bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with cognitive impairment and cognitive concerns in patients with metastatic non-small cell lung cancer
Authors: Eggen Annemarie C , Richard Nadine M , Bosma Ingeborg , Jalving Mathilde , Leighl Natasha B , Liu Geoffrey , Mah Kenneth , Higazy Randa , Shultz David B , Reyners Anna K L , Rodin Gary , Edelstein Kim
Published: September 2021

Background

Knowledge regarding cognitive problems in metastatic non-small cell lung cancer (mNSCLC) is limited. Such problems may include both patient-reported cognitive concerns and demonstrable cognitive impairment. Greater understanding of these outcomes is needed to inform rehabilitation strategies for these difficulties. We aimed to identify the frequency of cognitive problems and associated factors in patients with mNSCLC.

Methods

In this cross-sectional study, adults with mNSCLC completed validated neuropsychological tests and self-report questionnaires measuring cognitive concerns, neurobehavioral concerns, depression, demoralization, illness intrusiveness, self-esteem, and physical symptoms. Cognitive impairment (performance based) was defined according to International Cancer and Cognition Task Force criteria. Clinically significant cognitive concerns were defined by a score ≥1.5 SD below the normative mean on the Functional Assessment of Cancer Therapy-Cognitive Function Perceived Cognitive Impairment (FACT-Cog PCI). Univariate and multivariate logistic regression analyses were performed to identify associated factors.

Results

Of 238 patients approached, 77 participated (median age: 62 years; range: 37-82). Brain metastases were present in 41 patients (53%), and 23 (29%) received cranial irradiation. Cognitive impairment and cognitive concerns were present in 31 (40%) and 20 patients (26%), respectively. Cognitive impairment and cognitive concerns co-occurred in 10 patients (13%), but their severity was unrelated. Cognitive impairment was associated with cranial irradiation (odds ratio [OR] = 2.89; P = .04), whereas cognitive concerns were associated with greater illness intrusiveness (OR = 1.04; P = .03) and lower self-esteem (OR = 0.86; P = .03).

Conclusions

Cognitive impairment and cognitive concerns are both common in patients with mNSCLC but are not necessarily related, and their risk factors differ. The association of illness intrusiveness and self-esteem with cognitive concerns can inform therapeutic interventions in this population.
Two plastid POLLUX ion channel-like proteins are required for stress-triggered stromal Ca2+release
Authors: Völkner Carsten , Holzner Lorenz Josef , Day Philip M , Ashok Amra Dhabalia , Vries Jan de , Bölter Bettina , Kunz Hans-Henning
Published: September 2021

Two decades ago, large cation currents were discovered in the envelope membranes of Pisum sativum L. (pea) chloroplasts. The deduced K+-permeable channel was coined fast-activating chloroplast cation channel but its molecular identity remained elusive. To reveal candidates, we mined proteomic datasets of isolated pea envelopes. Our search uncovered distant members of the nuclear POLLUX ion channel family. Since pea is not amenable to molecular genetics, we used Arabidopsis thaliana to characterize the two gene homologs. Using several independent approaches, we show that both candidates localize to the chloroplast envelope membrane. The proteins, designated PLASTID ENVELOPE ION CHANNELS (PEC1/2), form oligomers with regulator of K+ conductance domains protruding into the intermembrane space. Heterologous expression of PEC1/2 rescues yeast mutants deficient in K+ uptake. Nuclear POLLUX ion channels cofunction with Ca2+ channels to generate Ca2+ signals, critical for establishing mycorrhizal symbiosis and root development. Chloroplasts also exhibit Ca2+ transients in the stroma, probably to relay abiotic and biotic cues between plastids and the nucleus via the cytosol. Our results show that pec1pec2 loss-of-function double mutants fail to trigger the characteristic stromal Ca2+ release observed in wild-type plants exposed to external stress stimuli. Besides this molecular abnormality, pec1pec2 double mutants do not show obvious phenotypes. Future studies of PEC proteins will help to decipher the plant’s stress-related Ca2+ signaling network and the role of plastids. More importantly, the discovery of PECs in the envelope membrane is another critical step towards completing the chloroplast ion transport protein inventory.
Biochemical and molecular properties of LHCX1, the essential regulator of dynamic photoprotection in diatoms
Authors: Giovagnetti Vasco , Jaubert Marianne , Shukla Mahendra K , Ungerer Petra , Bouly Jean-Pierre , Falciatore Angela , Ruban Alexander V
Published: September 2021

Light harvesting is regulated by a process triggered by the acidification of the thylakoid lumen, known as nonphotochemical “energy-dependent quenching” (qE). In diatoms, qE is controlled by the light-harvesting complex (LHC) protein LHCX1, while the LHC stress-related (LHCSR) and photosystem II subunit S proteins are essential for green algae and plants, respectively. Here, we report a biochemical and molecular characterization of LHCX1 to investigate its role in qE. We found that, when grown under intermittent light, Phaeodactylum tricornutum forms very large qE, due to LHCX1 constitutive upregulation. This “super qE” is abolished in LHCX1 knockout mutants. Biochemical and spectroscopic analyses of LHCX1 reveal that this protein might differ in the character of binding pigments relative to the major pool of light-harvesting antenna proteins. The possibility of transient pigment binding or not binding pigments at all is discussed. Targeted mutagenesis of putative protonatable residues (D95 and E205) in transgenic P. tricornutum lines does not alter qE capacity, showing that they are not involved in sensing lumen pH, differently from residues conserved in LHCSR3. Our results suggest functional divergence between LHCX1 and LHCSR3 in qE modulation. We propose that LHCX1 evolved independently to facilitate dynamic tracking of light fluctuations in turbulent waters. The evolution of LHCX(-like) proteins in organisms with secondary red plastids, such as diatoms, might have conferred a selective advantage in the control of dynamic photoprotection, ultimately resulting in their ecological success.
Riboswitch-mediated inducible expression of an astaxanthin biosynthetic operon in plastids
Authors: Agrawal Shreya , Karcher Daniel , Ruf Stephanie , Erban Alexander , Hertle Alexander P , Kopka Joachim , Bock Ralph
Published: September 2021

