bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality, Revascularization, and Cardioprotective Pharmacotherapy After Acute Coronary Syndrome in Patients With Severe Mental Illness: A Systematic Review and Meta-analysis
Authors: Chan Joe Kwun Nam , Chu Ryan Sai Ting , Hung Chun , Law Jenny Wai Yiu , Wong Corine Sau Man , Chang Wing Chung
Published: July 2022

Background and Hypothesis

People with severe mental illness (SMI) may experience excess mortality and inequitable treatment following acute coronary syndrome (ACS). However, cardioprotective pharmacotherapy and SMI diagnoses other than schizophrenia are rarely examined in previous reviews. We hypothesized that SMI including bipolar disorder (BD) is associated with increased post-ACS mortality, decreased revascularization, and cardioprotective medication receipt relative to those without SMI.

Study Design

We performed a meta-analysis to quantitatively synthesize estimates of post-ACS mortality, major adverse cardiac events (MACEs), and receipt of invasive coronary procedures and cardioprotective medications in patients with SMI, comprising schizophrenia, BD, and other nonaffective psychoses, relative to non-SMI counterparts. Subgroup analyses stratified by SMI subtypes (schizophrenia, BD), incident ACS status, and post-ACS time frame for outcome evaluation were conducted.

Study Results

Twenty-two studies were included (n = 12 235 501, including 503 686 SMI patients). SMI was associated with increased overall (relative risk [RR] = 1.40 [95% confidence interval = 1.21–1.62]), 1-year (1.68 [1.42–1.98]), and 30-day (1.26 [1.05–1.51]) post-ACS mortality, lower receipt of revascularization (odds ratio = 0.57 [0.49–0.67]), and cardioprotective medications (RR = 0.89 [0.85–0.94]), but comparable rates of any/specific MACEs relative to non-SMI patients. Incident ACS status conferred further increase in post-ACS mortality. Schizophrenia was associated with heightened mortality irrespective of incident ACS status, while BD was linked to significantly elevated mortality only in incident ACS cohort. Both schizophrenia and BD patients had lower revascularization rates. Post-ACS mortality risk remained significantly increased with mild attenuation after adjusting for revascularization.

Conclusions

SMI is associated with increased post-ACS mortality and undertreatment. Effective multipronged interventions are urgently needed to reduce these physical health disparities.
Effect of Gender-affirming Facial Feminization Surgery on Psychosocial Outcomes
Authors: Caprini Rachel M. , Oberoi Michelle K. , Dejam Dillon , Chan Candace H. , Potemra Hi’ilani M.K. , Morgan Katarina B.J. , Weimer Amy , Litwin Mark S. , Mendelsohn Abie H. , Lee Justine C.
Published: July 2022

Objective:

This study investigates the effect of gender-affirming facial feminization surgery (FFS) on psychosocial outcomes in patients with gender dysphoria.

Background:

Comprehensive analyses of psychosocial outcomes after gender-affirming FFS are absent in the literature resulting in a paucity of information on the impact of FFS on quality of life as well as ramifications in health insurance coverage of FFS.

Methods:

Scores from 11 validated, quantitative instruments from the Patient-Reported Outcomes Measurement Information System (PROMIS) assessing anxiety, anger, depression, global mental health, global physical health, satisfaction with sex life, positive affect, emotional support, social isolation, companionship, and meaning and purpose. Patients within the preoperative group (pre-FFS) were evaluated >30 days before surgery and patients within the postoperative group (post-FFS) were evaluated ≥10 weeks after surgery.

Results:

A total of 169 patients [mean (SD) age, 33.5 (10.8) years] were included. Compared with the pre-FFS group (n=107), the post-FFS group (n=62) reported improved scores anxiety (56.8±8.8 vs 60.1±7.9, P=0.01), anger (47.4±7.6 vs 51.2±9.6, P=0.01), depression (52.2±9.2 vs 57.0±8.9, P=0.001), positive affect (46.6±8.9 vs 42.9±8.7, P=0.01), meaning and purpose (49.9±10.7 vs 46.2±10.5, P=0.03), global mental health (46.7±7.6 vs 43.1±9.2, P=0.01), and social isolation (52.2±7.5 vs 55.4±7.4, P=0.01). Multivariable analysis to account for the effects of other gender-affirming surgeries, hormone therapy duration, preexisting mental health diagnoses, socioeconomic disparities, and patient-reported quality of social relationships on psychosocial functioning demonstrated that completion of FFS was independently predictive of improved scores.

Conclusions:

Gender-affirming FFS improves the quality of life by multiple psychosocial domains in transfeminine patients.
Completion Pancreatectomy After Pancreatoduodenectomy
Authors: Loos Martin , König Anna-Katharina , von Winkler Nikolai , Mehrabi Arianeb , Berchtold Christoph , Müller-Stich Beat P. , Schneider Martin , Hoffmann Katrin , Kulu Yakup , Feisst Manuel , Hinz Ulf , Lang Matthias , Goeppert Benjamin , Albrecht Thomas , Strobel Oliver , Büchler Markus W. , Hackert Thilo
Published: July 2022

Objective:

The objective of this study was to identify the indications for and report the outcomes of completion pancreatectomy (CPLP) in the postoperative course after pancreatoduodenectomy (PD).

