bluuebunny/crossref_metadata_2025 huggingface dataset:
Multisystem Inflammatory Syndrome in a Previously Vaccinated Adolescent Female With Sickle Cell Disease
Authors: DeJong Joshua , Sainato Rebecca , Forouhar Melissa , Robinson David , Kunz Anjali
Published: December 2021

Multisystem inflammatory syndrome in children (MIS-C) is a serious complication that is observed most commonly in pediatric patients following severe acute respiratory syndrome coronavirus 2 infections. However, the mechanism and predictors of disease are poorly understood. There are no prior reports of MIS-C among patients who have been fully vaccinated, and only a single case of MIS in an adult patient who had received his second shot just 4 days prior to symptom onset. Here, we present an adolescent with sickle cell disease who was fully vaccinated against severe acute respiratory syndrome coronavirus 2 and had no prior history of known or suspected infection, who presented in shock and was ultimately diagnosed with MIS-C. This case highlights the importance of clinical suspicion for MIS-C even when patients are fully vaccinated.
Characterizing Pain Leading to Emergency Medical Services Activation in Heart Failure
Authors: Smith Asa B. , Jung Miyeon , Lee Christopher , Pressler Susan J.
Published: December 2021

Background

Pain is a common but understudied symptom among patients with heart failure (HF) transported by emergency medical services (EMS). The aims were to determine explanatory factors of a primary complaint of pain and pain severity, and characterize pain among patients with HF transported by EMS.

Methods

Data from electronic health records of patients with HF transported by EMS within a midwestern United States county from 2009 to 2017 were analyzed. Descriptive statistics, χ2, analysis of variance, and logistic and multiple linear regression analyses were used.

Results

The sample (N = 4663) was predominantly women (58.1%) with self-reported race as Black (57.7%). The mean age was 64.2 ± 14.3 years. Pain was the primary complaint in 22.2% of the sample, with an average pain score of 6.8 ± 3.1 out of 10. The most common pain complaint was chest pain (68.1%). Factors associated with a primary pain complaint were younger age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.96–0.97), history of myocardial infarction (OR, 1.96; 95% CI, 1.55–2.49), and absence of shortness of breath (OR, 0.67; 95% CI, 0.58–0.77). Factors associated with higher pain severity were younger age (b = −0.05, SE = 0.013), being a woman (b = 1.17, SE = 0.357), and White race (b = −1.11, SE = 0.349).

Conclusions

Clinical and demographic factors need consideration in understanding pain in HF during EMS transport. Additional research is needed to examine these factors to improve pain management and reduce transports due to pain.
Effect of Dietary Sodium Restriction on the Quality of Life of Patients With Heart Failure
Authors: Zhu Chenya , Cheng Ming , Su Yue , Ma Tianyu , Lei Xiaoqing , Hou Yunying
Published: December 2021

Background

Dietary salt restriction is recommended by many guidelines for patients with heart failure (HF). Quality of life (QoL) is an important end point of this intervention. However, the literature is still limited regarding the effect of dietary salt restriction on QoL in patients with HF.

Aims

We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the effect of dietary sodium restriction on QoL in patients with HF.

Methods

We searched PubMed (MEDLINE), the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and Cumulative Index to Nursing and Allied Health from the establishment of each database to December 20, 2020. We included randomized controlled trials with sodium restriction as an intervention. The primary outcome was QoL, and the secondary outcomes were mortality, readmission, and fatigue. We obtained the full text of potentially relevant trials, extracted data from the included trials, assessed their risk of bias, and performed a meta-analysis.

Results

We included 10 trials (1011 participants with HF) with 7 days to 83 months of follow-up. Dietary sodium restriction did not improve QoL over the long term (>30 days) (P = .61). The pooled effects showed that this intervention might increase mortality risk (P < .00001). It did not reduce the readmission rate within the short term (≤30 days) (P = .78) but increased the readmission rate over the long term (P = .0003).

Conclusion

Our study did not show that interventions to restrict dietary sodium had a positive effect on patients with HF in terms of QoL, mortality, or readmission.
Brief Report: Undertreated Midlife Symptoms for Women Living With HIV Linked to Lack of Menopause Discussions With Care Providers
Authors: King Elizabeth M. , Kaida Angela , Mayer Ulrike , Albert Arianne , Gormley Rebecca , de Pokomandy Alexandra , Nicholson Valerie , Cardinal Claudette , Islam Shaz , Loutfy Mona , Murray Melanie C. M.
Published: December 2021

Background:

Increasingly, women living with HIV are entering menopause (ie, cessation of menses for ≥1 year) and experiencing midlife symptoms. Menopausal hormone therapy (MHT) is first-line therapy for bothersome hot flashes and early menopause (ie, before age 45 years); however, its use in women living with HIV is poorly described. We conducted a cross-sectional assessment of MHT uptake and barriers to use in this group.

Setting:

This study was conducted across 3 Canadian provinces from 2015 to 2017.

Methods:

Perimenopausal and postmenopausal women living with HIV (35 years or older) in the Canadian HIV Women's Sexual and Reproductive Health Cohort Study who answered questions related to MHT use were included. Univariable/multivariable logistic regression evaluated factors associated with MHT use, adjusted for age and contraindications.