The high-value carotenoid astaxanthin (3,3′-dihydroxy-β,β-carotene-4,4′-dione) is one of the most potent antioxidants in nature. In addition to its large-scale use in fish farming, the pigment has applications as a food supplement and an active ingredient in cosmetics and in pharmaceuticals for the treatment of diseases linked to reactive oxygen species. The biochemical pathway for astaxanthin synthesis has been introduced into seed plants, which do not naturally synthesize this pigment, by nuclear and plastid engineering. The highest accumulation rates have been achieved in transplastomic plants, but massive production of astaxanthin has resulted in severe growth retardation. What limits astaxanthin accumulation levels and what causes the mutant phenotype is unknown. Here, we addressed these questions by making astaxanthin synthesis in tobacco (Nicotiana tabacum) plastids inducible by a synthetic riboswitch. We show that, already in the uninduced state, astaxanthin accumulates to similarly high levels as in transplastomic plants expressing the pathway constitutively. Importantly, the inducible plants displayed wild-type–like growth properties and riboswitch induction resulted in a further increase in astaxanthin accumulation. Our data suggest that the mutant phenotype associated with constitutive astaxanthin synthesis is due to massive metabolite turnover, and indicate that astaxanthin accumulation is limited by the sequestration capacity of the plastid.
To the proteome and beyond: advances in single-cell omics profiling for plant systems
Authors: Clark Natalie M , Elmore James Mitch , Walley Justin W
Published: September 2021

Recent advances in single-cell proteomics for animal systems could be adapted for plants to increase our understanding of plant development, response to stimuli, and cell-to-cell signaling.
Presence and Correlation of Fusarium graminearum and Deoxynivalenol Accumulation in Silage Corn Plant Parts
Authors: Reed Hannah , Mueller Brian , Groves Carol L. , Smith Damon L.
Published: September 2021

Corn silage, made from Zea mays, is a high-energy feed that is important for feeding dairy cows. Plant diseases, such as those caused by Fusarium graminearum, can decrease silage corn yields and quality. F. graminearum (teleomorph Gibberella zeae) is an ascomycete fungus that causes Gibberella ear and stalk rot in corn. F. graminearum produces deoxynivalenol (DON), a secondary metabolite toxic to humans and animals. An understanding of the distribution of DON and F. graminearum throughout the corn plant is important for determining the quality of corn silage. A partitioned sample experiment that included two brown midrib silage hybrids and three fungicide treatments was conducted in research plots located in Arlington, WI, U.S.A., in 2018 and 2019. At harvest, stalk and ear parts were physically separated, dried, and ground for analysis. DON concentration (in parts per million) was determined using an enzyme-linked immunosorbent assay, and F. graminearum DNA concentration (in picograms per nanogram) was determined using quantitative PCR. DON and F. graminearum DNA were detected in all samples, demonstrating accumulation of the fungus in stalks and ears of the plant. In 2018, DON contamination was as high as 30 ppm and varied drastically between stalks and ears. In 2019, DON concentrations were much lower (<5 ppm), but were consistently higher in stalk samples than ear samples. Across all samples, DON concentrations and F. graminearum accumulation were highly correlated within the separated stalk (r = 0.78) and ear portions (r = 0.87) but were not correlated between ears and stalks. Depending on the weather and planting conditions in a given year, stalk infections or ear infections may occur by F. graminearum, leading to subsequent DON increases in those respective parts that are independent of each other.
Impact of Nerve Surgery on Opioid and Medication Use in Patients with Chronic Nerve Injuries
Authors: Felder John M. , Ducic Ivica
Published: September 2021

Introduction:

Limited information is available regarding the ability of nerve surgery to affect medication use patterns in patients with chronic pain or neuropathy due to nerve injury.

Methods:

A retrospective survey was distributed to all operative patients (N = 767) from a single nerve surgeon’s practice between 2014 and 2020. Data collected included demographics, specifics of the injury and symptoms, medication and opioid use before surgery, and medication/opioid use following surgery.

Results:

Out of the 767 patients, 209 (27.2%) completed the survey. Average age was 48.8 (SD = 19.1) years; 68.9% female and 31.1% male. More than 50% of the patients took at least three medications. More than 50% of the patients after surgery did not need medication or had significant reduction; 54.1% of the patients took opioid medication daily, and 97.3% of patients reported that narcotic medications did not resolve their problem. Patients rated the effectiveness (Likert scale 0–10) of opioid medications in general at an average 3.25 ± 2.03. Of patients who took opioids regularly, 61.6% reported a negative effect of these medications on daily or professional activities. After surgery, more than 50% of the patients did not need opioids or had a significant reduction in opioid usage.