Background:

CPLP may be considered or even inevitable for damage control after PD.

Methods:

A prospectively maintained database of all patients undergoing PD between 2001 and 2019 was searched for patients who underwent CPLP in the postoperative course after PD. Baseline characteristics, perioperative details, and outcomes of CPLP patients were analyzed and specific indications for CPLP were identified.

Results:

A total of 3953 consecutive patients underwent PD during the observation period. CPLP was performed in 120 patients (3%) after a median of 10 days following PD. The main indications for CPLP included postpancreatectomy acute necrotizing pancreatitis [n=47 (39%)] and postoperative pancreatic fistula complicated by hemorrhage [n=41 (34%)] or associated with uncontrollable leakage of the pancreatoenteric anastomosis [n=23 (19%)]. The overall 90-day mortality rate of all 3953 patients was 3.5% and 37% for patients undergoing CPLP.

Conclusions:

Our finding that only very few patients (3%) need CPLP suggests that conservative, interventional, and organ-preserving surgical measures are the mainstay of complication management after PD. Postpancreatectomy acute necrotizing pancreatitis, uncontrollable postoperative pancreatic fistula, and fistula-associated hemorrhage are highly dangerous and represent the main indications for CPLP after PD.
Translating Telemedicine to Thoracic Surgical Oncological Care: Performance Analysis and Patient Perceptions During the COVID-19 Pandemic
Authors: Harrington Caitlin A. , Hsu Meier , Tan Kay See , Medina Benjamin , Boerner Thomas , Adusumilli Prasad S. , Bains Manjit S. , Bott Matthew J. , Isbell James M. , Park Bernard J. , Sihag Smita , Rusch Valerie W. , Jones David R. , Rocco Gaetano , Molena Daniela
Published: July 2022

Objective:

The objective is to determine how the COVID-19 pandemic affected care for patients undergoing thoracic surgery for cancer.

Background:

The COVID-19 pandemic accelerated the adoption of telemedicine.

Methods:

Characteristics and outcomes of new patients seen between March 1 and June 30, 2019, and the same period in 2020 were compared. Patients who did not undergo surgery were excluded. Patients who had a telemedicine visit (new and established) in the 2020 period were asked to complete a survey.

Results:

In total, 624 new patients were seen in 2019 versus 299 in 2020 (52% reduction); 45% of patients (n=136) in 2020 were seen via telemedicine. There was no statistically significant difference in time to surgery, pathological upstaging, or postsurgical complications between 2019 and 2020. In total, 1085 patients (new and established) had a telemedicine visit in 2020; 239 (22%) completed the survey. A majority replied that telemedicine was equivalent to in-person care (77%), did not impair care quality (84%), resulted in less stress (69%) and shorter waits (86%), was more convenient (92%), saved money and commuting time (93%), and expanded who could attend visits (91%). Some patients regretted the loss of human interaction (71%). Most would opt for telemedicine after the pandemic (60%), although some would prefer in-person format for initial visits (55%) and visits with complex discussions (49%). Only 21% were uncomfortable with the telemedicine technology.

Conclusions:

Telemedicine enabled cancer care to continue during the COVID-19 pandemic without delays in surgery, cancer progression, or worsened postoperative morbidity and was generally well received.
Telehealth treatment for gambling disorder in the COVID-19 era: seismic shifts and silver linings
Authors: Smith Nathan D.L. , Jones Galen M. , Lucia Mark B.
Published: July 2022

Purpose of review

Gambling disorder is a serious mental health condition and the only behavioral addiction currently recognized by the American Psychiatric Association. Though prevalence and treatment seeking for gambling disorder have been stable for decades, the global COVID-19 pandemic has created a seismic shift in societal factors that influence gambling disorder and treatment availability. At the same time, the increasing availability of telehealth therapy for gambling disorder offers a new way to provide specialized treatment nationwide.

Recent findings

The present review discusses the seismic shifts in underlying risk factors, gambling availability, and reduced access to treatment. It also covers the emergence of telehealth treatment for gambling disorder, including its benefits and pitfalls.

In separate commentaries, several experts hypothesized that the pandemic was likely to increase mental health risk factors in society such as social isolation, job loss, and stress. In addition, access to online gambling also increased, while countries that locked down more strictly (like Singapore) saw a reduction in terrestrial gambling, countries that did not lock down strictly (like Sweden) did not see changes in gambling behavior. Telehealth was almost universally recommended as a good option for treatment in the studies we reviewed, though proper training and staffing are needed for telehealth to prove effective. Gambling disorder was only included in nationwide addiction telehealth programs in two countries.
Synapses, predictions, and prediction errors: a neocortical computational study of MDD using the temporal memory algorithm of HTM
Authors: Sherif Mohamed A. , Khalil Mostafa Z. , Shukla Rammohan , Brown Joshua C. , Carpenter Linda L.
Published: July 2022

Background

Synapses and spines are central in major depressive disorder (MDD) pathophysiology, recently highlighted by ketamine’s and psilocybin’s rapid antidepressant effects. The Bayesian brain and interoception perspectives formalize MDD as being “stuck” in affective states constantly predicting negative energy balance. We examined how synaptic atrophy relates to the predictive function of the neocortex and thus to symptoms, using temporal memory (TM), an unsupervised machine-learning algorithm. TM represents a single neocortical layer, learns in real-time using local Hebbian-learning rules, and extracts and predicts temporal sequences.

