bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Surgical Pathologist for the Detection of Immuno-oncologic Predictive Factors in Non-small Cell Lung Cancers
Authors: Mohanty Sambit K. , Mishra Sourav K. , Amin Mahul B. , Agaimy Abbas , Fuchs Florian
Published: April 2023

Until very recently, surgery, chemotherapy, and radiation therapy have been the mainstay of treatment in non-small cell carcinomas (NSCLCs). However, recent advances in molecular immunology have unveiled some of the complexity of the mechanisms regulating cellular immune responses and led to the successful targeting of immune checkpoints in attempts to enhance antitumor T-cell responses. Immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4, programmed cell death protein-1, and programmed death ligand (PD-L) 1 have been shown to play central roles in evading cancer immunity. Thus, these molecules have been targeted by inhibitors for the management of cancers forming the basis of immunotherapy. Advanced NSCLC has been the paradigm for the benefits of immunotherapy in any cancer. Treatment decisions are made based on the expression of PD-L1 on the tumor cells and the presence or absence of driver mutations. Patients with high PD-L1 expression (≥50%) and no driver mutations are treated with single-agent immunotherapy whereas, for all other patients with a lower level of PD-L1 expression, a combination of chemotherapy and immunotherapy is preferred. Thus, PD-L1 blockers are the only immunotherapeutic agents approved in advanced NSCLC without any oncogenic driver mutations. PD-L1 immunohistochemistry, however, may not be the best biomarker in view of its dynamic nature in time and space, and the benefits may be seen regardless of PD -L1 expression. Each immunotherapy molecule is prescribed based on the levels of PD-L1 expression as assessed by a Food and Drug Administration-approved companion diagnostic assay. Other biomarkers that have been studied include tumor mutational burden, the T-effector signature, tumor-infiltrating lymphocytes, radiomic assays, inflammation index, presence or absence of immune-related adverse events and specific driver mutations, and gut as well as local microbiome. At the current time, none of these biomarkers are routinely used in the clinical decision-making process for immunotherapy in NSCLC. However, in individual cases, they can be useful adjuncts to conventional therapy. This review describes our current understanding of the role of biomarkers as predictors of response to immune checkpoint molecules. To begin with a brief on cancer immunology in general and in NSCLC, in particular, is discussed. In the end, recent advancements in laboratory techniques for refining biomarker assays are described.
Enteral Nutrition During Extracorporeal Membrane Oxygenation in the Neonatal and Pediatric Populations: A Literature Review
Authors: Dennis Jocelyn L. , Jordan Jeremy , Rice Marti , Lee Amy E.
Published: April 2023

OBJECTIVES:

The number of infants and children requiring extracorporeal membrane oxygenation (ECMO) is rising. While critically ill, providers may believe that enteral nutrition puts the patient at risk for severe complications such as necrotizing enterocolitis. However, enteral nutrition is associated with the potential to improve the gut barrier and reduce the risk of morbidity and mortality. The purpose of this article is to review the existing evidence about providing exclusive enteral and parenteral nutrition and its association with rates of complications and mortality in critically ill neonatal and pediatric populations on ECMO.

DATA SOURCES:

Literature addressing enteral nutrition while on ECMO for neonatal and pediatric populations was searched using PubMed, CINAHL, and Scopus.

STUDY SELECTION:

Studies ranged from 1998 to 2022 and were conducted mostly in the PICU and neonatal ICU settings.

DATA EXTRACTION:

Fourteen articles were reviewed after inclusion and exclusion criteria were applied.

DATA SYNTHESIS:

Characteristics included an even number of males and females in samples from mostly PICUs. The predominant underlying illnesses were neonatal pulmonary disease and cardiac disease. Upon reviewing the literature, three major themes were revealed: no significant complications with enteral feeding, underutilization of enteral feeding, and reduced mortality with enteral feeding.

CONCLUSION:

The use of enteral nutrition in the neonatal and pediatric population while on ECMO has the potential to improve survival rates and reduce complications. Further studies are needed to investigate how to optimize this population’s nutrition and develop feeding protocols and pathways.
Severe Acute Respiratory Syndrome Coronavirus 2 in Infants Younger Than 90 Days Presenting to the Pediatric Emergency Department
Authors: Benenson-Weinberg Talia , Gross Itai , Bamberger Zeev , Guzner Noa , Wolf Dana , Gordon Oren , Nama Ahmad , Hashavya Saar
Published: April 2023

Objectives

There are scant data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in infants younger than 90 days. This study was designed to characterize COVID-19 presentation and clinical course in this age group and evaluate the risk of serious bacterial infection.

Methods

Data on all SARS-CoV-2–polymerase chain reaction-positive infants presenting to the pediatric emergency department (PED) were retrospectively collected, followed by a case-control study comparing those infants presenting with fever (COVID group) to febrile infants presenting to the PED and found to be SARS-CoV-2 negative (control group).