Conclusions:

Untreated nerve injuries lead to ongoing chronic pain, explaining why medications are mostly ineffective in eliminating symptoms. In this study, nerve surgery targeting the anatomical source of symptoms effectively reduced both opioid and nonopioid medication use.
Effects of Prescription Opioid Use on Traumatic Brain Injury Risk in Older Adults
Authors: Herrera Anthony V. , Wastila Linda , Brown Jessica P. , Chen Hegang , Gambert Steven R. , Albrecht Jennifer S.
Published: September 2021

Objective:

The objective of this study was to estimate the risk of traumatic brain injury (TBI) associated with opioid use among older adult Medicare beneficiaries.

Setting:

Five percent sample of Medicare administrative claims obtained for years 2011-2015.

Participants:

A total of 50 873 community-dwelling beneficiaries 65 years and older who sustained TBI.

Design:

Case-crossover study comparing opioid use in the 7 days prior to TBI with the control periods of 3, 6, and 9 months prior to TBI.

Main Measures:

TBI cases were identified using ICD-9 (International Classification of Diseases, Ninth Revision) and ICD-10 (International Classification of Diseases, Tenth Revision) codes. Prescription opioid exposure and concomitant nonopioid fall risk–increasing drug (FRID) use were determined by examining the prescription drug event file.

Results:

The 8257 opioid users (16.2%) were significantly younger (mean age 79.0 vs 80.8 years, P < .001). Relative to nonusers, opioid users were more likely to be women (77.0% vs 70.0%, P < .001) with a Charlson Comorbidity Index of 2 or more (43.7% vs 30.9%, P < .001) and higher concomitant FRID use (94.0% vs 82.7%, P < .001). Prescription opioid use independently increased the risk of TBI compared with nonusers (OR = 1.34; 95% CI, 1.28-1.40). In direct comparisons, we did not observe evidence of a significant difference in adjusted TBI risk between high- (≥90 morphine milligram equivalents) and standard-dose opioid prescriptions (OR = 1.01; 95% CI, 0.90-1.14) or between acute and chronic (≥90 days) opioid prescriptions (OR = 0.93; 95% CI, 0.84-1.02).

Conclusions:

Among older adult Medicare beneficiaries, prescription opioid use independently increased risk for TBI compared with nonusers after adjusting for concomitant FRID use. We found no significant difference in adjusted TBI risk between high-dose and standard-dose opioid use, nor did we find a significant difference in adjusted TBI risk between acute and chronic opioid use. This analysis can inform prescribing of opioids to community-dwelling older adults for pain management.
Venous Thromboembolism Chemoprophylaxis in Trauma and Emergency General Surgery Patients: A Systematic Review
Authors: Sanchez Carol , Nguyen Jackie , Baroutjian Amanda , Gill Sabrina , McKenney Mark , Elkbuli Adel
Published: September 2021

Background:

Appropriate venous thromboembolism (VTE) chemoprophylaxis in trauma and emergency general surgery (EGS) patients is crucial.

Objective:

The purpose of this study is to review the recent literature and offer recommendations for VTE chemoprophylaxis in trauma and EGS patients.

Methods:

We conducted a literature search from 2000 to 2021 for articles investigating VTE chemoprophylaxis in adult trauma and EGS patients. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.

Results:

Our search resulted in 34 articles. Most studies showed low-molecular-weight heparin (LMWH) is similar to unfractionated heparin (UFH) for VTE prevention; however, LMWH was more commonly used. Adjusted chemoprophylaxis dosing did not change the VTE rate but the timing did. Direct oral anticoagulants (DOACs) have been shown to be safe and effective in trauma and traumatic brain injury (TBI)/spinal cord injury (SCI). Studies showed VTE prophylaxis in EGS can be inconsistent and improves with guidelines that lower VTE events.

Conclusions:

There may be no benefit to receiving LMWH over UFH in trauma patients. In addition, different drugs under the class of LMWH do not change the incidence of VTE. Adjusted dosing of enoxaparin does not seem to affect VTE incidence. The use of DOACs in the trauma TBI and SCI setting has been shown to be safe and effective in reducing VTE. One important consideration with VTE prophylaxis may be the timing of prophylaxis initiation, specifically as it relates to TBI, with a higher likelihood of developing VTE as time progresses. EGS patients are at a high risk of VTE. Improved compliance with clinical guidelines in this population is correlated with decreased thrombotic events.
Mitochondrial DNA: Unraveling the “other” genome
Authors: Heuer Beth
Published: September 2021

The mitochondrial genome, which contains all of the hereditary information within human mitochondria, consists of 16,569 base pairs of double-stranded DNA that encode 37 genes. Pathogenic mutations of mitochondrial DNA (mtDNA) cause dysfunction of the respiratory chain and the process of oxidative phosphorylation (OXPHOS), leading to impaired adenosine triphosphate synthesis. Nuclear DNA (nDNA) mutations can affect structural subunits or assembly factors of one of the five OXPHOS complexes. Mitochondrial diseases are a heterogeneous group of disorders, ranging from mtDNA single-point mutations and large-scale deletions to mitochondrial depletion syndromes, resulting from nDNA pathogenic mutations. Manifestations of mitochondrial disease are multisystemic, and organs with substantial energy requirements are most typically affected. Mitochondrial disorders are progressive in nature, and prognosis is dependent on the organs involved and the rate and severity of disease progression. A multidisciplinary team approach is needed to monitor and manage disease sequelae.
Using a Patient Safety Analysis to Guide Infusion Therapy for Patients With COVID-19
Authors: Hagle Mary , Snyder Kate , Janicek Karen , Bell Kimberly , Dietz Beth , Gundacker Nathan , Kinter Angelina , Severson Annette
Published: September 2021