Results:

Among 464 women, 47.8% (222 of 464) had a first-line indication for MHT; however, only 11.8% (55 of 464) reported ever using MHT and 5.6% (26 of 464) were current users. Only 44.8% had ever discussed menopause with their care provider despite almost all women having regular HIV care (97.8%). African/Caribbean/Black women had lower unadjusted odds of MHT treatment compared with White women [odds ratio (OR) 0.42 (0.18–0.89); P = 0.034]. Those who had discussed menopause with their care provider had higher odds of treatment [OR 3.13 (1.74–5.86); P < 0.001]. In adjusted analyses, only women having had a menopause discussion remained significantly associated with MHT use [OR 2.97 (1.62–5.61); P < 0.001].

Conclusion:

Women living with HIV are seldom prescribed MHT despite frequent indication. MHT uptake was associated with care provider–led menopause discussions underscoring the need for care provider education on menopause management within HIV care.
Integrated Single-cell and Plasma Proteomic Modeling to Predict Surgical Site Complications: A Prospective Cohort Study
Authors: Rumer Kristen K. , Hedou Julien , Tsai Amy , Einhaus Jakob , Verdonk Franck , Stanley Natalie , Choisy Benjamin , Ganio Edward , Bonham Adam , Jacobsen Danielle , Warrington Beata , Gao Xiaoxiao , Tingle Martha , McAllister Tiffany N. , Fallahzadeh Ramin , Feyaerts Dorien , Stelzer Ina , Gaudilliere Dyani , Ando Kazuo , Shelton Andrew , Morris Arden , Kebebew Electron , Aghaeepour Nima , Kin Cindy , Angst Martin S. , Gaudilliere Brice
Published: December 2021

Objective:

The aim of this study was to determine whether single-cell and plasma proteomic elements of the host's immune response to surgery accurately identify patients who develop a surgical site complication (SSC) after major abdominal surgery.

Summary Background Data:

SSCs may occur in up to 25% of patients undergoing bowel resection, resulting in significant morbidity and economic burden. However, the accurate prediction of SSCs remains clinically challenging. Leveraging high-content proteomic technologies to comprehensively profile patients’ immune response to surgery is a promising approach to identify predictive biological factors of SSCs.

Methods:

Forty-one patients undergoing non-cancer bowel resection were prospectively enrolled. Blood samples collected before surgery and on postoperative day one (POD1) were analyzed using a combination of single-cell mass cytometry and plasma proteomics. The primary outcome was the occurrence of an SSC, including surgical site infection, anastomotic leak, or wound dehiscence within 30 days of surgery.

Results:

A multiomic model integrating the single-cell and plasma proteomic data collected on POD1 accurately differentiated patients with (n = 11) and without (n = 30) an SSC [area under the curve (AUC) = 0.86]. Model features included coregulated proinflammatory (eg, IL-6- and MyD88- signaling responses in myeloid cells) and immunosuppressive (eg, JAK/STAT signaling responses in M-MDSCs and Tregs) events preceding an SSC. Importantly, analysis of the immunological data obtained before surgery also yielded a model accurately predicting SSCs (AUC = 0.82).

Conclusions:

The multiomic analysis of patients’ immune response after surgery and immune state before surgery revealed systemic immune signatures preceding the development of SSCs. Our results suggest that integrating immunological data in perioperative risk assessment paradigms is a plausible strategy to guide individualized clinical care.
Association Between Surgical Opioid Prescriptions and Opioid Initiation by Opioid-naïve Spouses
Authors: Varady Nathan H. , Chen Antonia F. , Niu Ruijia , Chung Mei , Freccero David M. , Smith Eric L.
Published: December 2021

Objective:

To determine whether surgical opioid prescriptions are associated with increased risk of opioid initiation by operative patients’ spouses.

Summary of Background Data:

Adverse effects of surgical opioids on operative patients have been well described. Whether risks of surgical opioids extend to operative patients’ family members is unknown.

Methods:

This was a retrospective cohort study of opioid-naïve, married patients undergoing 1 of 11 common surgeries from January 1, 2011 to June 30, 2017. The adjusted association between surgical opioid prescriptions and opioid initiation by the operative patient’s spouse in the 6-months after surgery was assessed. Secondary analyses assessed how this association varied with postoperative time.

Results:

There were 318,022 patients (mean ± standard deviation age 48.8 ±9.3 years; 49.5% women). Among the 50,833 (16.0%) patients that did not fill a surgical opioid prescription, 2152 (4.2%) had spouses who filled an opioid prescription within 6-months of their surgery. In comparison, among the 267,189 (84.0%) patients who filled a surgical opioid prescription, 15,026 (5.6%) had spouses who filled opioid prescriptions within 6-months of their surgery [unadjusted P < 0.001; adjusted odds ratio (aOR) 1.37, 95% confidence interval (CI) 1.31–1.43, P < 0.001]. Associated risks were only mildly elevated in postoperative month 1 (aOR 1.11, 95% CI 1.00–1.23, P = 0.04) before increasing to a peak in postoperative month 3 (aOR 1.57,95% CI 1.391.76, P < 0.001).

Conclusions:

Surgical opioid prescriptions were associated with increased risk of opioid initiation by spouses of operative patients, suggesting that risks associated with surgical opioids may extend beyond the surgical patient. These findings may highlight the importance of preoperative counseling on safe opioid use, storage, and disposal for both patients and their partners.
Revised Nodal Staging Integrating Tumor Deposit Counts With Positive Lymph Nodes in Patients With Stage III Colon Cancer
Authors: Pyo Dae Hee , Kim Seok Hyung , Ha Sang Yoon , Yun Seong Hyeon , Cho Yong Beom , Huh Jung Wook , Park Yoon Ah , Shin Jung Kyong , Lee Woo Yong , Kim Hee Cheol
Published: December 2021

Objective:

We evaluated the prognostic value of tumor deposit (TD) counts and incorporated them with the number of positive lymph nodes to develop a revised nodal staging.