Results

Of the 96 PCR-positive SARS-CoV-2 infants who met the inclusion criteria, the most common presenting symptom was fever (74/96, 77.1%) followed by upper respiratory tract infection symptoms (42/96, 43.8%). Four (4.2%) presented with symptoms consistent with brief resolved unexplained event (4.2%).

Among the febrile infants, the presenting symptoms and vital signs were similar in the COVID and control groups, with the exception of irritability, which was more common in the control group (8% and 26%; P < 0.01). The SARS-CoV-2-positive infants had decreased inflammatory markers including: C-reactive protein (0.6 ± 1 mg/dL vs 2.1 ± 2.7 mg/dL; P < 0.0001), white blood cell count (9.3 ± 3.4 × 109/L vs 11.8 ± 5.1 × 109/L; P < 0.001), and absolute neutrophils count (3.4 ± 2.4 × 109/L vs 5.1 ± 3.7 × 109/L; P < 0.001). The rate of invasive bacterial infection was similar between groups (1.4% and 0%; P = 0.31). No mortality was recorded. Although not significantly different, urinary tract infections were less common in the COVID group (7% and 16%; P = 0.07)

Conclusions

The SARS-CoV-2 infection in infants aged 0 to 90 days who present to the PED seems to be mostly mild and self-limiting, with no increased risk of serious bacterial infection.
Minimal invasive treatment of trapeziometacarpal osteoarthritis: Results of a blinded, randomized controlled trial.
Authors: Winter Raimund , Tuca Alexandru-Cristian , Justich Ivo , Tschauner Sebastian , Friedl Herwig , Girsch Werner , Lebo Patricia , Zrim Robert , Lumenta David Benjamin , Kamolz Lars-P.
Published: April 2023

Background:

Surgical therapy for widespread CMC1 arthritis permanently alters the physiological anatomy of the hand. The injection of autologous substances into the thumb saddle joint could achieve temporary pain relief and delay surgical indications.

This trial aimed to compare the pain-reducing effects of autologous fat and/or platelet-rich plasma (PRP) with saline 0.9% in the infiltration therapy of carpometacarpal arthritis of the thumb (CMC1 arthritis).

Patients and Methods:

A blinded, randomized controlled trial was conducted. 95 patients with CMC1 arthritis were included in the study. The mean follow-up period was 2 years. Participants were injected with 1.5ml of autologous fat, PRP, autologous fat and PRP, or saline solution 0.9% into the CMC1 joint depending on the group allocation.

The primary outcome of this study was the evaluation of pain reduction in each treatment group.

Results:

The combination of fat and PRP was the only treatment that resulted in a significantly greater reduction in pain compared to 0.9% saline (p=0.003). Similarly, fat and PRP in combination was the only therapy group to achieve clinically relevant quick disabilities of arm, shoulder, and hand (Dash) score reduction, and the only group that showed a significantly better Short Form (SF)-36 score than 0.9% saline (p=0.016). No major complications were noted.

Conclusion:

In addition to pain reduction, the combination of autologous fat and PRP yields a relevant improvement in hand function and a corresponding improvement in quality of life, and seems to be a viable and safe alternative to short-acting glucocorticoids.
Combined great toe dorsal nail-skin flap and medial plantar flap for reconstruction of degloved finger loss
Authors: Tang Lin , Zhou Xin , Huang Shuqing , Zou Yonggen
Published: April 2023

Background:

Historically, the degloved finger with the total loss of nails and skin had been resurfaced into two stages. Further, proximal finger amputation requires an additional bone-tendon graft and an expanded great toe wraparound flap transfer for better outcomes. The article recommends a novel strategy to address these problems in a single stage using a dorsal nail-skin flap and medial plantar artery perforator (MPAP) flap.

Method:

From March 2015 to June 2018, nine fingers were performed to resurface with skin loss to the metacarpophalangeal (MCP) joint level, and three amputated fingers were reconstructed with an extra bone-joint-tendon graft simultaneously. The dorsal great toe donor was covered with a thin groin flap, and the medial plantar site was covered with a full-thickness skin graft. A standardized assessment of outcome in terms of sensory, functional, and esthetic performance was completed.

Results:

All flaps survived. The contour and length of the reconstructed digits were comparable with the contralateral finger. The mean static two-point discrimination was 11.0 mm (ranged, 9.0-14.0 mm). The average score of the Disabilities of the Arm, Shoulder and Hand questionnaire and Michigan Hand Outcomes Questionnaire were 2.5 (ranged,0-5) and 90.1 (ranged,82-96). The mean Foot and ankle disability index score was 95.6 (ranged, 93-99). At the last follow-up, the functional and aesthetic outcomes were satisfied for all fingers, as well as the restored sensory.

Conclusion:

This strategy may provide an alternative for the selected patients, seeking cosmetic resurface and functional reconstruction, preserving a weight-bearing plantar area with less morbidity.