In the United States, during the Coronavirus Disease 2019 (COVID-19) pandemic, patients with COVID-19 overwhelmed available intensive care beds, staffing levels were unpredictable, and personal protective equipment was limited. The safety of situating electronic infusion pumps outside patient rooms was evaluated using an internal risk assessment. Based on a low level of risk, a procedure was developed to direct clinicians as to when this process is appropriate during a national crisis. A standardized analysis, Healthcare Failure Mode and Effects Analysis, was conducted to identify all potential risks and implement actions that would eliminate or control the risk. No adverse events were reported. Safe systems and preparation can protect patients.
Elastomeric Pump Infusion Failures Caused by Inadequate Luer Lock Connector Engagement to Needleless Connectors
Authors: Lui Gough Yumu , Dickson Hugh G. , West Dana , Alexandrou Evan , Malone Matthew , Breen Paul P.
Published: September 2021

Needleless connectors are used widely across all types of vascular access devices and provide safe, needleless administration of intravenous fluids and medications. An analysis of patients from an outpatient parenteral antimicrobial therapy program is presented in which elastomeric pumps had failed to flow due to incomplete tightening of Luer lock needleless connections. An alert was issued to community nursing staff responsible for daily elastomeric pump changes to ensure that needleless connectors were properly checked for full tightening. The frequency of failure of flow events before and after the alert was reviewed. Force and torque profiles required to activate the internal mechanism of connectors were measured in the 4 most frequently used needleless connectors in the outpatient parenteral antimicrobial therapy program. The degree of torque and force required to activate the different needleless connectors varied and was identified as a factor contributing to inadequate connection with the elastomeric pump and consequent failure of flow. Repeated feedback to nursing staff over the study period about the force and torque required for needleless connector flow activation resulted in a highly significant decrease in the rate of failure of flow events per elastomeric pump from a rate of 0.0147 events per elastomeric pump per year in the last 3 months of 2018 to 0.0003 in the first 6 months of 2020 (difference = 0.0144 [CI, 0.0097–0.02]; P < .0001).
MuSK Myasthenia Gravis Presenting with Bilateral Vocal Cord Abduction Paresis
Authors: Santilli Ashley , Stitt Derek
Published: September 2021

Introduction:

Approximately 39% to 49% of patients with previously diagnosed acetylcholine receptor antibody-negative myasthenia gravis have been found to be muscle-specific tyrosine kinase (MuSK) antibody positive. These patients have a presentation that typically includes oculobulbar weakness, poorer response to cholinesterase inhibitors, and higher risk for acute clinical decompensation that necessitates plasma exchange. MuSK patients can require more aggressive maintenance immunosuppression earlier-on to maintain stability, often with rituximab.

Case Report:

The authors report the case of a 45-year-old woman who presented with months of worsening hoarseness and exertional dyspnea. Laryngoscopy revealed limited abduction of vocal cords bilaterally as the source of the complaint. Examination revealed ophthalmoparesis and fatigable proximal muscle weakness. She was found to have elevated MuSK antibodies that, along with evidence of neuromuscular junction transmission defect on nerve conduction studies, confirmed the diagnosis of MuSK myasthenia gravis. She experienced no improvement with pyridostigmine and decompensated despite receiving oral steroids, requiring intubation. However, she dramatically improved with plasma exchange and has since been doing well on rituximab therapy.

Conclusion:

Dysphonia with hoarse quality secondary to vocal cord abduction paresis is a rare presentation of myasthenia gravis, as opposed to the typical flaccid dysarthria seen in bulbar myasthenia and should raise suspicion for MuSK antibody positivity. MuSK myasthenia gravis cases can be more refractory to treatment with cholinesterase inhibitors and are more likely to cause exacerbations and myasthenia crisis. Therefore, early and accurate diagnosis with appropriate antibody testing is imperative to avoid delays in treatment to prevent potentially life-threatening outcomes.
The early impact of vaccination against SARS-CoV-2 in Region Stockholm, Sweden
Authors: Isitt Catherine , Sjöholm Daniel , Hergens Maria-Pia , Granath Fredrik , Nauclér Pontus
Published: September 2021

Vaccination against SARS-CoV-2 started in Region Stockholm, Sweden in December 2020 with those in long-term care facilities or receiving home care vaccinated first followed by those aged over 80 years. In this population-based, retrospective cohort study, we performed a Poisson regression to model the expected incidence of infections and deaths which we compared to the observed incidence and compared this to an unvaccinated control group of those aged 18-79 years. The aim of this study was to measure the early impact of the vaccination programme in Region Stockholm.

