis Dino , Kawakami Mamoru , Yamada Hiroshi , Inoue Nozomu , An Howard S.
Published: August 2023

Study Design.

This study compared hip stress among different types of lumbopelvic fusion based on finite element (FE) analysis.

Objective.

We believe that the number and placement of S2 alar iliac (AI) screws and whether the screws loosen likely influence hip joint stress in the FE model.

Summary of Background Data.

Spinopelvic fixation has been shown to increase the risk of progression for hip joint osteoarthritis. The biomechanical mechanism is not well understood. We hypothesize that the rigid pelvic fixation may induce stress at adjacent joints.

Materials and Methods.

A three-dimensional nonlinear FE model was constructed from the L4 vertebra to the femoral bone. From the intact model, we made four fusion models, each with different lower vertebrae instrumentation: (1) intact, (2) L4-S1 fusion, (3) L4-S2 AI screw fixation, (4) L4-S2 AI screw fixation with S2 AI screw loosening, and (5) L4-S1 and dual sacral AI screw fixation. A compressive load of 400 N was applied vertically to the L4 vertebra, followed by an additional 10 Nm bending moment about different axes to simulate either flexion, extension, left lateral bending, or right axial rotation. The distal femoral bone was completely restrained. The von Mises stress and angular motion were analyzed across the hip joints within each fusion construct model.

Results.

Hip joint cartilage stress and range of motion increased for all postures as pelvic fixation became more rigid. The dual sacral AI screw fixation model increased stress and angular motion at the hip joint more than intact model. Our results suggest that more rigid fixation of the pelvis induces additional stress on the hip joint, which may precipitate or accelerate adjacent joint disease.

Conclusions.

Dual sacral AI fixation led to the highest stress while loosening of S2 AI decreased stress on the hip joint. This study illustrates that more rigid fixation among lumbosacral fusion constructs increases biomechanical stress on the hip joints.
Patient-specific Implants for Treating Atrophic Mandibles
Authors: Shilo Dekel , Capucha Tal , Blanc Ori , Shilo Yaacobi Dafna , Emodi Omri , Rachmiel Adi
Published: August 2023

Extremely atrophic mandibles are difficult to treat. Most patients choose to live with removable dentures. However, what if the atrophy is so extreme that spontaneous fractures occur? The objective of this report is to offer a single-stage augmentation method, which uses patient-specific crib-shaped implants (PSI) combined with autogenous free bone grafts. PSI were planned using three-dimensional (3D) segmentation and 3D virtual-planning software. Implants were designed according to the patient’s mandible with a mesh-like structure and included large holes for allowing blood supply recovery. During surgery, the PSI fitted perfectly. In cases exhibiting malposition of the mandibular fragments, repositioning was performed using 3D virtual planning. When repositioning mandibular segments, the PSI served as a guide for the correct positioning. Iliac-crest bone graft was harvested and fixed as an onlay over the residual mandibular basal bone. External approach was used to avoid contamination. Six months following surgery, fixation wires were removed, and dental implants were positioned in the newly formed bone. The PSI allowed for rigid fixation, thus leading to optimal incorporation of the iliac-crest bone graft. No further augmentation was required. Bony continuity for future stability and secession of the spontaneous fractures was achieved. Dental implants were placed effortlessly. Treating extremely atrophic mandibles is an entity of its own and is considered one of the most challenging in craniofacial reconstruction. It mostly requires multiple operations with high rates of failure. We offer a novel method of 3D mandibular reconstruction, both vertically and horizontally, showing promising results and achieving enough bone for further dental rehabilitation.
Measuring Platinum Levels in Hair in Women with Silicone Breast Implants and Systemic Symptoms
Authors: Spit K.A. , Azahaf S. , de Blok C.J.M. , Nanayakkara P.W.B.
Published: August 2023

Background:

It has been suggested that compounds present in silicone breast implants (eg, silicone particles or heavy metals such as platinum) migrate into the body and can cause systemic symptoms in susceptible women, causing what is known as breast implant illness. This pilot study investigates possible associations between hair platinum levels in patients with breast implants and breast implant illness, and evaluates its possible use for diagnostic purposes.

Methods:

Patients were included from the silicone outpatient clinic at Amsterdam University Medical Centre. Platinum concentration in hair samples of 10 women with breast implants and systemic symptoms (group A) was compared with that in 10 women with breast implants but no symptoms (group B), and a control group of 10 women without implants or symptoms (group C), using laser ablation inductively coupled plasma mass spectrometry. Radiological imaging was used to assess implant ruptures or silicone leakage.