Clinical question/Level of Evidence:

Therapeutic, IV
Survival prediction in advanced cancer patients – a narrative review
Authors: Lee Shing Fung , Simone Charles B.
Published: April 2023

Purpose of review

The exploration for accurate ways to predict survival for advanced cancer patients continues to be a significant theme despite the advent of objective criteria and their combination with clinical criteria. The purpose of this article was to review some of the latest studies relating to prognostication and the capacity to predict survival during the terminal cancer stage.

Recent findings

Recent studies show notable prognostication approaches using genetic tests and advanced computation methods such as machine learning, which we will summarize.

Significant effort has been made to improve the accuracy of survival estimation for advanced cancer patients. The main goals are to optimize individualized patient management and uses of resources. Advanced techniques, including genetic markers and machine learning techniques, may improve the accuracy of prediction.
The untapped health and climate potential of cycling in France: a national assessment from individual travel data
Authors: Schwarz Emilie , Leroutier Marion , De Nazelle Audrey , Quirion Philippe , Jean Kévin
Published: April 2023

Background

Promoting active modes of transportation such as cycling may generate important public health, economic, and climate mitigation benefits. We aim to assess mortality and morbidity impacts of cycling in a country with relatively low levels of cycling, France, along with associated monetary benefits; we further assess the potential additional benefits of shifting a portion of short trips from cars to bikes, including projected greenhouse gas emissions savings.

Methods

Using individual data from a nationally-representative mobility survey, we described the French 2019 cycling levels by age and sex. We conducted a burden of disease analysis to assess the incidence of five chronic diseases (breast cancer, colon cancer, cardio-vascular diseases, dementia, and type-2 diabetes) and numbers of deaths prevented by cycling, based on national incidence and mortality data and dose-response relationships from meta-analyses. We assessed the corresponding direct medical cost savings and the intangible costs prevented based on the value of a statistical life year. Lastly, based on individual simulations, we assessed the likely additional benefits of shifting 25% of short (<5km) car trips were shifted to cycling.

Findings

The French adult (20-89 years) population was estimated to cycle on average of 1min 17sec pers-1.day-1in 2019, with important heterogeneity across gender and age. This yielded benefits of 1,919 (uncertainty interval, UI: 1,101-2,736) premature deaths and 5,963 (UI: 3,178-8,749) chronic disease cases prevented, with males enjoying nearly 75% of these benefits. Direct medical costs prevented were estimated at €191 million (UI: 98-285) annually, while the corresponding intangible costs were nearly 25 times higher (€4.8 billion, UI: 3.0-6.5). We estimated that in average, €1.02 (UI: 0.59-1.62) of intangible costs were prevented for every km cycled. Shifting 25% of short car trips to biking would yield approximatively a 2-fold increase in death prevented, while also generating important CO2emission reductions (0.257 MtCO2e, UI: 0.231-0.288).

Interpretation

In a country of low- to moderate cycling culture, cycling already generates important public health and health-related economic benefits. Further development of active transportation would increase these benefits while also contributing to climate change mitigation targets.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
A neural mass model for the EEG in ischemia
Authors: Kalia Manu , Ligtenstein Sophie L.B. , Meijer Hil G.E. , van Putten Michel J.A.M.
Published: April 2023

Normal brain function depends on continuous cerebral blood flow for the supply of oxygen and glucose, and is quickly compromised in conditions where the metabolic demand cannot be met. Insufficient cerebral perfusion can result in ischemic stroke, with symptoms ranging from loss of motor or language function to coma, depending on the brain areas affected. Cerebral ischemia also results in changes in the electroencephalogram. Initially, a reduction of the frequency of the rhythms occurs. Depending on the depth and duration of energy deprivation, this eventually leads to the disappearance of all rhythmic activity. Here, we study the relationship between electroencephalogram (EEG) phenomenology and cellular biophysical principles using a model of interacting thalamic and cortical neural masses coupled with energy-dependent synaptic transmission. Our model faithfully reproduces the characteristic EEG phenomenology during acute cerebral ischemia and shows that synaptic arrest occurs before cell swelling and irreversible neuronal depolarization. The early synaptic arrest is attributed to ion homeostatic failure due to dysfunctional Na+/K+-ATPase. Moreover, we show that the excitatory input from relay cells to the cortex controls rhythmic behavior. In particular, weak relay-interneuron interaction manifests in burst-like EEG behavior immediately prior to synaptic arrest. We corroborate our observations with human EEG data from patients undergoing carotid endarterectomy and patients after cardiac arrest with a postanoxic encephalopathy. The model thus reconciles the implications of stroke on a cellular, synaptic and circuit level and provides a basis for exploring other multi-scale therapeutic interventions.