Summary Background Data:

The current American Joint Committee on Cancer (AJCC) staging on colon cancer includes the TDs only for nodenegative patients, as N1c, and their counts are not considered.

Methods:

We included consecutive patients with stage III colorectal cancer who underwent curative resections between January 2010 and December 2019. The patients were grouped as TD 0, TD 1, TD 2, or TD ≥3 based on their TD counts. Disease-free survival and overall survival were compared.

Results:

Of 2446 eligible stage III patients, 658 (26.9%) had TDs. Among them, 500 (76.0%) patients concurrently had positive lymph nodes (LNs). TD counts were significantly related to worse disease-free survival (DFS) and overall survival regardless of pT stages or the number of positive LNs. The patients were restaged based on the integrated number of TD counts and positive LNs. The N3 stage, which had ≥10 integrated TDs and positive LNs, was newly classified. Among the patients who completed 6 months of adjuvant chemotherapy, those upstaged to N2 from an initial stage of N1 experienced significantly worse DFS than those confirmed as N1 in the revised N staging. The newly N3-staged patients showed significantly worse DFS than the patients initially staged as N2.

Conclusions:

Revised N staging using the integrated number of TD counts and positive LNs could predict DFS more accurately than current staging. It would also draw greater attention to the patients with high-risk stage III colon cancer staged as N3.
Mesenchymal stem cells after the proprocessing of tanshinone IIA attenuate cognitive deficits and oxidative stress injury in an amyloid β-peptide (25–35)-induced rodent model of Alzheimer’s disease
Authors: Ba Zhisheng , Shi Shangpeng , Huang Nanqu , Li Yuanyuan , Huang Juan , You Chao , Yang Xiaoyan , Liu Daishun , Yu Changyin , He Yuqi , Luo Yong
Published: December 2021

Objectives

To verify whether mesenchymal stem cells cocultured with tanshinone IIA may ameliorate Alzheimer’s disease by inhibiting oxidative stress.

Methods

Sixty male Sprague–Dawley rats were randomly divided into 4 groups named Sham, Aβ25–35, mesenchymal stem cells, and mesenchymal stem cells (tanshinone IIA). The rats were treated according to different groups. The neurobehavioral performance of Sprague–Dawley rats was evaluated via Morris water maze test. Histological changes were checked via hematoxylin-eosin staining. The levels of total antioxidant activity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and malondialdehyde in hippocampus were assayed by ELISA kit. The levels of Aβ, p-tau/tau, and p-AMP-activated protein kinase/AMP-activated protein kinase in hippocampus were checked by Western blot.

Results

Our research showed that the injection of mesenchymal stem cells (tanshinone IIA) into the hippocampus alleviated learning and memory deficits and reduced hippocampal neuronal injury in the Alzheimer’s disease rats. Moreover, mesenchymal stem cells (tanshinone IIA) treatment suppressed oxidative stress, attenuated Aβ accumulation reduced Tau hyperphosphorylation, and enhanced the activity of AMP-activated protein kinase in the hippocampus of the Alzheimer’s disease rats. However, there were almost no significant difference between the mesenchymal stem cells and Aβ25–35 groups.

Conclusions

Mesenchymal stem cells (tanshinone IIA) transplantation may be a potential treatment for curing Alzheimer’s disease, which may be related to the inhibition of oxidative stress.
Ginsenoside Rg1 inhibits oxidative stress and inflammation in rats with spinal cord injury via Nrf2/HO-1 signaling pathway
Authors: Zhang Zhen , Yang Kun , Mao Rui , Zhong Donghai , Xu Zehua , Xu Jie , Xiong Min
Published: December 2021

Objectives

In this study, our objective was to investigate the underlying mechanism of the neuroprotective role of ginsenoside Rg1 in attenuating spinal cord injury (SCI).

Methods

A rat SCI model was established and treated with ginsenoside Rg1 and nuclear factor erythroid 2-related factor2(Nrf2) inhibitor all-trans retinoic acid (ATRA). The protective effects of ginsenoside Rg1 were evaluated by Basso, Beattie and Bresnahan (BBB) scale, hematoxylin/eosin staining, ELISA assay, western blotting and quantitative reverse transcription PCR (RT-qPCR).

Results

Ginsenoside Rg1 alleviated neuronal edema and bleeding in the injured spinal cord, reduced inflammatory cell infiltration and cell necrosis, further repaired the injured spinal cord structure, improved BBB motor score in the SCI rat model and improved hind limb motor function. Meanwhile, ginsenoside Rg1 significantly increased the content of antioxidant enzymes superoxide dismutase and glutathione, and inhibited the production of oxidative marker malondialdehyde. In addition, ginsenoside Rg1also significantly inhibits the activities of the inflammatory factors tumor necrosis factor-α, interleukin-1β (IL-1β) and interleukin-6 (IL-6) to reduce the inflammatory response after trauma. Furthermore, western blot and RT-qPCR also suggested that ginsenoside Rg1 could activate the protein expression of Nrf2 and heme oxygenase-1 (HO-1) after SCI, and the inhibition of ATRA on these improvements further verified the neuroprotective effect of Nrf2 and HO-1 in ginsenoside Rg1 on SCI.