Methods

We trained a TM model on random sequences of upper-case alphabetical letters, representing sequences of affective states. To model depression, we progressively destroyed synapses in the TM model and examined how that affected the predictive capacity of the network.

Results

Destroying 50% of the synapses slightly reduced the number of predictions, followed by a marked drop with further destruction. However, reducing the synapses by 25% dropped the confidence in the predictions distinctly. So even though the network was making accurate predictions, the network was no longer confident about these predictions.

Conclusions

These findings explain how interoceptive cortices could be stuck in limited affective states with high prediction error. Growth of new synapses, e.g., with ketamine and psilocybin, would allow representing more futuristic predictions with higher confidence. To our knowledge, this is the first study to use the TM model to connect changes happening at synaptic levels to the Bayesian formulation of psychiatric symptomatology, making it possible to understand treatment mechanisms and possibly, develop new treatments.

Graphical abstract
Revealing Individual Neuroanatomical Heterogeneity in Alzheimer’s Disease
Authors: Verdi Serena , Kia Seyed Mostafa , Yong Keir , Tosun Duygu , Schott Jonathan M. , Marquand Andre F. , Cole James H. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2022

Alzheimer’s disease is clinically heterogeneous, in symptom profiles, progression rates and outcomes. This clinical heterogeneity is linked to underlying neuroanatomical heterogeneity. To explore this, we employed the emerging technique of neuroanatomical normative modelling to index regional patterns of variability in cortical thickness in individual patients from the large multi-site Alzheimer’s Disease Neuroimaging Initiative. We aimed to characterise individual differences and outliers in cortical thickness in patients with Alzheimer’s disease, people with mild cognitive impairment and cognitively normal controls. Furthermore, we assessed the relationships between cortical thickness heterogeneity and cognitive function, amyloid-beta, tau, ApoE genotype. Finally, we examined whether individual neuroanatomical normative maps were predictive of conversion from mild cognitive impairment to diagnosed Alzheimer’s disease. Data on cortical thickness from the 148 brain regions of the Destrieux FreeSurfer atlas was obtained from T1-weighted MRI scans of 1492 participants scanned at 62 different sites. A neuroanatomical normative model was developed to index normal cortical thickness distributions using a separate healthy reference dataset (n= 33,072), employing hierarchical Bayesian regression to predict cortical thickness per region using age and sex. These regional normative models were then fine-tuned to the ADNI dataset after which cortical thickness z-scores per region were calculated, resulting in a z-score ‘map’ for each participant. Regions with z-scores < -1.96 were classified as outliers. Patients with Alzheimer’s disease had a median of 12 outlier regions out of a possible 148. Individual patterns of outlier regions were highly variable, with the highest overlap in the parahippocampal gyrus at only 47% of patients. For 62 regions, over 90% of these patients had cortical thicknesses within the normal range. Patients with Alzheimer’s disease had significantly more outlier regions than people with mild cognitive impairment or controls [F(2, 1022) = 95.39), P = 2.0 x ×10−16]. They were also statistically more dissimilar to each other than were people with mild cognitive impairment or cognitive normal controls [F(2, 1024) = 209.42, P = 2.2×10−16]. Having a greater number of outlier regions was associated with worse cognitive function, CSF protein concentrations and an increased risk of converting from mild cognitive impairment to Alzheimer’s disease within three years (HR =1.028, 95% CI[1.016,1.039], P =1.8 ×10−16). Individualised normative maps of cortical thickness highlight the heterogeneity of Alzheimer’s effects on the brain. Regional outlier estimates have the potential to be a marker of disease and could be used to track an individual’s disease progression or treatment response in clinical trials.
Neural population dynamics in dorsal premotor cortex underlying a reach decision
Authors: Boucher Pierre O , Wang Tian , Carceroni Laura , Kane Gary , Shenoy Krishna V , Chandrasekaran Chandramouli
Published: July 2022

We investigated if a dynamical systems approach could help understand the link between decision-related neural activity and decision-making behavior, a fundamentally unresolved problem. The dynamical systems approach posits that neural dynamics can be parameterized by a state equation that has different initial conditions and evolves in time by combining at each time step, recurrent dynamics and inputs. For decisions, the two key predictions of the dynamical systems approach are that 1) initial conditions substantially predict subsequent dynamics and behavior and 2) inputs should combine with initial conditions to lead to different choice-related dynamics. We tested these predictions by investigating neural population dynamics in the dorsal premotor cortex (PMd) of monkeys performing a red-green reaction time (RT) checkerboard discrimination task where we varied the sensory evidence (i.e., the inputs). Prestimulus neural state, a proxy for the initial condition, predicted poststimulus neural trajectories and showed organized covariation with RT. Furthermore, faster RTs were associated with faster pre- and poststimulus dynamics as compared to slower RTs, with these effects observed within a stimulus difficulty. Poststimulus dynamics depended on both the sensory evidence and initial condition, with easier stimuli and “fast” initial conditions leading to the fastest choice-related dynamics whereas harder stimuli and “slow” initial conditions led to the slowest dynamics. Finally, changes in initial condition were related to the outcome of the previous trial, with slower pre- and poststimulus population dynamics and RTs on trials following an error as compared to trials following a correct response. Together these results suggest that decision-related activity in PMd is well described by a dynamical system where inputs combine with initial conditions that covary with eventual RT and previous outcome, to induce decision-related dynamics.
epialleleR: an R/Bioconductor package for sensitive allele-specific methylation analysis in NGS data
Authors: Nikolaienko Oleksii , Lønning Per Eystein , Knappskog Stian
Published: July 2022