Significance statement

Reliable synaptic transmission and preservation of ion gradients across cellular membranes are essential for physiological brain function and consume significant energy. During cerebral ischemia, synaptic arrest occurs early due to energy deprivation (ED), which is characterized clinically by the loss of physiological electroencephalographic (EEG) rhythms. In this work, we explore connections between cellular and network behavior during ED by means of a novel computational model that describes ion dynamics in the cortex and thalamus, and resulting EEG. We reproduce characteristic EEG behavior during ED and show that synaptic arrest occurs before other pathologies like swelling and depolarization. Moreover, we predict that low excitatory thalamocortical projections cause burst-like EEG patterns before synaptic arrest, which may explain observations regarding post-stroke synaptic reorganization.
Mental navigation and telekinesis with a hippocampal map-based brain-machine interface
Authors: Lai Chongxi , Tanaka Shinsuke , Harris Timothy D. , Lee Albert K.
Published: April 2023

The hippocampus is critical for recollecting and imagining experiences. This is believed to involve voluntarily drawing from hippocampal memory representations of people, events, and places, including the hippocampus’ map-like representations of familiar environments. However, whether the representations in such “cognitive maps” can be volitionally and selectively accessed is unknown. We developed a brain-machine interface to test if rats could control their hippocampal activity in a flexible, goal-directed, model-based manner. We show that rats can efficiently navigate or direct objects to arbitrary goal locations within a virtual reality arena solely by activating and sustaining appropriate hippocampal representations of remote places. This should provide insight into the mechanisms underlying episodic memory recall, mental simulation/planning, and imagination, and open up possibilities for high-level neural prosthetics utilizing hippocampal representations.
A cross-sectional study of the association between COVID-19 infection and psychological distress in Japanese workers
Authors: Tesen Hirofumi , Konno Yusuke , Tateishi Seiichiro , Mafune Kosuke , Tsuji Mayumi , Ogami Akira , Nagata Tomohisa , Matsugaki Ryutaro , Yoshimura Reiji , Fujino Yoshihisa ,   the CORoNaWork Project
Published: April 2023

The COVID-19 pandemic infected many people worldwide with SARS-CoV2. Psychological distress is one of the sequelae reported to occur in many of those infected (Choutka et al., 2022). We investigated the association between personal experience of COVID-19 infection and psychological distress in Japan. A total of 18,560 persons participated in the original survey, conducted in December 2020. After excluding unreliable responses, data from 14,901 persons who participated in a follow-up survey in December 2022-were included in the analysis. Odds ratios (ORs) were estimated by univariate and multiple logistic regression analysis with history of COVID-19 infection as the independent variable and presence of psychological distress as the dependent variable.

This results showed that the experience of COVID-19 infection is associated with psychological distress. Moreover, most cases of mental distress among those who experienced COVID-19 infection can be at least partly explained by a perception of unfair treatment.
A self-renewing biomimetic skeletal muscle construct engineered using induced myogenic progenitor cells
Authors: Kim Inseon , Lee Seunghun S. , Ghosh Adhideb , Ferguson Stephen J. , Bar-Nur Ori
Published: April 2023

Skeletal muscle is a highly organized and regenerative tissue that maintains its homeostasis primarily by activation and differentiation of muscle stem cells. Mimicking anin vitroskeletal muscle differentiation program that contains self-renewing adult muscle stem cells and aligned myotubes has been challenging. Here, we set out to engineer a biomimetic skeletal muscle construct that can self-regenerate and produce aligned myotubes using induced myogenic progenitor cells (iMPCs), a heterogeneous culture consisting of skeletal muscle stem, progenitor and differentiated cells. Utilizing electrospinning, we fabricated polycaprolactone (PCL) substrates that enabled iMPC-differentiation into aligned myotubes by controlling PCL fiber orientation. Newly-conceived constructs contained highly organized multinucleated myotubes in conjunction with self-renewing muscle stem cells, whose differentiation capacity was augmented by Matrigel supplementation. Additionally, we demonstrate using single cell RNA-sequencing (scRNA-seq) that iMPC-derived constructs faithfully recapitulate a step-wise myogenic differentiation program. Notably, when the constructs were subjected to a damaging myonecrotic agent, self-renewing muscle stem cells rapidly differentiated into aligned myotubes, akin to skeletal muscle repairin vivo. Taken together, we report on a novelin vitrosystem that mirrors myogenic regeneration and muscle fiber alignment, and can serve as a platform to study myogenesis, model muscular dystrophies or perform drug screens.
Interdependence patterns of multi-frequency oscillations predict visuomotor behavior
Authors: Bahuguna Jyotika , Schwey Antoine , Battaglia Demian , Malfait Nicole
Published: April 2023

We show that sensorimotor behavior can be reliably predicted from single-trial EEG oscillations fluctuating in a coordinated manner across brain regions, frequency bands and movement time epochs. We define high-dimensionaloscillatory portraitsto capture the interdependence between basicoscillatory elements, quantifying oscillations occurring in single-trials at specific frequencies, locations and time epochs. We find that the general structure of the element-interdependence networks (effective connectivity) remains stable across task conditions, reflecting an intrinsic coordination architecture and responds to changes in task constraints by subtle but consistently distinct topological reorganizations. Trial categories are reliably and significantly better separated using oscillatory portraits, than from the information contained in individual oscillatory elements, suggesting an inter-element coordination-based encoding. Furthermore, single-trial oscillatory portrait fluctuations are predictive of fine trial-to-trial variations in movement kinematics. Remarkably, movement accuracy appears to be reflected in the capacity of the oscillatory coordination architecture to flexibly update as an effect of movement-error integration.
PMIpred: A physics-informed web server for quantitative Protein-Membrane Interaction prediction
Authors: van Hilten Niek , Verwei Nino , Methorst Jeroen , Nase Carsten , Bernatavicius Andrius , Risselada Herre Jelger
Published: April 2023