Results:

A median platinum concentration of 0.09 μg per kg [IQR 0.04–0.15] was found in group A, 0.08 μg per kg [IQR 0.04–0.12] in group B, and 0.04 μg per kg [IQR 0.02–0.13] in group C, with no statistical significant difference between the groups (Kruskal-Wallis test, P = 0.43). No correlation between radiologically proven implant leakage and platinum level was found.

Conclusions:

There was no statistically significant difference in hair platinum levels in women with or without silicone breast implants or breast implant illness. Therefore, based on this pilot study, we do not recommend this test for clinical use. Given the small sample size, more research is required to fully assess its possible use for diagnostic purposes.
Predicting futility of upfront surgery in perihilar cholangiocarcinoma: Machine learning analytics model to optimize treatment allocation
Authors: Ratti Francesca , Marino Rebecca , Olthof Pim B. , Pratschke Johann , Erdmann Joris I. , Neumann Ulf P. , Prasad Raj , Jarnagin William R. , Schnitzbauer Andreas A. , Cescon Matteo , Guglielmi Alfredo , Lang Hauke , Nadalin Silvio , Topal Baki , Maithel Shishir K. , Hoogwater Frederik J.H. , Alikhanov Ruslan , Troisi Roberto , Sparrelid Ernesto , Roberts Keith J. , Malagò Massimo , Hagendoorn Jeroen , Malik Hassan Z. , Olde Damink Steven W.M. , Kazemier Geert , Schadde Erik , Charco Ramon , de Reuver Philip R. , Groot Koerkamp Bas , Aldrighetti Luca ,   The Perihilar Cholangiocarcinoma Collaboration Group
Published: August 2023

Background:

While resection remains the only curative option for perihilar cholangiocarcinoma, it is well known that such surgery is associated with a high risk of morbidity and mortality. Nevertheless, beyond facing life-threatening complications, patients may also develop early disease recurrence, defining a “futile” outcome in perihilar cholangiocarcinoma surgery. The aim of this study is to predict the high-risk category (futile group) where surgical benefits are reversed and alternative treatments may be considered.

Methods:

The study cohort included prospectively maintained data from 27 Western tertiary referral centers: the population was divided into a development and a validation cohort. The Framingham Heart Study methodology was used to develop a preoperative scoring system predicting the “futile” outcome.

Results:

A total of 2271 cases were analyzed: among them, 309 were classified within the “futile group” (13.6%). American Society of Anesthesiology (ASA) score ≥ 3 (OR 1.60; p = 0.005), bilirubin at diagnosis ≥50 mmol/L (OR 1.50; p = 0.025), Ca 19-9 ≥ 100 U/mL (OR 1.73; p = 0.013), preoperative cholangitis (OR 1.75; p = 0.002), portal vein involvement (OR 1.61; p = 0.020), tumor diameter ≥3 cm (OR 1.76; p < 0.001), and left-sided resection (OR 2.00; p < 0.001) were identified as independent predictors of futility. The point system developed, defined three (ie, low, intermediate, and high) risk classes, which showed good accuracy (AUC 0.755) when tested on the validation cohort.

Conclusions:

The possibility to accurately estimate, through a point system, the risk of severe postoperative morbidity and early recurrence, could be helpful in defining the best management strategy (surgery vs. nonsurgical treatments) according to preoperative features.
Centralization and democratization: Managing crisis communication in health care delivery
Authors: Hayirli Tuna C. , Stark Nicholas , Hardy James , Peabody Christopher R. , Kerrissey Michaela J.
Published: August 2023

Background

Communication is an essential organizational process for responding to adversity. Managers are often advised to communicate frequently and redundantly during crises. Nonetheless, systematic investigation of how information receivers perceive organizational communication amid crises has remained lacking.

Purpose

The aim of this study was to characterize features of effective internal crisis communication by examining how information-sharing processes unfolded during the initial stage of the COVID-19 pandemic.

Methodology

Between June and August 2020, we conducted 55 semistructured interviews with emergency department workers practicing in a variety of roles. We analyzed interview transcripts following constructivist constant comparative methods.

Results

Our findings revealed that at the onset of COVID-19 pandemic response, emergency department workers struggled with immense fear and anxiety amid high uncertainty and equivocality. Frequent and redundant communication, however, resulted in information delivery and uptake problems, worsening anxiety, and interpersonal tension. These problems were ameliorated by the emergence of contextual experts who centralized and democratized communication. Centralization standardized information received across roles, work schedules, and settings while decoupling internal communication from turbulence in the environment. Democratization made information accessible in a way that all could understand. It also ensured information senders’ receptiveness to feedback from information receivers. Centralization and democratization together worked to reduce sensed uncertainty and equivocality, which reduced anxiety and interpersonal tension.