Low-level mosaic methylation of theBRCA1gene promoter occurs in 5–8% of healthy individuals and is associated with a significantly elevated risk of breast and ovarian cancer. Similar events may also affect other tumour suppressor genes, potentially being a significant contributor to cancer burden. While this opens a new area for translational research, detection of low-level mosaic epigenetic events requires highly sensitive and robust methodology for methylation analysis. We here present epialleleR, a computational framework for sensitive detection, quantification and visualisation of mosaic epimutations in methylation sequencing data. Analysing simulated and real data sets, we provide in-depth assessments of epialleleR performance, and show that linkage to epihaplotype data is necessary to detect low-level methylation events. The epialleleR is freely available athttps://github.com/BBCG/epialleleRandhttps://bioconductor.org/packages/epialleleR/as an open source R/Bioconductor package.
Concurrent gliomas in patients with multiple sclerosis
Authors: Sahm Katharina , Kessler Tobias , Eisele Philipp , Ratliff Miriam , Sperk Elena , König Laila , Breckwoldt Michael O. , Seliger Corinna , Mildenberger Iris , Schrimpf Daniel , Herold-Mende Christel , Zeiner Pia S. , Tabatabai Ghazaleh , Meuth Sven G. , Capper David , Bendszus Martin , von Deimling Andreas , Wick Wolfgang , Sahm Felix , Platten Michael
Published: July 2022

Background

Concurrent malignant brain tumors in patients with multiple sclerosis (MS) constitute a rare but paradigmatic phenomenon for studying neuroimmunological mechanisms from both molecular and clinical perspectives.

Methods

A multicenter cohort of 26 patients diagnosed with both primary brain tumors and multiple sclerosis was studied for disease localization, tumor treatment-related MS activity, and molecular characteristics specific for diffuse glioma in MS patients.

Results

MS neither predisposes nor protects from the development of gliomas. Patients with glioblastoma WHO grade IV without IDH mutations had a longstanding history of MS, whereas patients diagnosed with IDH-mutant astrocytoma WHO grade II received multiple sclerosis diagnosis mostly at the same time or later. Concurrent MS was associated with a lesser extent of tumor resection and a worse prognosis in IDH-mutant glioma patients (PFS 32 vs. 64 months, p=0.0206). When assessing tumor-intrinsic differences no distinct subgroup-defining methylation pattern was identified in gliomas of MS patients compared to other glioma samples. However, differential methylation of immune-related genetic loci including human leukocyte antigen locus on 6p21 and interleukin locus on 5q31 was found in MS patients vs. matched non-MS patients. In line, inflammatory disease activity increased in 42% of multiple sclerosis patients after brain tumor radiotherapy suggesting a susceptibility of multiple sclerosis brain tissue to pro-inflammatory stimuli such as ionizing radiation.

Conclusions

Concurrent low-grade gliomas should be considered in multiple sclerosis patients with slowly progressive, expansive T2/FLAIR lesions. Our findings of typically reduced extent of resection in MS patients and increased MS activity after radiation inform future treatment decisions.

Key points

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Disease history and sequence of diagnosis differ in MS patients with high-vs low-grade glioma

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Gliomas of MS patients harbor subtle methylation changes in immune-related genetic regions

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Brain tumor radiotherapy is followed by MS disease activity

Importance of the study

Immune escape is a hallmark of diffuse glioma, while inflammation is the underlying mechanism of multiple sclerosis. These opposing mechanisms concur in patients that suffer in parallel from multiple sclerosis and glioma. This study is the first to investigate the tumor characteristics, tumor treatment responses and effect on multiple sclerosis activity of a cohort of patients with both diseases. The data warrant caution in the interpretation of suspicious lesions in imaging and suggests risk loci for the observed detrimental effects of radiation specific to MS patients.
Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi
Authors: Wadhwa Bharti , Malhotra Vikas , Kerai Sukhyanti , Husain Farah , Pandey Nalini Bala , Saxena Kirti N , Singh Vinay , Quinn Tom M , Li Feng , Gaughan Erin , Shankar-Hari Manu , Mills Bethany , Antonelli Jean , Bruce Annya , Finlayson Keith , Moore Anne , Dhaliwal Kevin , Edwards Christopher
Published: July 2022

Background

In this phase 2 randomised placebo-controlled clinical trial, we hypothesised that blocking mineralocorticoid receptors with spironolactone in patients with COVID-19 is safe and may reduce illness severity.

Methods

Hospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50mg day 1, then 25mg once daily for 21 days) or standard care in a 2:1 ratio. Both groups received dexamethasone 6mg for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF).