Motivation

Many membrane peripheral proteins have evolved to transiently interact with the surface of (curved) lipid bilayers. Currently, methods toquantitativelypredict sensing and binding free energies for protein sequences or structures are lacking, and such tools could greatly benefit the discovery of membrane-interacting motifs, as well as theirde novodesign.

Results

Here, we trained a transformer neural network model on molecular dynamics data for>50,000 peptides that is able to accurately predict the (relative) membrane-binding free energy for any given amino acid sequence. Using this information, our physics-informed model is able to classify a peptide’s membrane-associative activity as either non-binding, curvature sensing, or membrane binding. Moreover, this method can be applied to detect membraneinteraction regions in a wide variety of proteins, with comparable predictive performance as state-of-the-art data-driven tools like DREAMM, PPM3, and MODA, but with a wider applicability regarding protein diversity, and the added feature to distinguish curvature sensing from general membrane binding.

Availability

We made these tools available as a web server, coined Protein-Membrane Interaction predictor (PMIpred), which can be accessed athttps://pmipred.fkt.physik.tu-dortmund.de.
Probe capture enrichment sequencing ofamoAgenes discloses diverse ammonia-oxidizing archaeal and bacterial populations
Authors: Hiraoka Satoshi , Ijichi Minoru , Takeshima Hirohiko , Kumagai Yohei , Yang Ching-Chia , Makabe-Kobayashi Yoko , Fukuda Hideki , Yoshizawa Susumu , Iwasaki Wataru , Kogure Kazuhiro , Shiozaki Takuhei
Published: April 2023

The ammonia monooxygenase subunit A (amoA) gene has been used to investigate the phylogenetic diversity, spatial distribution, and activity of ammonia-oxidizing archaeal (AOA) and bacterial (AOB), which contribute significantly to the nitrogen cycle in various ecosystems. Amplicon sequencing ofamoAis a widely used method; however, it produces inaccurate results owing to the lack of a ‘universal’ primer set. Moreover, currently available primer sets suffer from amplification biases, which can lead to severe misinterpretation. Although shotgun metagenomic and metatranscriptomic analyses are alternative approaches without amplification bias, the low concentration of target genes in heterogeneous environmental DNA restricts a comprehensive analysis to a realizable sequencing depth. In this study, we developed a method foramoAenrichment sequencing using a hybridization capture technique. Using metagenomic mock community samples, our approach effectively enrichedamoAgenes with low compositional changes, outperforming amplification and meta-omics sequencing analyses. Following the analysis of metatranscriptomic marine samples, we predicted 80 operational taxonomic units (OTUs) assigned to either AOA or AOB, of which 30 OTUs were unidentified using simple metatranscriptomic oramoAgene amplicon sequencing. Mapped read ratios to all the detected OTUs were significantly higher for the capture samples (50.4 ± 27.2%) than for non-capture samples (0.05 ± 0.02%), demonstrating the high enrichment efficiency of the method. The analysis also revealed the spatial diversity of AOA ecotypes with high sensitivity and phylogenetic resolution, which are difficult to examine using conventional approaches.
Title: Toleration of Frameshift Mutations in mRNA Sequences Encoding the N-terminal Peptides of Bacterial Type III Effectors
Authors: Yang Jielin , Lu Moyang , Yu Mingyang , Wang Xinlong , Zhao Ziyi , Luo Lijun , Cai Xuxia , Chen Runhong , Hu Yueming , Wang Yejun
Published: April 2023

Gram-negative bacteria deliver effector proteins into eukaryotic host cells through type III and type IV secretion systems, causing infections and diseases. It remains unclear about the signals guiding the specific secretion of the effectors. Here, we adopted anin silicoapproach to analyze the mRNA sequences encoding the putative peptides essential for effective secretion and translocation of type III and IV effectors. A surprisingly high proportion of type III effectors showed tolerance on frameshift mutations in signal-encoding mRNA sequences, and in contrast, very low percentage of type IV effectors showed the similar frameshift tolerance. The type III effectors with frameshift tolerance of secretion signals were widely distributed in effector or signal families and bacterial species. Natural frameshifts could be identified in type III effector genes, which were often remedied in time by nearby paired insertions or deletions. Frameshift-derived peptide sequences also retained the common properties present in the signal peptides of raw type III effectors. Natural language processing models were adopted to represent the common features in the mRNA sequences encoding N-terminal peptides of type III effectors or C-terminal peptides of type IV effectors, with which transfer learning models could well predict the effectors, especially type IV effectors. The observations in the study would facilitate us understand the nature and evolution of secretion signals of type III and IV effectors.