Conclusion

Ginsenoside Rg1 has a neuroprotective effect on SCI and can improve motor dysfunction caused by injury. The underlying mechanism may play antioxidative stress and anti-inflammatory effect by regulating the Nrf2/HO-1 signaling pathway.
The activation of hypothalamic AMP-activated protein kinase by oxidative stress is related to hyperphagia in diabetic rats
Authors: Mendoza-Bello Juan M. , Barragán-Bonilla Martha I. , Ramírez Mónica , Flores-Alfaro Eugenia , Millán-Vega Alejandro , Parra-Abarca Juan , Espinoza-Rojo Mónica
Published: December 2021

Objective

During diabetes, there are increased blood glucose levels and oxidative stress. The relationship between oxidative stress and the phosphorylation of AMP-activated protein kinase at the hypothalamic level has been little studied. The objective of this study was to analyze the relationship between oxidative stress and AMP-activated protein kinase activation in Wistar rats with hyperphagia and hyperglycemia.

Methods

Rats at 7, 14, and 28 days with diabetes were used. Control rats were included. Food intake was calculated to determine hyperphagia. The hypothalamus was extracted to evaluate oxidative stress markers by spectrophotometry; phosphorylation of AMP-activated protein kinase, growth hormone receptor 1a, and neuropeptide Y expression were determined by Western blot.

Results

There was a significant increase in the consumption of food in the experimental groups. The level of malondialdehyde decreased in the 7-day group (33%) and increased significantly in the 28-day group (90%), glutathione peroxidase activity increased in the 7-day group (70%) and decreased in the 28-day group (34%), and the phosphorylation of AMP-activated protein kinase increased significantly in the 28-day group (86%). Under ex-vivo conditions in animals with 28 days of hyperglycemia, glutathione peroxidase activity increased 195%, the malondialdehyde level decreased 87%, phosphorylation of AMP-activated protein kinase decreased 53%, and growth hormone receptor 1a expression decreased 66%, when treating hyperglycemic hypothalamic tissue with an antioxidant. NPY expression increased in hyperglycemia, and antioxidant treatment did not regulate its expression.

Conclusions

The activation of AMP-activated protein kinase is related with an increase in oxidative stress markers in hyperglycemic and hyperphagic rats.
The neural bases of vertebrate motor behaviour through the lens of evolution
Authors: Suryanarayana Shreyas M. , Robertson Brita , Grillner Sten
Published: December 2021

The primary driver of the evolution of the vertebrate nervous system has been the necessity to move, along with the requirement of controlling the plethora of motor behavioural repertoires seen among the vast and diverse vertebrate species. Understanding the neural basis of motor control through the perspective of evolution, mandates thorough examinations of the nervous systems of species in critical phylogenetic positions. We present here, a broad review of studies on the neural motor infrastructure of the lamprey, a basal and ancient vertebrate, which enjoys a unique phylogenetic position as being an extant representative of the earliest group of vertebrates. From the central pattern generators in the spinal cord to the microcircuits of the pallial cortex, work on the lamprey brain over the years, has provided detailed insights into the basic organization (abauplan) of the ancestral vertebrate brain, and narrates a compelling account of common ancestry of fundamental aspects of the neural bases for motion control, maintained through half a billion years of vertebrate evolution.

This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.
Evolution of behavioural control from chordates to primates
Authors: Cisek Paul
Published: December 2021

This article outlines a hypothetical sequence of evolutionary innovations, along the lineage that produced humans, which extended behavioural control from simple feedback loops to sophisticated control of diverse species-typical actions. I begin with basic feedback mechanisms of ancient mobile animals and follow the major niche transitions from aquatic to terrestrial life, the retreat into nocturnality in early mammals, the transition to arboreal life and the return to diurnality. Along the way, I propose a sequence of elaboration and diversification of the behavioural repertoire and associated neuroanatomical substrates. This includes midbrain control of approach versus escape actions, telencephalic control of local versus long-range foraging, detection of affordances by the dorsal pallium, diversified control of nocturnal foraging in the mammalian neocortex and expansion of primate frontal, temporal and parietal cortex to support a wide variety of primate-specific behavioural strategies. The result is a proposed functional architecture consisting of parallel control systems, each dedicated to specifying the affordances for guiding particular species-typical actions, which compete against each other through a hierarchy of selection mechanisms.

This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.
The neuroecology of the water-to-land transition and the evolution of the vertebrate brain
Authors: MacIver Malcolm A. , Finlay Barbara L.
Published: December 2021

The water-to-land transition in vertebrate evolution offers an unusual opportunity to consider computational affordances of a new ecology for the brain. All sensory modalities are changed, particularly a greatly enlarged visual sensorium owing to air versus water as a medium, and expanded by mobile eyes and neck. The multiplication of limbs, as evolved to exploit aspects of life on land, is a comparable computational challenge. As the total mass of living organisms on land is a hundredfold larger than the mass underwater, computational improvements promise great rewards. In water, the midbrain tectum coordinates approach/avoid decisions, contextualized by water flow and by the animal’s body state and learning. On land, the relative motions of sensory surfaces and effectors must be resolved, adding on computational architectures from the dorsal pallium, such as the parietal cortex. For the large-brained and long-living denizens of land, making the right decision when the wrong one means death may be the basis of planning, which allows animals to learn from hypothetical experience before enactment. Integration of value-weighted, memorized panoramas in basal ganglia/frontal cortex circuitry, with allocentric cognitive maps of the hippocampus and its associated cortices becomes a cognitive habit-to-plan transition as substantial as the change in ecology.