Infections and deaths reduced substantially amongst the first two groups targeted for SARS-CoV-2 vaccination with an estimated total 3112 infections prevented, and 854 deaths prevented in these two groups from 4 weeks after the introduction of vaccination through to 2nd May 2021.
An observational study of clinical and health system factors associated with catheter ablation and early ablation treatment for atrial fibrillation in Australia
Authors: Quiroz Juan C , Brieger David , Jorm Louisa , Sy Raymond W , Falster Michael O , Gallego Luxan Blanca
Published: September 2021

Objective: To investigate clinical and health system factors associated with receiving catheter ablation (CA) for non-valvular atrial fibrillation (AF).
Study Design and Setting: We used hospital administrative data linked with death registrations in New South Wales, Australia for patients with a primary diagnosis of AF between 2009 and 2017. We investigated factors associated with receiving CA (using Cox regression) and early ablation (using logistic regression).
Results: Cardioversion during index admission (hazard ratio [HR] 1.96; 95% CI 1.75-2.19), year of index admission (HR 1.07; 1.07; 95% CI 1.05-1.10), private patient status (HR 2.65; 95% CI 2.35-2.97), and living in more advantaged areas (HR 1.18; 95% CI 1.13-1.22) were associated with a higher likelihood of receiving CA. Private patient status (odds ratio [OR] 2.04; 95% CI 1.59-2.61) and a history of cardioversion (OR 1.25; 95% CI 1.0-1.57) and diabetes (OR 1.6; 95% CI 1.06-2.41) were associated with receiving early ablation.
Conclusion: Beyond clinical factors, private patients are more likely to receive CA and earlier ablation than their public counterparts. Whether the earlier access to ablation procedures in private patients is leading to differences in outcomes among patients with atrial fibrillation remains to be explored.
Behavioral state tunes mouse vision to ethological features through pupil dilation
Authors: Franke Katrin , Willeke Konstantin F. , Ponder Kayla , Galdamez Mario , Muhammad Taliah , Patel Saumil , Froudarakis Emmanouil , Reimer Jacob , Sinz Fabian , Tolias Andreas S.
Published: September 2021

Sensory processing changes with behavioral context to increase computational flexibility. In the visual system, active behavioral states enhance sensory responses but typically leave the preferred stimuli of neurons unchanged. Here we find that behavioral state does modulate stimulus selectivity in mouse visual cortex in the context of colored natural scenes. Using population imaging, behavior, pharmacology, and deep neural networks, we identified a shift of color selectivity towards ultraviolet stimuli exclusively caused by pupil dilation, resulting in a dynamic switch from rod to cone photoreceptors, extending their role beyond night and day vision. This facilitated the detection of ethological stimuli, such as aerial predators against the twilight sky. In contrast to previous studies that have used pupil dilation as an indirect measure of brain state, our results suggest that the brain uses pupil dilation itself to differentially recruit rods and cones on short timescales to tune visual representations to behavioral demands.
A Novel Optical Design Enabling Lightweight and Large Field-of-View Head-Mounted Microscopes
Authors: Scherrer J. R. , Lynch Galen F. , Zhang Jie J. , Fee Michale S.
Published: September 2021

We present a novel fluorescence microscope light path that enables imaging, during free behavior, of thousands of neurons in mice and hundreds of neurons in juvenile songbirds. The light path eliminates traditional illumination optics, allowing for head-mounted microscopes that have both a lower weight and a larger field-of-view (FOV) than previously possible. Using this light path, we designed two microscopes: one optimized for field-of-view (∼4 mm FOV; 1.4 g), and the other optimized for weight (1.0 mm FOV; 1.0 g).
Organization and engagement of a prefrontal-olfactory network during olfactory selective attention
Authors: Cansler Hillary L. , in ’t Zandt Estelle E , Carlson Kaitlin S. , Khan Waseh T. , Ma Minghong , Wesson Daniel W.
Published: September 2021

Sensory perception is profoundly shaped by attention. Attending to an odor strongly regulates if and how a smell is perceived – yet the brain systems involved in this process are unknown. Here we report integration of the medial prefrontal cortex (mPFC), a collection of brain regions integral to attention, with the olfactory system in the context of selective attention to odors. First, we used tracing methods to establish the tubular striatum (TuS, also known as the olfactory tubercle) as the primary olfactory region to receive direct mPFC input in rats. Next, we recorded local field potentials from the olfactory bulb (OB), mPFC, and TuS while rats completed an olfactory selective attention task. Gamma power and coupling of gamma oscillations with theta phase were consistently high as rats flexibly switched their attention to odors. Beta and theta synchrony between mPFC and olfactory regions were elevated as rats switched their attention to odors. Finally, we found that sniffing was consistent despite shifting attentional demands, suggesting that the mPFC-OB theta coherence is independent of changes in active sampling. Together, these findings begin to define an olfactory attention network wherein mPFC activity, as well as that within olfactory regions, are coordinated in manners based upon attentional states.
The landscape of toxic intermediates in the metabolic networks of pathogenic fungi reveals targets for antifungal drugs
Authors: Ewald Jan , Jansen Paul Mathias , Brunke Sascha , Hiller Davina , Luther Christian H. , González-Díaz Humbert , Dittrich Marcus T. , Fleißner André , Hube Bernhard , Schuster Stefan , Kaleta Christoph
Published: September 2021

The burden of fungal infections for humans, animals and plants is widely underestimated and comprises deadly infections as well as great economic costs. Despite that, antifungal drugs are scarce and emergence of resistance in fungal strains contributes to a high mortality. To overcome this shortage, we propose toxic intermediates and their controlling enzymes in metabolic pathways as a resource for new targets and provide a web-service, FunTox-Networks to explore the landscape of toxic intermediates in the metabolic networks of fungal pathogens. The toxicity of metabolites is predicted by a new random forest regression model and is available for over one hundred fungal species. Further, for major fungal pathogens, metabolic networks from the KEGG database were enriched with data of toxicity and regulatory effort for each enzyme to support identification of targets. We determined several toxic intermediates in fungal-specific pathways like amino acid synthesis, nitrogen and sulfur assimilation, and the glyoxylate bypass. For the latter, we show experimentally that growth of the pathogen Candida albicans is inhibited when the detoxifying enzymes Mls1 and Hbr2 are deleted and toxic glyoxylate accumulates in the cell. Thus, toxic pathway intermediates and their controlling enzymes represent an untapped resource of antifungal targets.
The Sec61 translocon is a therapeutic vulnerability in Multiple Myeloma
Authors: Domenger Antoine , Choisy Caroline , Baron Ludivine , Mayau Véronique , Deriano Ludovic , Arnulf Bertrand , Bories Jean-Christophe , Dadaglio Gilles , Demangel Caroline
Published: September 2021