Conclusion

Establishing frequent and redundant communication strategies does not necessarily address the anxiety and interpersonal tension produced by uncertainty and equivocality in crises.

Practice Implications

Centralization and democratization of crisis communication can reduce anxiety, improve coordination, and promote a safer workplace and patient care environment.
Clinical characteristics of neutropenic patients under antithyroid drug: Twelve-year experience in a medical center
Authors: Tseng Chih-Hsueh , Tseng Chi-Lung , Chen Harn-Shen , Chen Pei-Lung , Huang Chun-Jui
Published: August 2023

Background:

Thionamide-induced agranulocytosis (TiA) is a rare adverse event with a reported incidence of approximately 0.1% to 1.75%. Prompt recognition of TiA is critical to reduce the mortality rate. However, the differential diagnosis between cases of TiA and non-TiA neutropenia can be challenging due to the potential simultaneous involvement of other causes of neutropenia, such as concomitant chemotherapy, liver dysfunction, or infection. The aim of the present study was to investigate the possible factors associated with the development of TiA.

Methods:

This was a retrospective cohort study of patients treated with antithyroid drugs (ATDs) in Taipei Veterans General Hospital, Taipei, Taiwan, from 2006 to 2018. Patients who developed a neutropenic event during treatment with ATDs were identified from their medical records. The diagnosis of TiA was based on the following: (1) development of neutropenia during treatment or within 7 days after previous exposure to the same ATDs; (2) complete resolution of neutropenia within 1 month after discontinuation of the culprit drug with an absolute neutrophil count (ANC) >1500/μL; and (3) exclusion of other causes of neutropenia. The incidence and risk factors of TiA were analyzed and compared with those of non-TiA neutropenia.

Results:

Among 6644 patients treated with ATDs, 66 (mean age: 53 ± 15 years; 16.2% men) developed a neutropenic event and 20 were diagnosed with TiA (incidence: 0.3%). In the univariate analysis, compared with non-TiA neutropenia, TiA was associated with a lower Charlson Comorbidity Index, shorter treatment duration, lower cumulative ATD dosage, higher ATD dosage, higher ANC, and higher levels of free T4 at the time of the neutropenic event. In the multivariate logistic regression analysis, after adjusting for age, gender and the time to neutropenia, the cumulative ATD dose to neutropenia and ATD dosage at the time of the neutropenic event, Charlson Comorbidity Index, free T4 levels (odds ratio [OR], 4.44; 95% CI, 1.48-13.25), and ANC (OR, 1.00; 95% CI, 1.00-1.01) remained independently associated with TiA.

Conclusion:

Patients with TiA were more likely to have higher levels of free T4 and ANC at the time of the neutropenic event vs those with non-TiA neutropenia.
Urokinase administration for intraventricular hemorrhage in adults: A retrospective analysis of hemorrhage volume reduction and clinical outcomes
Authors: Li Chi-Ruei , Yang Meng-Yin , Cheng Wen-Yu , Tseng Huan-Chin , Lin Yi-Ying , Liu Yu-Hao , Shen Chiung-Chyi , Yen Chun-Ming
Published: August 2023

Background:

Intraventricular hemorrhage (IVH) is a type of ventricular bleeding that results in significant morbidity and mortality. Multiple studies have investigated the use of urokinase in IVH treatment. The use of urokinase may lead to higher rates of hematoma resolution and lower mortality rates. However, further studies are required to determine efficacy of urokinase administration. This study examined the association between urokinase use, IVH volume reduction, and clinical outcomes.

Methods:

In total, 94 adult patients with hypertensive intracerebral hemorrhage with ventricular extension or primary IVH were enrolled between 2015 and 2021. Participants were categorized into two groups: “EVD combined with fibrinolysis” and “EVD only.” The primary objective was to assess the reduction of IVH severity. Additionally, the study evaluated the functional outcomes and shunt dependency rate as secondary outcomes. Non-contrast computed tomography scans were obtained to measure the severity of IVH using the mGRAEB score. The main outcomes were the association among urokinase administration, reduced IVH severity, and functional outcomes.