Results

120 patients were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had lower aldosterone levels on day 7 and lower D-dimer levels on days 4 and 7 (day 7 D-dimer mean SpiroDex 1.15µg/mL, Dex 3.15 µg/mL, p = 0.0004). There was no increase in adverse events in patients receiving SpiroDex.Post hocanalysis demonstrated reduced clinical deterioration (pre specified as escalating to WHO OS category >4) in the SpiroDex group vs Dex group (5.4% vs 19.6%).

Conclusion

Low dose oral spironolactone in addition to dexamethasone was safe and reduced D-Dimer and aldosterone. Although time to recovery was not significantly reduced, fewer patients progressed to severe disease. Phase 3 randomised controlled trials with spironolactone should be considered.
Kinematic and neuromuscular characterization of cognitive involvement in gait control in healthy young adults
Authors: Lana Valentin , Frère Julien , Cabibel Vincent , Réguème Tristan , Lefèvre Nicolas , Vlamynck Elodie , Decker Leslie M.
Published: July 2022

The signature of cognitive involvement in gait control has rarely been studied using both kinematic and neuromuscular features. The present study aimed to address this gap. Twenty-four healthy young adults walked on an instrumented treadmill in a virtual environment under two optic flow conditions: normal (NOF) and perturbed (POF, continuous mediolateral pseudorandom oscillations). Each condition was performed under single-task and dual-task conditions of increasing difficulty (1-, 2-, 3-back). Subjective mental workload (raw NASA-TLX), cognitive performance (mean reaction time and d-prime), kinematic (steadiness, variability and complexity in the mediolateral and anteroposterior directions) and neuromuscular (duration and variability of motor primitives) control of gait were assessed. The cognitive performance and the number and composition of motor modules were unaffected by simultaneous walking, regardless of the optic flow condition. Kinematic and neuromuscular variability was greater under POF compared to NOF conditions. Young adults sought to counteract POF by rapidly correcting task-relevant gait fluctuations. The depletion of cognitive resources through dual-tasking led to reduced kinematic and neuromuscular variability and this occurred to the same extent regardless of simultaneous working memory (WM) load. Increasing WM load led to a prioritization of gait control in the mediolateral direction over the anteroposterior direction. The impact of POF on kinematic variability (step velocity) was reduced when a cognitive task was performed simultaneously, but this phenomenon was no modulated by WM load. Collectively, these results shed important light on how young adults adjust the processes involved in goal-directed locomotion when exposed to varying levels of task and environmental constraints.

NEW & NOTEWORTHY

The kinematic and neuromuscular signatures of cognitive involvement in gait control have rarely been studied jointly. We sought to address this issue using gait perturbation and dual-task paradigms. The protocol consisted of a fixed-speed treadmill walk to which visual and cognitive constraints were applied separately and together. The results revealed that young adults optimally regulated their gait to cope with these constraints by maintaining relatively stable muscle synergies and flexibly allocating attentional resources.
RORc expressing immune cells negatively regulate tertiary lymphoid structure formation and support their pro-tumorigenic functions
Authors: Cinnamon Einat , Stein Ilan , Zino Elvira , Rabinovich Stav , Shovman Yehuda , Schlesinger Yehuda , Salame Tomer-Meir , Reich-Zeliger Shlomit , Lotem Michal , Ben-Neriah Yinon , Parnas Oren , Pikarsky Eli
Published: July 2022

Tertiary lymphoid structures (TLSs) are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy. In liver cancer, TLSs have been reported to be pro-tumorigenic as they harbor tumor progenitor cells and nurture their growth. The processes involved in TLS development and the acquisition of a pro- or anti-tumorigenic phenotype in cancer are largely unknown. RORc expressing immune cells have been previously implicated in TLS formation, however we find that they are not necessary for TLS neogenesis in the context of inflammation-associated liver cancer. On the contrary, RORc expressing cells negatively regulate TLS formation, since in their absence TLSs form in excess. CD4 cells are essential for liver TLS formation whereas B cells are required for TLS formation specifically in the absence of RORc expressing cells. Importantly, in chronically inflamed livers lacking RORc expressing cells, TLSs become anti-tumorigenic, resulting in reduced tumor load. Comparing liver pro- and anti-tumorigenic TLSs by transcriptional, proteomic and immunohistochemical analyses, revealed enrichment of exhausted CD8 cells that retained effector functions as well as germinal center B cells and plasma cells in anti-tumorigenic TLSs. Cell depletion experiments revealed a role mainly for B cells in limiting tumor development, possibly via tumor directed antibodies. Thus, RORc expressing cells negatively regulate B cell responses, and facilitate the pro-tumorigenic functions of hepatic TLSs.
Predator-Prey Interactions Give Rise to Scale-Invariant Ecosystems
Authors: Salahshour Mohammad
Published: July 2022