Multiple Myeloma (MM) is an incurable malignancy characterized by the uncontrolled expansion of plasma cells in the bone marrow. While proteasome inhibitors like bortezomib efficiently halt MM progression, drug resistance or toxicity inevitably develop. Here, we used a recently discovered inhibitor, mycolactone, to assess the interest of targeting the Sec61 translocon in MM. In human cell lines and tumors from MM patients, mycolactone triggered pro-apoptotic endoplasmic reticulum stress responses synergizing with bortezomib for induction of MM cell death, irrespective of their resistance to proteasome inhibition. Notably, this synergy was selective of cancer cells and extended to B cell acute lymphoblastic leukemia. Sec61 blockade also caused collateral defects in MM secretion of immunoglobulins and expression of pro-survival interleukin (IL)-6 receptor and CD40, whose activation stimulates IL-6 production. Further, the mycolactone-bortezomib combination demonstrated superior therapeutic efficacy over single drug treatments in immunodeficient mice engrafted with MM cells, without inducing toxic side effects. Collectively, these findings establish Sec61 blockers as novel anti-MM agents and reveal the interest of targeting both the translocon and the proteasome in proteostasis-addicted tumors.
Vulnerability to cavitation is linked to home climate precipitation across eight eucalypt species
Authors: Coleman David , Merchant Andrew , Salter William T.
Published: September 2021

Vulnerability to cavitation in leaves is the result of highly adaptive anatomical and physiological traits that can be linked to water availability in a species’ climate of origin. Despite similar gross leaf morphology, eucalypt species are often confined to specific climate envelopes across the variable rainfall environments of Australia. In this study, we investigate how the progression of cavitation differs among eucalypts and whether this is related to other hydraulic and physical leaf traits. We used the Optical Visualisation technique to capture cavitation progression across the leaves of eight eucalypt species (Angophora crassifolia, Corymbia tessellaris, Eucalyptus atrata, Eucalyptus grandis, Eucalyptus laevopinea, Eucalyptus longifolia, Eucalyptus macrandra, Eucalyptus tereticornis) from a wide range of climates and grown in a common garden setting. Vulnerability to cavitation, represented by the leaf water potential required for 50% cavitation of leaf vessels, varied significantly among species (−3.48 MPa to −8.25 MPa) and correlated linearly with home climate precipitation and leaf SLA (R2of 0.64 and 0.75, respectively). P12-P88, the range of water potentials between which 12% to 88% of cavitation occurs, was decoupled from P50 but also correlated with leaf SLA (R2of 0.72). We suggest the magnitude of P12-P88 may be representative of a species’ drought strategy – a large P12-P88 signifying leaves that exhibit drought tolerance (retention of leaves under drought conditions) and a small P12-P88 signifying drought avoidance (leaf shedding after a threshold of drought is reached). Our results agree with other studies that highlight these cavitation metrics as genetically fixed traits. Turgor loss point, on the other hand, may be more plastic, as evidenced by the low variability of this trait across these eucalypt species grown in a common garden environment. Further study will help to establish the SLA-related anatomical traits that impart cavitation resistance and to extend these conclusions to a greater number of species and home climates.
Reduced H+channel activity disrupts pH homeostasis and calcification in coccolithophores at low ocean pH
Authors: Kottmeier Dorothee , Chrachri Abdul , Langer Gerald , Helliwell Katherine , Wheeler Glen L. , Brownlee Colin
Published: September 2021

Coccolithophores produce the bulk of ocean biogenic calcium carbonate but this process is predicted to be negatively affected by future ocean acidification scenarios. Since coccolithophores calcify intracellularly, the mechanisms through which changes in seawater carbonate chemistry affect calcification remain unclear. Here we show that voltage-gated H+channels in the plasma membrane ofCoccolithus braarudiiserve to regulate pH and maintain calcification under normal conditions, but have greatly reduced activity in cells acclimated to low pH. This disrupts intracellular pH homeostasis and impairs the ability ofC. braarudiito remove H+generated by the calcification process, leading to specific coccolith malformations. These coccolith malformations can be reproduced by pharmacological inhibition of H+channels. Heavily-calcified coccolithophore species such asC. braarudii, which make the major contribution to carbonate export to the deep ocean, have a large intracellular H+load and are likely to be most vulnerable to future decreases in ocean pH.
Ineffective neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine sera
Authors: Uriu Keiya , Kimura Izumi , Shirakawa Kotaro , Takaori-Kondo Akifumi , Nakada Taka-aki , Kaneda Atsushi ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Nakagawa So , Sato Kei
Published: September 2021