Results:

There were no significant differences in the reduction rate of mGRAEB scores within a 7-day period (−50.0 [−64.4 to −32.5] % vs −44.2 [−59.3 to −7.9] %; p = 0.489). In addition, investigation of the third and fourth ventricles showed similar findings between the two groups. Urokinase treatment was not associated with significant differences in the modified Rankin Scale (5.0 (4.0–5.0) vs. 4.5 (4.0-5.0), p = 0.674) or shunt dependency rate (33.3% vs 39.3%, p = 0.58).

Conclusion:

This study found that intraventricular urokinase use in patients with IVH was not associated with reduced IVH severity. In addition, urokinase use was not associated with better functional outcomes or minor shunt dependency rates.
Views of Multiple Sclerosis Patients About Key Elements for a Decision Aid: A Qualitative Study
Authors: Robles-Sanchez Miguel-Angel , Moharra Montse , Bosch-Farré Cristina , Hernández-Leal María José , Montalban Xavier , Sastre-Garriga Jaume , Ramió-Torrentà Lluís , Bertran-Noguer Carme
Published: August 2023

BACKGROUND: Patients with multiple sclerosis (MS) may experience decisional conflict during treatment choice. Shared decision making (SDM), whereby patients and health professionals, primarily nurses, collaborate in making decisions, reduces this decisional conflict. It requires understanding large amounts of information and may be complex, especially when decisions affect patients' autonomy and quality and prolongation of life. Patient decision aids are tools in facilitating SDM. This study aimed to identify the key elements from the perspective of patients with relapsing-remitting MS to create a patient decision aid in the Spanish sociocultural context. METHODS: This is a qualitative study using focus groups led by a clinical nurse specialist. Semistructured interviews included healthcare needs and demands, the SDM process, and general characteristics of a peer support program. After the transcription of interview recordings, data were analyzed by thematic analysis and a constructivist naturalistic approach. RESULTS: Patients with MS (27) from Spain participated in 4 focus groups of 90 to 120 minutes each. Three overarching themes were identified: information access to sufficient high-quality data; knowledge of available treatment options, including efficacy, adverse effects, frequency, administration route, and the impact on daily life; decision-making role, engaged versus nonengaged patients. The former require support in facilitating their active involvement in decisions, whereas the latter prefer more passive health models. CONCLUSION: The needs identified by patients with relapsing-remitting MS regarding treatment choice in the Spanish setting align with those reported by other studies. The identified themes provide valuable information to design and develop a virtual patient decision aid jointly by clinical MS nurses and patients according to the International Patient Decision Aid Standards Collaboration criteria. This aid will help improve understanding between nurses and patients during SDM and facilitate the process.
Extracorporeal Membrane Oxygenation for Acute Respiratory Failure Due to COVID-19: A Multicenter Matched Cohort Study
Authors: Whitmore Sage P. , Cyr Katherine J. , Cohen Elliott S. , Schlauch Daniel J. , Gidwani Hitesh V. , Sterling Rachel K. , Castiglia Robert P. , Stell Owen T. , Jarzembowski Jamie L. , Kunavarapu Chandra R. , McRae Andrew T. , Dellavolpe Jeffrey D.
Published: August 2023

Mechanical ventilation for respiratory failure due to COVID-19 is associated with significant morbidity and mortality. Veno-venous extracorporeal membrane oxygenation (ECMO) is an attractive management option. This study sought to determine the effect of ECMO on hospital mortality and discharge condition in this population. We conducted a retrospective multicenter study to emulate a pragmatic targeted trial comparing ECMO to mechanical ventilation without ECMO for severe COVID-19. Data were gathered from a large hospital network database in the US. Adults admitted with COVID-19 were included if they were managed with ECMO or mechanical ventilation for severe hypoxemia and excluded if they had significant comorbidities or lacked functional independence on admission. The groups underwent coarsened exact matching on multiple clinical variables. The primary outcome was adjusted in-hospital mortality; secondary outcomes included ventilator days, intensive care days, and discharge destination. A total of 278 ECMO patients were matched to 2,054 comparison patients. Adjusted in-hospital mortality was significantly less in the ECMO group (38.8% vs. 60.1%, p < 0.001). Extracorporeal membrane oxygenation was associated with higher rates of liberation from mechanical ventilation, intensive care discharge, and favorable discharge destination. These findings support the use of ECMO for well-selected patients with severe acute respiratory failure due to COVID-19.
Cutaneous Neuroendocrine Mucinous Carcinomas Are Low-grade But May Be Associated With Other Cancers
Authors: Adkins Kathryn E. , Busam Klaus , Pulitzer Melissa
Published: August 2023