A large body of empirical evidence has shown that scaling laws and power-law distributions are ubiquitous features of ecological systems. However, it is not clear what factors give rise to such universal regularities and how scaling laws and scale-invariant distributions relate to each other. Here, I show scaling laws can be a simple consequence of scale-invariant distributions, and both result from simple commonalities of apparently different ecosystems. I introduce a simple model of predator-prey interactions in which predators and prey move on a two-dimensional space in search of resources that they use to survive and reproduce. The model predicts predator-prey systems can be found in different phases: as primary resources increase, the system exhibits a series of consecutive transitions to different phases with equilibrium dynamics and top-down control of the food web, non-equilibrium dynamics with bottom-up control, or unstable dynamics. While unstable predator-prey dynamics can result in a homogeneous environment by enrichment of resources, resource heterogeneity restores the stability of the system. Scale-invariant group size distribution and a rich set of scaling laws result in the non-equilibrium phase. By developing a general theory, I argue scaling laws can result from the scale-invariance of group size distributions under broad conditions. While some of the scaling laws predicted by the model await empirical examination, consistently with a recently discovered empirical pattern, the model shows predator abundance and prey production show a sublinear scaling with prey abundance. The model links the nature of the control in the food web, prey’s and predators’ behavioral responses to each other, and their life histories. While in small densities, mass-action law holds, and a weak density dependence and top-down control follows, in large densities, a shelter effect - the benefit of living in groups for preys - plays a role and makes prey production non-invariant to density fluctuations. Due to higher density fluctuations in higher densities, prey per-capita production in large densities decreases. This leads to a longer lifespan and lower population turnover of prey, and a scale-invariant ecosystem with bottom-up control in large densities.
Regulation of hair cell and stomatal size by a hair-cell specific peroxidase in the grassBrachypodium distachyon
Authors: Nunes Tiago D. G. , Berg Lea S. , Slawinska Magdalena W. , Zhang Dan , Redt Leonie , Sibout Richard , Vogel John P. , Laudencia-Chingcuanco Debbie , Jesenofsky Barbara , Lindner Heike , Raissig Michael T.
Published: July 2022

The leaf epidermis is the outermost cell layer forming the interface between plants and the atmosphere that must both provide a robust barrier against (a)biotic stressors and facilitate carbon dioxide uptake and leaf transpiration1. To achieve these opposing requirements, the plant epidermis developed a wide range of specialized cell types such as stomata and hair cells. While factors forming these individual cell types are known2–5, it is poorly understood how their number and size is coordinated. Here, we identified a role forBdPRX76/BdPOX, a class III peroxidase, in regulating hair cell and stomatal size in the model grassBrachypodium distachyon. Inbdpoxmutants prickle hair cells were smaller and stomata were longer. Because stomatal density remained unchanged, the negative correlation between stomatal size and density was disrupted inbdpoxand resulted in higher stomatal conductance and lower intrinsic water-use efficiency.BdPOXwas exclusively expressed in hair cells suggesting thatBdPOXcell-autonomously promotes hair cell size and indirectly restricts stomatal length. Cell wall autofluorescence and lignin stainings indicated a role for BdPOX in lignification or crosslinking of related phenolic compounds at the hair cell base. Ectopic expression ofBdPOXin the stomatal lineage increased phenolic autofluorescence in guard cell walls and restricted stomatal elongation inbdpox. Together, we highlight a developmental interplay between hair cells and stomata that optimizes epidermal functionality. We propose that cell-type-specific changes disrupt this interplay and lead to compensatory developmental defects in other epidermal cell types.
Single cell multi-omic mapping of subclonal architecture and pathway phenotype in primary gastric and metastatic colon cancers
Authors: Bai Xiangqi , Lau Billy , Grimes Susan M. , Sathe Anuja , Ji Hanlee P.
Published: July 2022

Single cell genomics provides a high-resolution profile of intratumoral heterogeneity and subclonal structure in primary and metastatic tumors. Notably, metastases and therapeutic resistant tumors often originate from distinct subclones. These distinct cellular populations are an important contributor to adaptation and resistance to ongoing therapy. Single cell DNA-sequencing (scDNA-seq) defines subclones but does not provide biological information about cell types. Single cell RNA-sequencing (scRNA-seq) provides biological information but is less useful for identifying different subclones. The integrated scDNA-seq and scRNA-seq data from the same tumor cell population provides both subclone structure and biology. To understand the cellular genomic variation of different subclones in primary and metastatic cancers, we developed an approach to integrate multi-omics data from both types of single cells. This joint data set represented thousands of normal and tumor cells derived from a set of primary gastric and metastatic colorectal cancers. The extensive cellular sampling provided robust characterization of the subclonal architecture of gastric and colorectal cancers. We reconstructed the subclonal architecture using the cells in G0/G1 phase. The scDNA-seq provided a ground truth for copy number-based subclones. From the scRNA-seq data, the epithelial cells in G0/G1 were identified and assigned to specific subclones by a correlation algorithm based on gene dosage. The inferred CNV profiles from the scRNA-seq epithelial cells were assigned subclones identified from the scDNA-seq. Afterward, we determined the biological pathway activities of specific clones. Overall, integrative multi-omics analysis of single-cell datasets is more informative than any individual genomic modality, provides deep insights into the intratumoral heterogeneity, and reveals subclonal biology.
Status of Genome Function Annotation in Model Organisms and Crops
Authors: Xue Bo , Rhee Seung Y
Published: July 2022