This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.
Refocusing neuroscience: moving away from mental categories and towards complex behaviours
Authors: Pessoa Luiz , Medina Loreta , Desfilis Ester
Published: December 2021

Mental terms—such as perception, cognition, action, emotion, as well as attention, memory, decision-making—are epistemically sterile. We support our thesis based on extensive comparative neuroanatomy knowledge of the organization of the vertebrate brain. Evolutionary pressures have moulded the central nervous system to promote survival. Careful characterization of the vertebrate brain shows that its architecture supports an enormous amount of communication and integration of signals, especially in birds and mammals. The general architecture supports a degree of ‘computational flexibility’ that enables animals to cope successfully with complex and ever-changing environments. Here, we suggest that the vertebrate neuroarchitecture does not respect the boundaries of standard mental terms, and propose that neuroscience should aim to unravel the dynamic coupling between large-scale brain circuits and complex, naturalistic behaviours.

This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.
Escaping the nocturnal bottleneck, and the evolution of the dorsal and ventral streams of visual processing in primates
Authors: Kaas Jon H. , Qi Hui-Xin , Stepniewska Iwona
Published: December 2021

Early mammals were small and nocturnal. Their visual systems had regressed and they had poor vision. After the extinction of the dinosaurs 66 mya, some but not all escaped the ‘nocturnal bottleneck’ by recovering high-acuity vision. By contrast, early primates escaped the bottleneck within the age of dinosaurs by having large forward-facing eyes and acute vision while remaining nocturnal. We propose that these primates differed from other mammals by changing the balance between two sources of visual information to cortex. Thus, cortical processing became less dependent on a relay of information from the superior colliculus (SC) to temporal cortex and more dependent on information distributed from primary visual cortex (V1). In addition, the two major classes of visual information from the retina became highly segregated into magnocellular (M cell) projections from V1 to the primate-specific temporal visual area (MT), and parvocellular-dominated projections to the dorsolateral visual area (DL or V4). The greatly expanded P cell inputs from V1 informed the ventral stream of cortical processing involving temporal and frontal cortex. The M cell pathways from V1 and the SC informed the dorsal stream of cortical processing involving MT, surrounding temporal cortex, and parietal–frontal sensorimotor domains.

This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.
Developmental resilience of synaptome architecture
Authors: Tomas-Roca Laura , Qiu Zhen , Fransén Erik , Gokhale Ragini , Bulovaite Edita , Price David J. , Komiyama Noboru H. , Grant Seth G.N.
Published: December 2021

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence occur in many disorders1–10, suggesting that brain circuits possess an intrinsic capacity to repair themselves. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model11. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the postnatal expansion of synapse diversity and acquisition of normal synaptome architecture were delayed in all brain regions, interfering with network and cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synaptome architecture to its normal developmental trajectory. Synapse subtypes with high rates of protein turnover mediated these events. These results show synaptome remodelling confers resilience to neurodevelopmental disorders.
A multi-state dynamic process confers mechano-adaptation to the bacterial flagellar motor
Authors: Wadhwa Navish , Sassi Alberto , Berg Howard C. , Tu Yuhai
Published: December 2021

Adaptation is a defining feature of living systems. The bacterial flagellar motor adapts to changes in the external mechanical environment by adding or removing torque-generating stator units. However, the molecular mechanism for mechanosensitive motor remodeling remains unclear. Here, we induced stator disassembly using electrorotation, followed by the time-dependent assembly of the individual stator units into the motor after electrorotation was terminated. From these experiments, we extracted detailed statistics of the dwell times that comprise the stochastic dynamics of the binding and unbinding of stator units. Dwell times reveal multiple timescales, indicating the existence of multiple binding states of the stator units. Based on these results, we propose a minimal model in which the stator unit can occupy four different states – two bound states with very different rates of unbinding, a diffusive unbound state, and a transiently detached state. Our minimal model quantitatively explains multiple features of the experimental data and allows us to determine the transition rates among all four states. Our experiments and modeling suggest a mechanism of mechano-adaptive remodeling of the bacterial flagellar motor in which torque generated by bound stator units controls their effective unbinding rate by modulating the transition between the two bound states. Furthermore, the binding rate of stator units with the motor has a non-monotonic dependence on the number of bound units, likely because of two counteracting effects of motor rotation on the binding process.
Rapid selection of P323L in the SARS-CoV-2 polymerase (NSP12) in humans and non-human primate models and confers a large plaque phenotype
Authors: Dong Xiaofeng , Goldswain Hannah , Penrice-Randal Rebekah , Shawli Ghada T. , Prince Tessa , Williamson Maia Kavanagh , Randle Nadine , Jones Benjamin , Salguero Francisco J , Tree Julia A. , Hall Yper , Hartley Catherine , Erdmann Maximilian , Bazire James , Jearanaiwitayakul Tuksin ,   ISARIC4C investigators, Semple Malcolm G. , Openshaw Peter J. M. , Baille J. Kenneth , Emmett Stevan R. , Digard Paul , Matthews David A. , Turtle Lance , Darby Alistair , Davidson Andrew D. , Carroll Miles W. , Hiscox Julian A.
Published: December 2021