Primary cutaneous mucinous sweat gland carcinoma is said to be prognostically stratifiable by neuroendocrine differentiation, however, this assertion is based on historical data and older staining techniques. We aimed to evaluate the percentage of mucinous and nonmucinous adnexal tumors expressing the newer, more sensitive neuroendocrine marker insulinoma-associated protein 1 (INSM1), and to assess clinicopathologic features in patients cohorted by this phenotype. Of 12 available adnexal/cutaneous adenocarcinomas, 9 were mucinous, 3/9 of which were INSM1-negative, and 2/3 with nodal metastases. Of 3 nonmucinous cases, all were INSM1-negative, 1/3 with nodal metastasis, and 2/3 with lymphovascular invasion. In contrast, of 6 mucinous INSM1-positive cases, no cases had LVI or metastasis, however, 3 patients died during follow-up, 2 from breast or urothelial cancer. A fourth patient developed breast carcinoma. INSM1-positive tumors, from cheek (3), scalp (2), and chin (1) were estrogen receptor and progesterone receptor positive. No cases of apocrine adenoma or hidrocystoma, basal cell, or sebaceous carcinoma labeled with INSM1. While most primary cutaneous mucinous carcinomas are of the neuroendocrine type, our study confirms the presence of occasional non-neuroendocrine mucinous carcinomas. We validate the association of such tumors and nonmucinous non-neuroendocrine adnexal carcinoma with intermediate-grade behavior, including lymph node metastases, but not death. Conversely, neuroendocrine expressing primary cutaneous mucinous carcinoma may represent the well-differentiated neuroendocrine neoplasm/neuroendocrine tumor primary to skin, with low-grade behavior, but attendant risk of germline susceptibility to other aggressive extracutaneous tumors. Routine assessment of cutaneous adnexal carcinoma with INSM1 and longer term follow-up and cancer screening of patients with positive staining is recommended.
Social Regulation of the Neural Threat Response Predicts Subsequent Markers of Physical Health
Authors: Lin Jingrun , Namaky Nauder , Costello Meghan , Uchino Bert N. , Allen Joseph P. , Coan James A.
Published: August 2023

Objective

Social support has been linked to a vast range of beneficial health outcomes. However, the physiological mechanisms of social support are not well characterized. Drawing on functional magnetic resonance imaging and health-related outcome data, this study aimed to understand how neural measures of “yielding”—the reduction of brain activity during social support—moderate the link between social support and health.

Methods

We used a data set where 78 participants around the age of 24 years were exposed to the threat of shock when holding the hand of a partner. At ages 28 to 30 years, participants returned for a health visit where inflammatory activity and heart rate variability were recorded.

Results

Findings showed a significant interaction between dorsal anterior cingulate cortex–related yielding and perceived social support on C-reactive protein levels (β = −0.95, SE = 0.42, z = −2.24, p = .025, 95% confidence interval = −1.77 to −0.12). We also found a significant interaction between hypothalamus-related yielding and perceived social support on baseline heart rate variability (β = 0.51, SE = 0.23, z = 2.19, p = .028, 95% confidence interval = 0.05 to 0.97).

Conclusions

Greater perceived social support was associated with lower C-reactive protein levels and greater baseline heart rate variability among individuals who were more likely to yield to social support in the dorsal anterior cingulate cortex and hypothalamus years earlier. The current study highlights the construct of yielding in the link between social support and physical health.
Flight for fish in drug discovery: a review of zebrafish-based screening of molecules
Authors: Dash Surjya Narayan , Patnaik Lipika
Published: August 2023

Human disease and biological practices are modelled in zebrafish (Danio rerio) at various phases of drug development as well as toxicity evaluation. The zebrafish is ideal forin vivopathological research and high-resolution investigation of disease progress. Zebrafish has an advantage over other mammalian models, it is cost-effective, it has external development and embryo transparency, easy to apply genetic manipulations, and open to both forward and reverse genetic techniques. Drug screening in zebrafish is suitable for target identification, illness modelling, high-throughput screening of compounds for inhibition or prevention of disease phenotypes and developing new drugs. Several drugs that have recently entered the clinic or clinical trials have their origins in zebrafish. The sophisticated screening methods used in zebrafish models are expected to play a significant role in advancing drug development programmes. This review highlights the current developments in drug discovery processes, including understanding the action of drugs in the context of disease and screening novel candidates in neurological diseases, cardiovascular diseases, glomerulopathies and cancer. Additionally, it summarizes the current techniques and approaches for the selection of small molecules and current technical limitations on the execution of zebrafish drug screening tests.
Skewed distribution of spines is independent of presynaptic transmitter release and synaptic plasticity, and emerges early during adult neurogenesis
Authors: Rößler Nina , Jungenitz Tassilo , Sigler Albrecht , Bird Alexander , Mittag Martin , Rhee Jeong Seop , Deller Thomas , Cuntz Hermann , Brose Nils , Schwarzacher Stephan W. , Jedlicka Peter
Published: August 2023