Significance

It has been a debate on the nature of signals for translocation of type III secreted effectors for a long time. Meanwhile, there has been no examination on the possibility of mRNA being as translocation signals for type IV or other types of secreted effectors. By computational simulation, the study demonstrated the protein nature of translocation signals for both type IV effectors and most type III effectors. Despite wide frameshift tolerance and atypical common features in mRNA sequences encoding the putative N-terminal signal sequences of type III effectors, more typical common physicochemical and amino acid composition properties between the mutation-derived and raw peptides, and the frequent self-correction phenomenon for naturally happening frameshifts supported the translocation signals at protein level of type III effectors. The common features in mRNA sequences encoding the translocation signal peptides of type III and IV effectors could also be combined in models for better prediction of the effectors respectively.
Direct monitoring of the thermodynamics and kinetics of DNA and RNA dinucleotide dehybridization from gaps and overhangs
Authors: Ashwood Brennan , Jones Michael S. , Radakovic Aleksandar , Khanna Smayan , Lee Yumin , Sachleben Joseph R. , Szostak Jack W. , Ferguson Andrew L. , Tokmakoff Andrei
Published: April 2023

Hybridization of short nucleic acid segments (<4 nucleotides) to single-strand templates occurs as a critical intermediate in processes such as non-enzymatic nucleic acid replication and toehold-mediated strand displacement. These templates often contain adjacent duplex segments that stabilize base pairing with single-strand gaps or overhangs, but the thermodynamics and kinetics of hybridization in such contexts are poorly understood due to experimental challenges of probing weak binding and rapid structural dynamics. Here we develop an approach to directly measure the thermodynamics and kinetics of DNA and RNA dinucleotide dehybridization using steady-state and temperature-jump infrared spectroscopy. Our results suggest that dinucleotide binding is stabilized through coaxial stacking interactions with the adjacent duplex segments as well as from potential non-canonical base pairing configurations and structural dynamics of gap and overhang templates revealed using molecular dynamics simulations. We measure timescales for dissociation ranging from 0.2 to 40 µs depending on the template and temperature. Dinucleotide hybridization and dehybridization involves a significant free energy barrier with characteristics resembling that of canonical oligonucleotides. Together, our work provides an initial step for predicting the stability and kinetics of hybridization between short nucleic acid segments and various templates.
Hormonal coordination of peripheral motor output and corollary discharge in a communication system
Authors: Fukutomi Matasaburo , Carlson Bruce A.
Published: April 2023

Steroid hormones remodel neural networks to induce developmental or seasonal changes in animal behavior, but little is known about hormonal modulation of sensorimotor integration. Here, we investigate hormonal effects on a predictive motor signal, termed corollary discharge, that modulates sensory processing in weakly electric mormyrid fish. In the electrosensory pathway mediating communication behavior, inhibition activated by a corollary discharge precisely blocks sensory responses to self-generated electric pulses, allowing the downstream circuit to selectively analyze communication signals from nearby fish. These electric pulses are elongated by increasing testosterone levels in males during the breeding season. Using systematic testosterone treatment, we induced electric-pulse elongation in fish and found that the timing of electroreceptor spiking responses to self-generated pulses (reafference) was delayed as electric pulse duration increased. Recording evoked potentials from a midbrain electrosensory nucleus revealed that the timing of corollary discharge inhibition was delayed and elongated by testosterone. Further, this shift in corollary discharge timing was precisely matched to the shift in timing of the reafferent spikes. We then asked whether the shift in inhibition timing was caused by direct action of testosterone on the corollary discharge circuit or plasticity of the circuit through altered sensory feedback. We surgically silenced the electric organs of fish and found similar hormonal modulation of corollary discharge timing between intact and silent fish, suggesting that sensory feedback was not required for this shift. These results demonstrate that testosterone directly and independently modulates peripheral motor output and a predictive motor signal in a coordinated manner.

Significance

Self-other discrimination is essential for animals. Internal predictive motor signals, or corollary discharge, provide motor information to sensory areas so that animals can perceive self- and other-generated stimuli differently. As behavior and associated sensory feedback change with development, corollary discharge must adjust accordingly. Using weakly electric mormyrid fish, we show that the steroid hormone testosterone alters electric signaling behavior and the resulting sensory feedback, as well as the timing of corollary discharge, to precisely match the altered sensory feedback. We also found that the altered sensory feedback itself is not necessary to drive this corollary discharge modulation. Our findings demonstrate that testosterone directly and independently regulates peripheral motor output and corollary discharge in a coordinated manner.
Isoform-specific nicotinic responses are present in distinct subtypes of prefrontal layer V pyramidal neurons
Authors: Patel Ashutosh V. , Nguyen Anthony , Paletta Pietro , Choleris Elena , Bailey Craig D.C.
Published: April 2023