Since entry into genome-enabled biology several decades ago, much progress has been made in determining, describing, and disseminating functions of genes and their products. Yet, this information is still difficult to access for many scientists and for most genomes. To provide easy access and graphical summary to the status of genome function annotation for model organisms and bioenergy and food crop species, we created a web application (https://genomeannotation.rheelab.org) to visualize, search, and download genome annotation data for 28 species. The summary graphics and data tables will be updated semi-annually and snapshots will be archived to provide a historical record of the progress of genome function annotation efforts. Clear and simple visualization of updated gene function annotation, including the extent of what is unknown, will help address the grand challenge of elucidating functions of all genes in organisms.
Monanthotaxis bali (Annonaceae) a new Critically Endangered (possibly extinct) montane forest treelet from Bali Ngemba, Cameroon
Authors: Cheek Martin , Darbyshire Iain , Onana Jean Michel
Published: July 2022

Monanthotaxis bali is the only known, solely montane (occurring solely above 2000 m alt.) species of the genus. It joins Monanthotaxis orophila (Rwanda) and M. discolor (Tanzania), two other species that can also occur above 2000 m alt. Monanthotaxis bali is an addition to the small number (28) of the tree species of the surviving montane forests of the Cameroon Highlands of which only eight other species are endemic.

Due to its supra-axillary inflorescences, and petals arranged in one whorl but with the outer petals overlapping the inner petals distally, and rounded flower buds, the new species is placed in Hoekstra’s clade B of Monanthotaxis. The new species is unusual in being a treelet in a predominantly lianescent genus, and in lacking the glaucous underside of the leaf-blades that usually characterises the genus. Monanthotaxis bali takes the number of continental African species of the genus to 80, and makes Cameroon, with 30 species, the most species-diverse country for the genus.

Monanthotaxis bali is known only from the Bali Ngemba Forest Reserve, a forest remnant under pressure of degradation and clearance in the Bamenda Highlands of Cameroon. It may already be extinct due to logging and agricultural activities. Here it is described, illustrated, mapped and assessed as Critically Endangered (Possibly Extinct) using the IUCN 2012 criteria.
CometAnalyser: a user-friendly, open-source deep-learning microscopy tool for quantitative comet assay analysis
Authors: Beleon Attila , Pignatta Sara , Arienti Chiara , Carbonaro Antonella , Horvath Peter , Martinelli Giovanni , Castellani Gastone , Tesei Anna , Piccinini Filippo
Published: July 2022

Comet assay provides an easy solution to estimate DNA damage in single cells through microscopy assessment. It is widely used in the analysis of genotoxic damages induced by radiotherapy or chemotherapeutic agents. DNA damage is quantified at the single-cell level by computing the displacement between the genetic material within the nucleus, typically called “comet head”, and the genetic material in the surrounding part of the cell, considered as the “comet tail”. Today, the number of works based on Comet Assay analyses is really impressive. In this work, besides revising the solutions available to obtain reproducible and reliable quantitative data, we developed an easy-to-use tool named CometAnalyser. It is designed for the analysis of both fluorescent and silver-stained wide-field microscopy images and allows to automatically segment and classify the comets, besides extracting Tail Moment and several other intensity/morphological features for performing statistical analysis. CometAnalyser is an open-source deep-learning tool. It works with Windows, Macintosh, and UNIX-based systems. Source code, standalone versions, user manual, sample images, video tutorial and further documentation are freely available at: https://sourceforge.net/p/cometanalyser.

HIGHLIGHTS

Comet assay provides an easy solution to estimate DNA damage in single cells.

Today, an impressive number of works are based on Comet Assay analyses, especially in the field of cancer research.

Comet assay was originally performed as a qualitative analysis.

None of the free tools today available work on both fluorescent- and silver-stained images.

We developed CometAnalyser, an open-source deep-learning tool designed for easy segmentation and classification of comets in fluorescent- and silver-stained images.
Zinc ions prevent α-synuclein aggregation by enhancing chaperone function of human serum albumin
Authors: Al-Harthi Samah , Kharchenko Vladlena , Mandal Papita , Gourdoupis Spyridon , Jaremko Lukasz
Published: July 2022

Metal ions present in cellular microenvironment have been implicated as drivers of aggregation of amyloid forming proteins. Zinc (Zn2+) ions have been reported to directly interact with α-synuclein (AS), a causative agent of Parkinson’s disease and other neurodegenerative diseases, and promote its aggregation. AS is a small intrinsically disordered protein (IDP) i.e., understanding molecular factors that drive its misfolding and aggregation has been challenging since methods used routinely to study protein structure are not effective for IDPs. Here, we report the atomic details of Zn2+ binding to AS at physiological conditions using proton-less NMR techniques that can be applied to highly dynamic systems like IDPs. We also examined how human serum albumin (HSA), the most abundant protein in human blood, binds to AS and whether Zn2+ and/or ionic strength affect this. We conclude that Zn2+ enhances the anti-aggregation chaperoning role of HSA that relies on protecting the hydrophobic N-terminal and NAC regions of AS, rather than polar negatively charged C-terminus. This suggested a previously undocumented role of Zn2+ in HSA function and AS aggregation.
miR targetome of primary human keratinocytes reveals a function for non-conserved binding sites
Authors: Thiagarajan Lalitha , Zhang Jingqing , Griffiths-Jones Sam , Kurinna Svitlana
Published: July 2022