The mutational landscape of SARS-CoV-2 varies at both the dominant viral genome sequence and minor genomic variant population. An early change associated with transmissibility was the D614G substitution in the spike protein. This appeared to be accompanied by a P323L substitution in the viral polymerase (NSP12), but this latter change was not under strong selective pressure. Investigation of P323L/D614G changes in the human population showed rapid emergence during the containment phase and early surge phase of wave 1 in the UK. This rapid substitution was from minor genomic variants to become part of the dominant viral genome sequence. A rapid emergence of 323L but not 614G was observed in a non-human primate model of COVID-19 using a starting virus with P323 and D614 in the dominant genome sequence and 323L and 614G in the minor variant population. In cell culture, a recombinant virus with 323L in NSP12 had a larger plaque size than the same recombinant virus with P323. These data suggest that it may be possible to predict the emergence of a new variant based on tracking the distribution and frequency of minor variant genomes at a population level, rather than just focusing on providing information on the dominant viral genome sequence e.g., consensus level reporting. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.
Elevated ozone concentration and nitrogen addition increase poplar rust severity by shifting the phyllosphere microbial community
Authors: Tao Siqi , Zhang Yunxia , Tian Chengming , Duplessis Sébastien , Zhang Naili
Published: December 2021

The tropospheric ozone and nitrogen deposition are two major environmental pollutants. Numerous studies have focused on the negative impacts of elevated O3and the complementary effect of soil N addition to tree physiological characteristics. However, it was notoriously ignored of how elevated O3with N addition affect tree immunity in face of pathogen infection, as well as of the important roles of phyllosphere microbiome community in host-pathogen-environment interplay. Here, we examined the effects of elevated O3and soil N addition on poplar leaf rust (Melampsora larici-populina) severity of two susceptible hybrid poplars (clone ‘107’:Populus euramericanacv. ‘74/76’; clone ‘546’:P. deltoides⊆P. cathayana) in Free-Air-Controlled-Environment plots, besides, the link betweenMlp-susceptibility and changes in microbial community was determined using Miseq amplicon sequencing. Rust severity of clone ‘107’ significantly increased under elevated O3or N addition only, however, the negative impact of elevated O3could be significantly alleviated when simultaneously conducting N addition, likewise, this trade-off was also found in its phyllosphere microbialα-diversity responding to elevated O3and N addition. However, the rust severity of clone ‘546’ did not significantly differ in the cases of elevated O3and N addition.Mlpinfection altered microbial community composition and increased its sensitivity to elevated O3assessed by significantly different abundance of taxa. Elevated O3and N addition reduced the complexity of microbial community, which may explain the increased severity of poplar rust. These findings demonstrated that poplars need shifting phyllosphere microbial associations to optimize plant immunity in response to environmental changes.

Importance

Exploitation of the interaction mechanisms between host plants and pathogens is the essential basis in disease control. However, while much was known about the molecular determinants in pathogenesis process in the past decades, less is known about the role of nonpathogenic microbial community in plant-pathogen interaction, especially when some host plants are currently encountering severe environmental stresses, such as elevated ozone concentration and superfluous nitrogen addition. Thus, we targeted at the widespread and detriment rust disease (poplar-poplar rust) to dissect the influences of elevated ozone and nitrogen addition on rust disease severity and how phyllosphere microbial groups interacting with both poplars and rust pathogen under these biotic stresses. Our findings could be used to prescribe ecological information about poplar plantation in areas with high levels of ozone pollution and better understand the important roles of microbiome in plant heath.
Zooplankton as a transitional host forEscherichia coliin freshwater
Authors: di Cesare Andrea , Riva Francesco , Colinas Noemi , Borgomaneiro Giulia , Borin Sara , Cabello-Yeves Pedro J. , Canale Claudia , Cedraro Nicholas , Citterio Barbara , Crotti Elena , Mangiaterra Gianmarco , Mapelli Francesca , Mondino Vincenzo , Vignaroli Carla , Quaranta Walter , Corno Gianluca , Fontaneto Diego , Eckert Ester M
Published: December 2021

This study shows thatEscherichia colican be temporarily enriched in zooplankton in natural conditions and that these bacteria can belong to different phylogroups and sequence types including environmental as well as clinical and animal isolates. We isolated 10E. colistrains and sequenced the genomes of two of them. Phylogenetically the two isolates were closer to strains isolated from poultry meat than with freshwaterE. coli, albeit their genomes were smaller than those from poultry. After isolation and fluorescent protein tagging of strains ED1 and ED157 we show thatDaphniasp. can take up these strains and release them alive again, thus forming a temporary host forE. coli. In a chemostat experiment we show that the association does not prolong the bacterial long-term survival, but that at low abundances it does also not significantly reduce the bacterial numbers. We demonstrate thatE. colidoes not belong to the core microbiota ofDaphnia, suffers from competition by the natural microbiota ofDaphnia, but can profit from its carapax to survive in water. All in all, this study suggests that the association ofE. colitoDaphniais only temporary but that the cells are viable therein and this might allow encounters with other bacteria for genetic exchange and potential genomic adaptations to the freshwater environment.