The neurotransmitter acetylcholine supports goal-directed cognitive functions via activation of its nicotinic and muscarinic classes of receptors within the prefrontal cortex. These receptors are expressed on pyramidal neurons located within layer V of the prefrontal cortex, which integrate afferent signals and contribute toward cognitive circuits via efferent projections to cortical and subcortical targets. Using whole-cell electrophysiology, retrograde labelling, and neuron reconstruction in the juvenile mouse prefrontal cortex, we identified three unique isoform-specific nicotinic receptor responses that are present in distinct subtypes of layer V pyramidal neurons. Broadly, we observed α7 or α7/β2* nicotinic responses in burst-firing neurons that project to the contralateral cortex or nucleus accumbens, respectively, and β2* nicotinic responses in regular-firing neurons that project to the ventromedial thalamus. These findings provide insight into a receptor isoform-specific mechanism by which nicotinic acetylcholine neurotransmission may support cognitive functions via modulation of distinct efferent projections from this brain region.
Fully-primed slowly-recovering vesicles mediate presynaptic LTP at neocortical neurons
Authors: Weichard Iron , Taschenberger Holger , Gsell Felix , Bornschein Grit , Ritzau-Jost Andreas , Schmidt Hartmut , Kittel Robert J. , Eilers Jens , Neher Erwin , Hallermann Stefan , Nerlich Jana
Published: April 2023

Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic depression during high-frequency transmission and a decelerated recovery from depression due to an increased occurrence of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate (cAMP) and diacylglycerol (DAG) signaling pathways, which are both known to promote synaptic vesicle priming mimicked electrically-induced LTP and slowed the recovery from depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.
Cholinergic Modulation is Necessary for Upward Firing Rate Homeostasis in Rodent Visual Cortex
Authors: Bottorff Juliet , Padgett Sydney , Turrigiano Gina G.
Published: April 2023

Bidirectional homeostatic plasticity allows neurons and circuits to maintain stable firing in the face of developmental or learning-induced perturbations. In primary visual cortex (V1), upward firing rate homeostasis (FRH) only occurs during active wake (AW) and downward during sleep, but how this behavioral state-dependent gating is accomplished is unknown. Here we focus on how AW enables upward FRH in V1 of juvenile Long Evans rats. A major difference between quiet wake (QW) when upward FRH is absent, and AW when it is present, is increased cholinergic (ACh) tone; we therefore chemogenetically inhibited V1-projecting basal forebrain cholinergic (BF ACh) neurons while inducing upward FRH using visual deprivation, and found that upward FRH was completely abolished. Next, we examined the impact on synaptic scaling and intrinsic excitability, two important cellular targets of homeostatic regulation. BF ACh inhibition impaired synaptic scaling up, and dramatically decreased the intrinsic excitability of activity-deprived V1 pyramidal neurons, consistent with the block of upward FRH. Interestingly, knock down of the highly abundant M1 ACh receptor in V1 failed to phenocopy the effects of decreased BF ACh activity on intrinsic excitability, suggesting either that BF ACh activity acts through a different receptor within V1, or acts indirectly via other brain regions or cell types. Together, our results show that BF ACh modulation is a key enabler of upward homeostatic plasticity, and more broadly suggest that neuromodulatory tone is a critical factor that segregates upward and downward homeostatic plasticity into distinct behavioral states.

SIGNIFICANCE STATEMENT

Hebbian, positive feedback-based and homeostatic, negative feedback-based plasticity mechanisms are necessary to maintain the functionality of flexible yet stable complex neuronal circuits. Growing evidence suggests a role for behavioral state in temporally segregating these opposing plasticity mechanisms, but how behavioral states enact this gating remains unknown. Here, we tested the role of acetylcholine (ACh), a widespread neuromodulator largely released during active wake, in the regulation of upward homeostatic plasticity. We found that ACh modulation is indeed necessary for the expression of active wake-gated upward firing rate homeostasis, likely due to its role in maintaining intrinsic excitability of cortical pyramidal neurons. Our results suggest potential mechanisms by which neuromodulatory tone may enable behavioral state gating of homeostatic plasticity.
The motif composition of variable number tandem repeats impacts gene expression
Authors: Lu Tsung-Yu , Smaruj Paulina N. , Fudenberg Geoffrey , Mancuso Nicholas , Chaisson Mark J.P.
Published: April 2023