The homeostasis of the human body is protected by the skin, where the process of keratinocyte differentiation in outer layers has a crucial role. Cessation of proliferation in the basal layer of keratinocytes and initiation of their subrabasal functions are tightly controlled at the level of gene transcription and message translation. A subset of mRNAs has to be repressed during differentiation, and microRNAs are known to contribute to this by directly binding mRNAs at the 3’UTRs. Using results of RNA sequencing from human primary keratinocytes during induced differentiation, we evaluated the predicted binding of highly, moderately, and lowly expressed miRs to their target mRNAs. We found that moderately expressed miRs can regulate more mRNAs, and that they do so using both conserved and non-conserved canonical binding. The cumulative score for the majority of repressed mRNAs revealed a surprisingly weak binding to miRs, and we found a significant contribution of non-conserved sites to the repression of the targets. While the presence of at least one conserved site was necessary for the miR function, its weak binding may be reinforced by a non-conserved site. Together, we found that the combination of conserved and non-conserved sites lower the binding threshold for miR-mRNA interactions to assume a tighter repression of the mRNA target during cell differentiation.
Serial crystallography with multi-stage merging of thousands of images
Authors: Soares Alexei S. , Yamada Yusuke , Jakoncic Jean , McSweeney Sean , Sweet Robert M. , Skinner John , Foadi James , Fuchs Martin R. , Schneider Dieter K. , Shi Wuxian , Andi Babak , Andrews Lawrence C. , Bernstein Herbert J.
Published: July 2022

KAMO and BLEND provide particularly effective tools to automatically manage the merging of large numbers of data sets from serial crystallography. The requirement for manual intervention in the process can be reduced by extending BLEND to support additional clustering options such as the use of more accurate cell distance metrics and the use of reflection-intensity correlation coefficients to infer `distances' among sets of reflections. This increases the sensitivity to differences in unit-cell parameters and allows clustering to assemble nearly complete data sets on the basis of intensity or amplitude differences. If the data sets are already sufficiently complete to permit it, one applies KAMO once and clusters the data using intensities only. When starting from incomplete data sets, one applies KAMO twice, first using unit-cell parameters. In this step, either the simple cell vector distance of the original BLEND or the more sensitive NCDist is used. This step tends to find clusters of sufficient size such that, when merged, each cluster is sufficiently complete to allow reflection intensities or amplitudes to be compared. One then uses KAMO again using the correlation between reflections with a common hkl to merge clusters in a way that is sensitive to structural differences that may not have perturbed the unit-cell parameters sufficiently to make meaningful clusters. Many groups have developed effective clustering algorithms that use a measurable physical parameter from each diffraction still or wedge to cluster the data into categories which then can be merged, one hopes, to yield the electron density from a single protein form. Since these physical parameters are often largely independent of one another, it should be possible to greatly improve the efficacy of data-clustering software by using a multi-stage partitioning strategy. Here, one possible approach to multi-stage data clustering is demonstrated. The strategy is to use unit-cell clustering until the merged data are sufficiently complete and then to use intensity-based clustering. Using this strategy, it is demonstrated that it is possible to accurately cluster data sets from crystals that have subtle differences.
Negative goodwill and postmerger operating performance: evidence from Japan
Authors: Amano Yoshiaki
Published: July 2022

Purpose

This study examines the relation between negative goodwill (NGW) and operating performance after mergers and acquisitions (M&A).

Design/methodology/approach

This is a comparative analysis of post-M&A operating performance for 228 transactions involving listed Japanese firms that generated negative or positive goodwill.

Findings

First, post-M&A operating performance is lower when the transaction generates NGW. Second, the negative relation between NGW and post-M&A performance is stronger when managers have incentives for earnings management and when target firms perform poorly before M&A. Third, changes in the accounting treatment of NGW alter the relative importance of earnings management incentives and target firms' poor pre-M&A performance.

Originality/value

Prior studies attribute the negative relation between NGW and post-M&A performance solely to acquiring firms' managers' earnings management incentives. The current study finds that the target firm's poor pre-M&A performance is also associated with the relation between NGW and post-M&A performance.
The role of perceived usefulness and annoyance on programmatic advertising: the moderating effect of Internet user privacy and cookies
Authors: Núnez-Barriopedro Estela , Cuesta-Valiño Pedro , Mansori-Amar Sara
Published: July 2022

Purpose

The study of the background to programmatic advertising is of great interest in the context of digital marketing. Therefore, the main aim of this research is to define a structural equation modelling (SEM) model, which allows studying the relationship between the usefulness and privacy of online ads to increase the effectiveness and efficiency of campaigns through the use of computation and big data.

Design/methodology/approach

A cross-sectional descriptive study based on the Web Browsers Survey was carried out on a sample of 24,062 Internet users by the Association for Media Research. The partial least squares structural equation modelling method (PLS-SEM) was applied to evaluate the model with the study constructs and test the hypotheses.

Findings

The result of this research allows us to know how perceived usefulness (U) and perceived annoyance (A) affect users' privacy concerns (P) and concerns about the storage and use of their data through cookies (C). The authors also seek if there is any relationship between privacy concerns (P) and cookies (C) on users' level of Internet usage (IU).

Originality/value

One of the novelties of this study is the consideration not only of Internet user perceptions but also their concerns about privacy and the use of cookies, as key variables in the strategic management of the use of programmatic advertising in digital marketing.