Dendritic spines are crucial for excitatory synaptic transmission as the size of a spine head correlates with the strength of its synapse. The distribution of spine head sizes follows a lognormal-like distribution with more small spines than large ones. We analysed the impact of synaptic activity and plasticity on the spine size distribution in adult-born hippocampal granule cells from rats with induced homo- and heterosynaptic long-term plasticity
in vivo
and CA1 pyramidal cells from Munc13–1/Munc13–2 knockout mice with completely blocked synaptic transmission. Neither the induction of extrinsic synaptic plasticity nor the blockage of presynaptic activity degrades the lognormal-like distribution but changes its mean, variance and skewness. The skewed distribution develops early in the life of the neuron. Our findings and their computational modelling support the idea that intrinsic synaptic plasticity is sufficient for the generation, while a combination of intrinsic and extrinsic synaptic plasticity maintains lognormal-like distribution of spines.
Reproductive and environmental traits explain the variation in egg size among Medusozoa (Cnidaria)
Authors: García-Rodríguez Jimena , Cunha Amanda Ferreira , Morales-Guerrero Adriana , González-Chaves Adrian , Camacho Agustín , Miranda Lucília Souza , Serrano Filipe C. , Jaimes-Becerra Adrian , Marques Antonio Carlos
Published: August 2023

Medusozoa (Cnidaria) are characterized by diverse life cycles, with different semaphoronts (medusa, medusoid, fixed gonophore, polyp) representing the sexual phase and carrying the gametes. Although egg size is often considered a proxy to understand reproductive and developmental traits of medusozoans, understanding of the processes influencing egg size variation in the group under an evolutionary context is still limited. We carried out a comprehensive review of the variation of egg size in Medusozoa to test whether this variation is related to biological/sexual or environmental traits. Egg size presents a strong phylogenetic signal (λ= 0.79,K= 0.67), explaining why closely related species with different reproductive strategies and different individual sizes have similar egg sizes. However, variation in egg size is influenced by the number of eggs, depth and temperature, with larger eggs frequently present in species with few eggs (1–15), in deep-sea species and in cold-water species. Conversely, the production of small eggs among cold-water species of Staurozoa might be associated with the development of a small benthic larvae in this group. Our study reinforces that egg sizes respond to reproductive and environmental traits, although egg size is highly conserved within medusa classes.
Particulate matter concentration in Davao City airshed and its trend over the years
Authors: Anunciado Marife B.
Published: August 2023

Davao City airshed was selected for air quality mapping using particulate matter (PM) concentrations. PM data were taken from the regulatory office, Environmental Management Bureau XI, from 2016 to 2021 to understand annual variation and determine trends that may be attributed to seasonal changes in the region. PM concentrations were spatially interpolated using Inverse distance weighting (IDW) feature, an interpolation technique of ArcGIS. PM concentration and distribution over the years showed no similar patterns, both for PM10and PM2.5. No annual similarities of PM concentration were observed, and distribution varies yearly. No seasonal trends were shown on the interpolated maps for PM. However, there was an overall PM concentration decrease and distribution covered fewer affected areas over time. PM concentration in 2016 were generally at a level within the defined limit of NAAQGV except for some AQMS locations and years but sparingly exceeding the NAAQGV limit over time. Results show that PM emissions were lower suggesting a possible success on the regulation policies in the Davao City airshed through reduction or better management of air pollutant emissions.
Sensitization of meningeal afferents to locomotion-related meningeal deformations in a migraine model
Authors: Blaeser Andrew S , Zhao Jun , Sugden Arthur U , Carneiro-Nascimento Simone , Andermann Mark L , Levy Dan
Published: August 2023