Understanding the impact of DNA variation on human traits is a fundamental question in human genetics. Variable number tandem repeats (VNTRs) make up ∼3% of the human genome but are often excluded from association analysis owing to poor read mappability or divergent repeat content. Although methods exist to estimate VNTR length from short-read data, it is known that VNTRs vary in both length and repeat (motif) composition. Here, we use a repeat-pangenome graph (RPGG) constructed on 35 haplotype-resolved assemblies to detect variation in both VNTR length and repeat composition. We align population-scale data from the Genotype-Tissue Expression (GTEx) Consortium to examine how variations in sequence composition may be linked to expression, including cases independent of overall VNTR length. We find that 9422 out of 39,125 VNTRs are associated with nearby gene expression through motif variations, of which only 23.4% are accessible from length. Fine-mapping identifies 174 genes to be likely driven by variation in certain VNTR motifs and not overall length. We highlight two genes,CACNA1CandRNF213, that have expression associated with motif variation, showing the utility of RPGG analysis as a new approach for trait association in multiallelic and highly variable loci.
A small-angle X-ray scattering study of red blood cells in continuous flow
Authors: Burchert Jan-Philipp , Graceffa Rita , Saldanha Oliva , Burghammer Manfred , Köster Sarah
Published: April 2023

Owing to their large penetration depth and high resolution, X-rays are ideally suited to study structures and structural changes within intact biological cells. For this reason, X-ray-based techniques have been used to investigate adhesive cells on solid supports. However, these techniques cannot easily be transferred to the investigation of suspended cells in flow. Here, an X-ray compatible microfluidic device that serves as a sample delivery system and measurement environment for such studies is presented. As a proof of concept, the microfluidic device is applied to investigate chemically fixed bovine red blood cells by small-angle X-ray scattering (SAXS). A very good agreement is found between in-flow and static SAXS data. Moreover, the data are fitted with a hard-sphere model and screened Coulomb interactions to obtain the radius of the protein hemoglobin within the cells. Thus, the utility of this device for studying suspended cells with SAXS in continuous flow is demonstrated.
FLEXR: automated multi-conformer model building using electron-density map sampling
Authors: Stachowski Timothy R. , Fischer Marcus
Published: April 2023

Protein conformational dynamics that may inform biology often lie dormant in high-resolution electron-density maps. While an estimated ∼18% of side chains in high-resolution models contain alternative conformations, these are underrepresented in current PDB models due to difficulties in manually detecting, building and inspecting alternative conformers. To overcome this challenge, we developed an automated multi-conformer modeling program,FLEXR. UsingRinger-based electron-density sampling,FLEXRbuilds explicit multi-conformer models for refinement. Thereby, it bridges the gap of detecting hidden alternate states in electron-density maps and including them in structural models for refinement, inspection and deposition. Using a series of high-quality crystal structures (0.8–1.85 Å resolution), we show that the multi-conformer models produced byFLEXRuncover new insights that are missing in models built either manually or using current tools. Specifically,FLEXRmodels revealed hidden side chains and backbone conformations in ligand-binding sites that may redefine protein–ligand binding mechanisms. Ultimately, the tool facilitates crystallographers with opportunities to include explicit multi-conformer states in their high-resolution crystallographic models. One key advantage is that such models may better reflect interesting higher energy features in electron-density maps that are rarely consulted by the community at large, which can then be productively used for ligand discovery downstream.FLEXRis open source and publicly available on GitHub at https://github.com/TheFischerLab/FLEXR.
Safety climate in construction: a systematic literature review
Authors: Xia Nini , Ding Sichao , Ling Tao , Tang Yuchun
Published: April 2023

Purpose

Safety climate plays an important role in the high-risk construction industry. Advances have been made in the understanding of construction safety climate in terms of four interrelated themes, specifically, its definition, measurement, antecedents and consequences. However, knowledge remains fragmented as the studies are scattered, and a systematic review covering these four themes is lacking. To address this research gap, this study aims to perform a systematic literature review of construction safety climate literature regarding the four themes.

Design/methodology/approach

Following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) protocol guidelines, 178 eligible articles were obtained. This study provided thematic analysis of the 178 papers to identify what is known and what is not yet fully known regarding the four themes of construction safety climate. This study also conducted a descriptive analysis to identify the influential scholars, keywords, theories and research methods used by the literature, and finally presented an integrative framework directing future research.

Findings

The literature has not reached a consensus on the definition and measurement of construction safety climate. While it has identified the impact of safety climate on both behavioral and accident consequences, it has paid less attention to the antecedents and their underlying mechanisms regarding safety climate. Fang D. and Lingard H. are identified as the most influential authors in this field. “Questionnaire” and “safety behavior” are the keywords most closely related to safety climate. Unfortunately, the existing evidence for the causal relationships between safety climate and its antecedents and consequences is weak, as many studies lack clear theoretical substance, use a concurrent research design and focus only on individual-level climate perceptions. Finally, to support the development of construction safety climate around the four themes, potential research directions and research methods supporting them are illustrated.

Originality/value

This review makes contributions by integrating existing construction studies covering its definition, measurement, antecedents and consequences. This review also makes contributions to specific themes: no review exists on the antecedents of construction safety climate, and this review fills that gap; with regard to consequences, the existing reviews focus either on safety outcomes or safety behavior, but this review included both of them and further elaborated the different theories underpinning the relationships between safety climate and them. It is hoped that this systematic review will be helpful to the research community toward developing a nomologic network and promoting knowledge integration with respect to construction safety climate.