On August 30, 2021, the WHO classified the SARS-CoV-2 Mu variant (B.1.621 lineage) as a new variant of interest. The WHO defines “comparative assessment of virus characteristics and public health risks” as primary action in response to the emergence of new SARS-CoV-2 variants. Here, we demonstrate that the Mu variant is highly resistant to sera from COVID-19 convalescents and BNT162b2-vaccinated individuals. Direct comparison of different SARS-CoV-2 spike proteins revealed that Mu spike is more resistant to serum-mediated neutralization than all other currently recognized variants of interest (VOI) and concern (VOC). This includes the Beta variant (B.1.351) that has been suggested to represent the most resistant variant to convalescent and vaccinated sera to date (e.g., Collier et al, Nature, 2021; Wang et al, Nature, 2021). Since breakthrough infection by newly emerging variants is a major concern during the current COVID-19 pandemic (Bergwerk et al., NEJM, 2021), we believe that our findings are of significant public health interest. Our results will help to better assess the risk posed by the Mu variant for vaccinated, previously infected and naïve populations.
Structure and dynamics of Toll immunoreceptor activation in the mosquito Aedes aegypti
Authors: Saucereau Yoann , Wilson Tom H. , Tang Matthew C. K. , Moncrieffe Martin C. , Hardwick Steven W. , Chirgadze Dimitri Y. , Soares Sandro G. , Marcaida Maria Jose , Gay Nick , Gangloff Monique
Published: September 2021

Aedes aegypti has evolved to become an efficient vector for arboviruses but the mechanisms of host-pathogen tolerance are unknown. Immunoreceptor Toll and its ligand Spaetzle have undergone duplication which may allow neofunctionalization and adaptation. Here we present cryo-EM structures and biophysical characterisation of low affinity Toll5A complexes that display transient but specific interactions with Spaetzle1C, forming asymmetric complexes, with only one ligand clearly resolved. Loop structures of Spaetzle1C and Toll5A intercalate, temporarily bridging the receptor C-termini to promote signalling. By contrast unbound receptors form head-to-head homodimers that keep the juxtamembrane regions far apart in an inactive conformation. Interestingly the transcriptional signature of Spaetzle1C differs from other Spaetzle cytokines and controls genes involved in innate immunity, metabolism and tissue regeneration. Taken together our results explain how upregulation of Spaetzle1C in the midgut and Toll5A in the salivary gland shape the concomitant immune response.
Two engineered AAV capsid variants for efficient transduction of human cortical neurons directly converted from iPSC
Authors: Fischer Sandra , Weinmann Jonas , Gillardon Frank
Published: September 2021

Recombinant adeno-associated virus (AAV) is the most widely used vector for gene therapy in clinical trials. To increase transduction efficiency and specificity, novel engineered AAV variants with modified capsid sequences are evaluated in human cell cultures and non-human primates. In the present study, we tested two novel AAV capsid variants, AAV2-NNPTPSR and AAV9-NVVRSSS, in human cortical neurons, which were directly converted from human induced pluripotent stem cells and cocultured with rat primary astrocytes. AAV2-NNPTPSR variant efficiently transduced both induced human cortical glutamatergic neurons and induced human cortical GABAergic interneurons. By contrast, AAV9-NVVRSSS variant transduced both induced human cortical neurons and cocultured rat primary astrocytes. High viral titers (1×10E5 viral genomes per cell) caused a significant decrease in viability of induced human cortical neurons. Low viral titers (1×10E4 viral genomes per cell) lead to a significant increase in the neuronal activity marker c-Fos in transduced human neurons following treatment with a potassium channel blocker, which may indicate functional alterations induced by viral transduction and/or transgene expression.
In vivocharacterization and application of a novel potassium channel-based optogenetic silencer in the healthy and epileptic mouse hippocampus
Authors: Kleis P , Paschen E , Häussler U , Bernal Sierra YA , Haas CA
Published: September 2021

The performance of available optogenetic inhibitors remains insufficient due to low light sensitivity, short-lasting photocurrents, and unintended changes in ion distributions. To overcome these limitations, a novel potassium channel-based optogenetic silencer was developed and successfully applied in variousin vitroand acutein vivosettings (Bernal Sierra et al., 2018). This tool, a two-component construct called PACK, comprises a photoactivated adenylyl cyclase (bPAC) and a cAMP-dependent potassium channel (SthK). Here, we examined the long-term inhibitory action and side effects of the PACK construct in healthy and epileptic adult male mice. We targeted hippocampal CA1 pyramidal cells using a viral vector and enabled illumination of these neurons via an implanted optic fiber. Local field potential (LFP) recordings from the CA1 of freely moving mice revealed significantly reduced neuronal activity during 50-minute intermittent illumination, especially in the beta and gamma frequency ranges. Adversely, PACK expression in healthy mice induced chronic astrogliosis, dispersion of pyramidal cells, and generalized seizures. These side effects were independent of the light application and were also present in mice expressing bPAC without the potassium channel. Additionally, light-activation of bPAC alone increased neuronal activity, presumably via enhanced cAMP signaling. In chronically epileptic mice, the dark activity of bPAC/PACK in CA1 prevented the spread of spontaneous epileptiform activity from the seizure focus to the contralateral bPAC/PACK-expressing hippocampus. Taken together, the PACK tool is a potent optogenetic inhibitor but requires refinement of its light-sensitive domain to avoid unexpected physiological changes.