Importance

The contamination of freshwaters with faecal derived bacteria is of major concern regarding drinking water acquisition and recreational activities. Ecological interactions promoting their persistence are still very scarcely studied. This study, which analyses the survival ofE. coliin the presence of zooplankton, is thus of ecological as well as water safety relevance.
Convalescence from prototype SARS-CoV-2 protects Syrian hamsters from disease caused by the Omicron variant
Authors: Ryan Kathryn A. , Watson Robert J. , Bewley Kevin R. , Burton Christopher , Carnell Oliver , Cavell Breeze E. , Challis Amy , Coombes Naomi S. , Emery Kirsty , Fell Rachel , Fotheringham Susan A. , Gooch Karen E. , Gowan Kathryn , Handley Alastair , Harris Debbie J. , Humphreys Richard , Johnson Rachel , Knott Daniel , Lister Sian , Morley Daniel , Ngabo Didier , Osman Karen L. , Paterson Jemma , Penn Elizabeth J. , Pullan Steven T. , Richards Kevin S. , Shaik Imam , Summers Sian , Thomas Stephen R. , Weldon Thomas , Wiblin Nathan R. , Vipond Richard , Hallis Bassam , Funnell Simon G. P. , Hall Yper
Published: December 2021

The mutation profile of the SARS-CoV-2 Omicron variant poses a concern for naturally acquired and vaccine-induced immunity. We investigated the ability of prior infection with an early SARS-CoV-2, 99.99% identical to Wuhan-Hu-1, to protect against disease caused by the Omicron variant. We established that infection with Omicron in naïve Syrian hamsters resulted in a less severe disease than a comparable dose of prototype SARS-CoV-2 (Australia/VIC01/2020), with fewer clinical signs and less weight loss. We present data to show that these clinical observations were almost absent in convalescent hamsters challenged with the same dose of Omicron 50 days after an initial infection with Australia/VIC01/2020. The data provide evidence for immunity raised against prototype SARS-CoV-2 being protective against Omicron in the Syrian hamster model. Further investigation is required to conclusively determine whether Omicron is less pathogenic in Syrian hamsters and whether this is predictive of pathogenicity in humans.
The omicron (B.1.1.529) SARS-CoV-2 variant of concern does not readily infect Syrian hamsters
Authors: Abdelnabi Rana , Foo Caroline S. , Zhang Xin , Lemmens Viktor , Maes Piet , Slechten Bram , Raymenants Joren , André Emmanuel , Weynand Birgit , Dallemier Kai , Neyts Johan
Published: December 2021

The emergence of SARS-CoV-2 variants of concern (VoCs) has exacerbated the COVID-19 pandemic. End of November 2021, a new SARS-CoV-2 variant namely the omicron (B.1.1.529) emerged. Since this omicron variant is heavily mutated in the spike protein, WHO classified this variant as the 5th variant of concern (VoC). We previously demonstrated that the other SARS-CoV-2 VoCs replicate efficiently in Syrian hamsters, alike also the ancestral strains. We here wanted to explore the infectivity of the omicron variant in comparison to the ancestral D614G strain. Strikingly, in hamsters that had been infected with the omicron variant, a 3 log10 lower viral RNA load was detected in the lungs as compared to animals infected with D614G and no infectious virus was detectable in this organ. Moreover, histopathological examination of the lungs from omicron-infecetd hamsters revealed no signs of peri-bronchial inflammation or bronchopneumonia. Further experiments are needed to determine whether the omicron VoC replicates possibly more efficiently in the upper respiratory tract of hamsters than in their lungs.
Survival and detection of bivalve transmissible neoplasia from the soft-shell clam Mya arenaria (MarBTN) in seawater
Authors: Giersch Rachael M. , Hart Samuel F.M. , Reddy Satyatejas G. , Yonemitsu Marisa A. , Orellana Rosales María J. , Korn Madelyn , Geleta Brook M. , Countway Peter D. , Fernández Robledo José A. , Metzger Michael J.
Published: December 2021

Many pathogens can cause cancer, but cancer itself does not normally act as an infectious agent. However, transmissible cancers have been found in a few cases in nature: in Tasmanian devils, dogs, and several bivalve species. The transmissible cancers in dogs and devils are known to spread through direct physical contact, but the exact route of transmission of bivalve transmissible neoplasia (BTN) has not yet been confirmed. It has been hypothesized that cancer cells could be released by diseased animals and spread through the water column to infect/engraft into other animals. To test the feasibility of this proposed mechanism of transmission, we tested the ability of BTN cells from the soft-shell clam (Mya arenaria BTN, or MarBTN) to survive in artificial seawater. We found that BTN cells are highly sensitive to salinity, with acute toxicity at salinity levels lower than those found in their environment. BTN cells also survive longer at lower temperatures, with >48% of cells surviving a week in seawater at temperatures from 4°C to 16°C, and 49% surviving for more than two weeks at 4°C. With one clam donor, living cells were observed for more than eight weeks at 4°C. We also used qPCR of environmental DNA (eDNA) to detect the presence of BTN-specific DNA in the environment. We observed release of BTN-specific DNA into the water of aquaria from tanks with highly BTN-positive clams, and we detected BTN-specific DNA in seawater samples collected from BTN-endemic areas, although the level detected was much lower. Overall, these data show that BTN cells can survive well in seawater, and they are released into the water by diseased animals, supporting the hypothesis that BTN is spread from animal-to-animal by cells through seawater.
Distinct cDC subsets co-operate in CD40 agonist response while suppressive microenvironments and lack of antigens subvert efficacy
Authors: Murgaski Aleksandar , Kiss Máté , Van Damme Helena , Kancheva Daliya , Vanmeerbeek Isaure , Keirsse Jiri , Hadadi Eva , Brughmans Jan , Arnouk Sana M. , Hamouda Ahmed E. I. , Debraekeleer Ayla , Bosteels Victor , Elkrim Yvon , Boon Louis , Hoves Sabine , Vandamme Niels , Deschoemaeker Sofie , Janssens Sophie , Garg Abhishek D. , Schmittnägel Martina , Ries Carola H. , Laoui Damya
Published: December 2021