Migraine headache is hypothesized to involve the activation and sensitization of trigeminal sensory afferents that innervate the cranial meninges. To better understand migraine pathophysiology and improve clinical translation, we used two-photon calcium imaging via a closed cranial window in awake mice to investigate changes in the responses of meningeal afferent fibers using a preclinical model of migraine involving cortical spreading depolarization (CSD). A single CSD episode caused a seconds-long wave of calcium activation that propagated across afferents and along the length of individual afferents. Surprisingly, unlike previous studies in anesthetized animals with exposed meninges, only a very small afferent population was persistently activated in our awake mouse preparation, questioning the relevance of this neuronal response to the onset of migraine pain. In contrast, we identified a larger subset of meningeal afferents that developed augmented responses to acute three-dimensional meningeal deformations that occur in response to locomotion bouts. We observed increased responsiveness in a subset of afferents that were already somewhat sensitive to meningeal deformation before CSD. Furthermore, another subset of previously insensitive afferents also became sensitive to meningeal deformation following CSD. Our data provides new insights into the mechanisms underlying migraine, including the emergence of enhanced meningeal afferent responses to movement-related meningeal deformations as a potential neural substrate underlying the worsening of migraine headache during physical activity.
ProjectSVR: Mapping single-cell RNA-seq data to reference atlases by supported vector regression
Authors: Gao Jianing , Guo Shipeng , Zhang Yuanwei
Published: August 2023

The rapid accumulation of public single-cell RNA-seq (scRNA-seq) data and advances in integration algorithms make it possible to build the organ and body-scale cell atlases after overcoming the batch effect originating from different studies, donors, and sequence platforms. However, projecting the query cells onto the carefully constructed reference atlas to rapidly interpret cell states remains challenging. Here, we present ProjectSVR (https://github.com/jarninggau/ProjectSVR), a machine learning-based algorithm for mapping the query cells onto well-constructed reference embeddings. We demonstrate the effectiveness of ProjectSVR in multiple case studies of different tissue and experimental design, including (1) interpreting the decidual immune microenvironment from recurrent pregnancy loss (RPL) patients, (2) resolving the tumor-infiltrated T cell states from patients receiving anti-PD1 treatment, (3) mapping the genetic-perturbed mouse germ cells to integrated mouse testicular cell atlas (mTCA) for inferring their arrested developmental stage, and (4) evaluating in vitro induced meiosis by via mapping the induced germ cells onto mTCA. Taken together, our results show that ProjectSVR is a useful tool for reference mapping and make the scRNA-seq data analysis more convenient when well-annotated atlases emerge.
Pseudomonas Putida Dynamics of Adaptation under Prolonged Resource Exhaustion
Authors: Gross Jonathan , Katz Sophia , Hershberg Ruth
Published: August 2023

Many non-sporulating Bacterial species survive prolonged resource exhaustion, by entering a state termed long-term stationary phase (LTSP). Here, we performed LTSP evolutionary experiments on the bacteriumPseudomonas putida, followed by whole genome sequencing of evolved clones. We show thatP. putidais able to persist and adapt genetically under LTSP. We observed a gradual accumulation of mutations within the evolvingP. putidapopulations. Within each population, independently evolving lineages are established early on and persist throughout the four-month-long experiment. Mutations accumulate in a highly convergent manner, with similar loci being mutated across independently evolving populations. Across populations, mutators emerge, that due to mutations within mismatch repair genes developed a much higher rate of mutation than other clones with which they co-existed within their respective populations. While these general dynamics of the adaptive process are quite similar to those we previously observed in the model bacteriumEscherichia coli, the specific loci that are involved in adaptation only partially overlap betweenP. putidaandE. coli.

Significance statement

Bacteria often face conditions of prolonged nutrient limitation, following periods of growth. One strategy for dealing with this challenge is entry into a state termed long-term stationary phase (LTSP), in which a small minority of cells within a population can survive and persist, by recycling the remains of their deceased brethren. Here, we broaden our understanding of adaptation under LTSP, by studying it in the bacteriumPseudomonas putida. We show that many of the dynamics of LTSP genetic adaptation are quite general, as reflected by great similarity to what was previously observed in the model bacteriumEscherichia coli. However, the specific loci that are involved in adaptation substantially vary betweenP. putidaandE. coli.
Propagation of neuronal micronuclei regulates microglial states
Authors: Yano Sarasa , Asami Natsu , Kishi Yusuke , Kubotani Hikari , Hattori Yuki , Kitazawa Ayako , Hayashi Kanehiro , Kubo Ken-ichiro , Saeki Mai , Maeda Chihiro , Akiyama Kaito , Okajima-Takahashi Tomomi , Sato Ban , Gotoh Yukiko , Nakajima Kazunori , Ichinohe Takeshi , Nagata Takeshi , Chiba Tomoki , Tsuruta Fuminori
Published: August 2023