Significance statement

Optogenetics allows precise manipulation of neuronal activity via genetically encoded light-sensitive proteins. Unfortunately, available optogenetic inhibitors are not suitable for prolonged use. The newly developed two-component potassium channel-based optogenetic inhibitor, PACK, has been identified as a potent silencer of neurons in various acute experiments. Here, we characterized the PACK construct in freely behaving healthy and epileptic mice. We targeted the PACK silencer specifically to CA1 pyramidal neurons, where illumination with short light pulses at low frequencies reliably reduced neuronal activity. In chronically epileptic mice, PACK prevented the spread of epileptiform activity from the seizure focus to the contralateral PACK-expressing hippocampus. The major disadvantage of the PACK silencer is its light-sensitive domain, the bPAC adenylyl cyclase, which may induce side effects.
Genetic epidemiology of blood type, disease and trait variants, and genome-wide genetic diversity in over 11,000 domestic cats
Authors: Anderson Heidi , Davison Stephen , Lytle Katherine M. , Honkanen Leena , Freyer Jamie , Mathlin Julia , Kyöstilä Kaisa , Inman Laura , Louviere Annette , Foran Rebecca Chodroff , Forman Oliver P. , Lohi Hannes , Donner Jonas
Published: September 2021

In the largest DNA-based study of domestic cat to date, 11,036 individuals (10,419 pedigreed cats from 91 breeds and breed types and 617 non-pedigreed cats) were genotyped via commercial panel testing, elucidating the distribution and frequency of known genetic variants associated with blood type, disease and physical traits across cat breeds. Blood group determining variants, which are relevant clinically and in cat breeding, were genotyped to assess the across breed distribution of blood types A, B and AB. Extensive panel testing identified 13 disease-associated variants in 48 breeds or breed types for which the variant had not previously been observed, strengthening the argument for panel testing across populations. The study also indicates that multiple breed clubs have effectively used DNA testing to reduce disease-associated genetic variants within certain pedigreed cat populations. Appearance-associated genetic variation in all cats is also discussed. Additionally, we combined genotypic data with phenotype information and clinical documentation, actively conducted owner and veterinarian interviews, and recruited cats for clinical examination to investigate the causality of a number of tested variants across different breed backgrounds. Lastly, genome-wide informative SNP heterozygosity levels were calculated to obtain a comparable measure of the genetic diversity in different cat breeds.

This study represents the first comprehensive exploration of informative Mendelian variants in felines by screening over 10,000 domestic cats. The results qualitatively contribute to the understanding of feline variant heritage and genetic diversity and demonstrate the clinical utility and importance of such information in supporting breeding programs and the research community. The work also highlights the crucial commitment of pedigreed cat breeders and registries in supporting the establishment of large genomic databases that when combined with phenotype information can advance scientific understanding and provide insights that can be applied to improve the health and welfare of cats.
Erythroid spectrin binding modulates peroxidase and catalase activity of heme proteins
Authors: Bose Dipayan , Aggarwal Shantanu , Das Debashree , Narayana Chandrabhas , Chakrabarti Abhijit
Published: September 2021

Hemoglobin oxidation due to oxidative stress and disease conditions leads to generation of ROS (reactive oxygen species) and membrane attachment of hemoglobin in-vivo, where its redox activity leads to peroxidative damage of membrane lipids and proteins. Spectrin, the major component of the RBC membrane skeleton, is known to interact with hemoglobin and, here this interaction is shown to increase hemoglobin peroxidase activity in the presence of reducing substrate ABTS (2’, 2’-Azino-Bis-3-Ethylbenzothiazoline-6-Sulfonic Acid). It is also shown that in the absence of reducing substrate, spectrin forms covalently cross-linked aggregates with hemoglobin which display no peroxidase activity. This may have implications in the clearance of ROS and limiting peroxidative damage. Spectrin is found to modulate the peroxidase activity of different hemoglobin variants like A, E, and S, and of isolated globin chains from each of these variants. This may be of importance in disease states like sickle cell disease and HbE-β-thalassemia, where increased oxidative damage and free globin subunits are present due to the defects inherent in the hemoglobin variants associated with these diseases. This hypothesis is corroborated by lipid peroxidation experiments. The modulatory role of spectrin is shown to extend to other heme proteins, namely catalase and cytochrome-c. Experiments with free heme and Raman spectroscopy of heme proteins in the presence of spectrin show that structural alterations occur in the heme moiety of the heme proteins on spectrin binding, which may be the structural basis of increased enzyme activity.
Oxytocin neurons mediates the effect of social isolation via the VTA circuits
Authors: Musardo Stefano , Contestabile Alessandro , Mairesse Jerome , Baud Olivier , Bellone Camilla
Published: September 2021

Social interaction during adolescence strongly influences brain function and behaviour, and the recent pandemic has emphasized the devastating effect of social distancing on mental health. While accumulating evidences have shown the importance of the reward system in encoding specific aspects of social interaction, the consequences of social isolation on the reward system and the development of social skills later in adulthood are still largely unknown. Here, we found that one week of social isolation during adolescence in mice increased social interaction at the expense of social habituation and social novelty preference. Behavioural changes were accompanied by the acute hyperexcitability of dopamine (DA) neurons in the ventral segmental area (VTA) and long-lasting expression of GluA2-lacking AMPARs at excitatory inputs onto DA neurons that project to the prefrontal cortex (PFC). Social isolation-dependent behavioural deficits and changes in neural activity and synaptic plasticity were reversed by chemogenetic inhibition of oxytocin neurons in the paraventricular nucleus (PVN) of the hypothalamus. These results demonstrate that social isolation has acute and long-lasting effects on social interaction and suggest that these effects are mediated by homeostatic adaptations within the reward circuit.