Agonistic αCD40 therapy has shown to inhibit cancer progression, but only in a fraction of patients. Hence, understanding the cancer cell-intrinsic and microenvironmental determinants of αCD40 therapy response is crucial to identify responsive patient populations and design efficient combination treatments. Here, we showed that the therapeutic efficacy of αCD40 in responder melanoma tumours, relied on pre-existing cDC1-primed CD8+ T cells, however cDC1s were dispensable after αCD40 administration. Surprisingly, in response to αCD40 the abundance of activated cDCs, potentially derived from cDC2s increased, thereby further activating antitumour CD8+ T cells. Hence, distinct cDC subsets are required to induce αCD40 responses. By contrast, lung tumours, characterised by a high abundance of macrophages, were resistant to αCD40 therapy. Combining αCD40 therapy with macrophage depletion led to tumour growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell-death inducing chemotherapy sensitised non-immunogenic tumours to αCD40 therapy.
Transgenic resources for functional studies on the hsrω gene in Drosophila
Authors: Sahu Ranjan Kumar , Trivedi Deepti , Lakhotia Subhash Chandra
Published: December 2021

The hsrω gene of Drosophila melanogaster, an early discovered non-coding developmentally active and stress-inducible gene, has pleiotropic actions through its multiple nuclear and cytoplasmic non-coding transcripts. With a view to understand this diverse functions and mechanisms of actions of this gene, we generated a series of transgenic lines for over-expression or RNAi of different transcripts and CRISPR-Cas9 mediated deletion alleles. These are described here.
EMX2 transcriptionally regulates Nfib expression in neural progenitor cells during early cortical development
Authors: Lim Jonathan W. C. , Bunt Jens , Bridges Caitlin R. , Moey Ching , Jacobs Matisse T. , Chen Kok-Siong , Richards Linda J.
Published: December 2021

The nuclear factor one (NFI) transcription factors play key roles in regulating the onset of both neuronal and glial differentiation during cortical development. Reduced NFI expression results in delayed differentiation, which is associated with neurodevelopmental disorders in humans that include intellectual disability, agenesis of the corpus callosum and macrocephaly. Despite their importance, our understanding of how individual NFI family members are regulated during cortical development remains limited. Here, we demonstrate that in mice, the homeobox transcription factor EMX2 regulates Nfib expression in radial glial cells during cortical development. Using a combination of bioinformatics, molecular and histological approaches, we demonstrate that EMX2 is able to bind to the Nfib promoter to up-regulate Nfib expression. Unexpectedly, in vivo over-expression of EMX2 in wildtype animals does not further up-regulate NFIB but instead leads to its down-regulation. Therefore, our findings suggest that EMX2 is capable of both activating and repressing Nfib, in a context-dependent manner. This bi-directional control over Nfib expression enables fine-tuning of the total level of NFI proteins expressed and could be important for cell-type specific NFI functions.
A unifying perspective of the ultrafast photo-dynamics of Orange Carotenoid Protein from Synechocystis: peril of high-power excitation, existence of different S* states and influence of tagging
Authors: Niziński Stanisław , Wilson Adjéle , Uriarte Lucas M. , Ruckebusch Cyril , Andreeva Elena A. , Schlichting Ilme , Colletier Jacques-Philippe , Kirilovsky Diana , Burdzinski Gotard , Sliwa Michel
Published: December 2021

A substantial number of Orange Carotenoid Protein (OCP) studies have aimed to describe the evolution of singlet excited states leading to the formation of photo-activated form, OCPR. The most recent one suggests that three picosecond-lived excited states are formed after the sub-100 fs decay of the initial S2 state. The S* state which has the longest reported lifetime of a few to tens of picoseconds is considered to be the precursor of the first red photoproduct P1. Here, we report the ultrafast photo-dynamics of the OCP from Synechocystis PCC 6803, carried out using Visible-NIR femtosecond time-resolved absorption spectroscopy as a function of the excitation pulse power and wavelength. We found that a carotenoid radical cation can form even at relatively low excitation power, obscuring the determination of photo-activation yields for P1. Moreover, the comparison of green (540 nm) and blue (470 nm) excitations revealed the existence of an hitherto uncharacterized excited state, denoted as S∼, living a few tens of picoseconds and formed only upon 470 nm excitation. Since neither the P1 quantum yield nor the photo-activation speed over hundreds of seconds vary under green and blue continuous irradiation, this S∼ species is unlikely to be involved in the photo-activation mechanism leading to OCPR. We also addressed the effect of His-tagging at the N- or C-termini on excited state photo-physical properties. Differences in spectral signatures and lifetimes of the different excited states were observed, at variance with the usual assumption that His-tagging hardly influences protein dynamics and function. Altogether our results advocate for careful consideration of the excitation power and His-tag position when comparing the photo-activation of different OCP variants, and beg to revisit the notion that S* is the precursor of photoactivated OCPR.

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