Microglia, resident immune cells in the central nervous system, undergo morphological and functional changes in response to signals from the local environment and mature into various homeostatic states. However, niche signals underlying microglial development and maturation remain largely unknown. In this study, we show that neuronal micronuclei propagate microglia, followed by changing microglial states during the postnatal period. We discovered that neurons passing through a dense region of the developing neocortex give rise to micronuclei and release them into the extracellular space. Moreover, neuronal micronuclei were incorporated into microglia and affected morphological changes. Loss of thecGASgene alleviates effects on micronucleus-dependent morphological changes. Notably, neuronal micronuclei-harboring microglia exhibit unique transcriptome signatures. These results demonstrate that neuronal micronuclei serve as niche signals that produce novel microglial states. Our findings provide a potential mechanism for regulating the microglial state in the early-postnatal neocortex.
IN VIVOISOLATION OF A QUIESCENT MELANOMA POPULATION WITH INVASIVE PROPERTIES UNVEILS A TRANSCRIPTIONAL REPROGRAMMING DRIVEN BY THE TUMOR NICHE
Authors: Fiorenza Lotti , Marine Meliksetyan , Marco Malferrari , Nicolò Quaresima , Stefania Rapino , Velia Mollo , Ilaria Ferrarotto , Thalia Vlachou , Daniela Bossi , Giuseppe Pelicci Pier , Lucilla Luzi , Luisa Lanfrancone
Published: August 2023

Melanoma is a heterogeneous tumor composed of many interacting cellular populations and highly plastic melanoma cells that pass through distinct cell states to adapt to the surrounding microenvironment. Slow cycling is a transient state that defines a minor population of cells with cancer-initiating features. These cells are enriched upon drug therapy and can trigger cancer relapse and metastasis dissemination when they acquire proliferative potential. This population is still not entirely characterized.

Here we provide evidence of the existence of a slow cycling melanoma population isolatedin vivofrom melanoma PDXs using the H2B-GFP system. These cells display a highly invasive phenotype and are able to dynamically respond to cancer microenvironmental stimuli. Single cell transcriptomic analysis unveils a significant transcriptional heterogeneity of GFP-retaining slow cycling cells, defining a quiescent subpopulation of cells. These cells show a different phenotype in primary tumors and matched metastases, suggesting that tumor niche pressure drives a transcriptional reprogramming of quiescent cells during melanoma progression.
NK cell-induced damage toP.falciparum-infected erythrocytes requires ligand-specific recognition and releases parasitophorous vacuoles that are phagocytosed by monocytes in the presence of immune IgG
Authors: Sekar Padmapriya , Rajagopalan Sumati , Shabani Estela , Kanjee Usheer , Schureck Marc A. , Arora Gunjan , Peterson Mary E. , Traore Boubacar , Crompton Peter D. , Duraisingh Manoj T. , Desai Sanjay A. , Long Eric O.
Published: August 2023

Natural killer (NK) cells lyse virus-infected cells and transformed cells through polarized delivery of lytic effector molecules into target cells. We have shown that NK cells lysePlasmodium falciparum-infected red blood cells (iRBC) via antibody-dependent cellular cytotoxicity (ADCC). A high frequency of adaptive NK cells, with elevated intrinsic ADCC activity, in people chronically exposed to malaria transmission is associated with reduced parasitemia and resistance to disease. How NK cells bind to iRBC and the outcome of iRBC lysis by NK cells has not been investigated. We applied gene ablation in inducible erythrocyte precursors and antibody-blocking experiments with iRBC to demonstrate a central role of CD58 and ICAM-4 as ligands for adhesion by NK cells via CD2 and integrin αMβ2, respectively. Adhesion was dependent on opsonization of iRBC by IgG. Live imaging and quantitative flow cytometry of NK-mediated ADCC toward iRBC revealed that damage to the iRBC plasma membrane preceded damage toP. falciparumwithin parasitophorous vacuoles (PV). PV were identified and tracked with aP.falciparumstrain that expresses the PV membrane-associated protein EXP2 tagged with GFP. After NK-mediated ADCC, PV were either found inside iRBC ghosts or released intact and devoid of RBC plasma membrane. Electron microscopy images of ADCC cultures revealed tight NK–iRBC synapses and free GFP+vesicles similar to GFP+PV isolated from iRBC lysates by cell sorting. The titer of IgG in plasma of malaria-exposed individuals that bound PV was two orders of magnitude higher than IgG that bound iRBC. This immune IgG stimulated efficient phagocytosis of PV by primary monocytes. The selective NK-mediated damage to iRBC, resulting in release of PV, and subsequent phagocytosis of PV by monocytes may combine for efficient killing and removal of intra-erythrocyticP.falciparumparasite. This mechanism may mitigate the inflammation and malaria symptoms during blood-stageP. falciparuminfection.