bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci
Authors: Abood Abdullah , Mesner Larry , Rosenow Will , Al-Barghouthi Basel M. , Horwitz Nina , Morgan Elise F. , Gerstenfeld Louis C. , Farber Charles R.
Published: November 2021

Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long non-coding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor SNPs demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (FDR correction<0.05) with BMD through TWAS and had a colocalizing eQTL (regional colocalization probability (RCP)>0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis.
Casirivimab and imdevimab for the treatment of hospitalized patients with COVID-19
Authors: Somersan-Karakaya Selin , Mylonakis Eleftherios , Menon Vidya P. , Wells Jason C. , Ali Shazia , Sivapalasingam Sumathi , Sun Yiping , Bhore Rafia , Mei Jingning , Miller Jutta , Cupelli Lisa , Hooper Andrea T. , Hamilton Jennifer D. , Pan Cynthia , Pham Viet , Zhao Yuming , Hosain Romana , Mahmood Adnan , Davis John D. , Turner Kenneth C. , Kim Yunji , Cook Amanda , Kowal Bari , Soo Yuhwen , DiCioccio A. Thomas , Geba Gregory P. , Stahl Neil , Lipsich Leah , Braunstein Ned , Herman Gary A. , Yancopoulos George D. , Weinreich David M. ,   COVID-19 Phase 2/3 Hospitalized Trial Team
Published: November 2021

Background

Hospitalized patients with COVID-19 experience high mortality rates, ranging from 10% to 30%. Combined casirivimab and imdevimab (CAS+IMD) is authorized for use in outpatients with COVID-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with CAS+IMD; however, in most of the world, anti-spike monoclonal antibody therapy is currently not approved for hospitalized patients.

Methods

In this phase I/II/III double-blind placebo-controlled trial, patients hospitalized with COVID-19 were randomized (1:1:1) to 2.4 g or 8.0 g of CAS+IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response.

Results

1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the least squares mean difference (CAS+IMD vs placebo) for time-weighted average change from baseline viral load was –0.28 log10 copies/mL (95% confidence interval [CI] –0.51 to –0.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS+IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI 24.2–74.0; nominal P = .0032). No safety concerns were noted.

Conclusions

In hospitalized patients with COVID-19 on low-flow or no oxygen, CAS+IMD treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients.
Prediction of the need for intensive oxygen supplementation during the hospitalization among patients with COVID 19 admitted to an academic health system in Texas, USA: a retrospective cohort study and development of a multivariable regression model
Authors: Davis John W. , Wang Beilin , Tomczak Ewa , Fu Chia-Chi , Harmouch Wissam , Reynoso David , Keiser Philip , Cabada Miguel M.
Published: November 2021

Objective

The severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has caused a pandemic claiming more than 4 million lives worldwide. Overwhelming Coronavirus-Disease-2019 (COVID-19) respiratory failure placed tremendous demands on healthcare systems increasing the death toll. Cost-effective prognostic tools to characterize COVID-19 patients’ likely to progress to severe hypoxemic respiratory failure are still needed.

Design

We conducted a retrospective cohort study to develop a model utilizing demographic and clinical data collected in the first 12-hours admission to explore associations with severe hypoxemic respiratory failure in unvaccinated and hospitalized COVID-19 patients.

Setting

University based healthcare system including 6 hospitals located in the Galveston, Brazoria and Harris counties of Texas.

Participants

Adult patients diagnosed with COVID-19 and admitted to one of six hospitals between March 19thand June 31st, 2020.

Primary outcome

The primary outcome was defined as reaching a WHO ordinal scale between 6-9 at any time during admission, which corresponded to severe hypoxemic respiratory failure requiring high-flow oxygen supplementation or mechanical ventilation.

Results

We included 329 participants in the model cohort and 62 (18.8%) met the primary outcome. Our multivariable regression model found that lactate dehydrogenase (OR 2.36), qSOFA score (OR: 2.26), and neutrophil to lymphocyte ratio (OR:1.15) were significant predictors of severe disease. The final model showed an area under curve (AUC) of 0.84. The sensitivity analysis and point of influence analysis did not reveal inconsistencies.

Conclusions

Our study suggests that a combination of accessible demographic and clinical information collected on admission may predict the progression to severe COVID-19 among adult patients with mild and moderate disease. This model requires external validation prior to its use.

STRENGTHS AND LIMITATIONS OF THIS STUDY

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Our study utilized objective and measurable demographic and clinical information regularly available in healthcare settings even among patients unable to communicate.

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Our primary outcome corresponds to WHO ordinal score which would allow compare our results to other studies and in other settings.

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Our model could serve as an effective point of service tool during early admission to assist in clinical management and allocation of resources to unvaccinated patients.

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Our study is a retrospective study of unvaccinated COVID19 patients, and validation of our prediction model in the rest of our study population is still needed.

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In addition, testing our model in a more recent cohort after emergence of new SARS-CoV-2 variants will be needed to assess its robustness.
The learning curve of murine subretinal injection among clinically trained ophthalmic surgeons
Authors: Huang Peirong , Narendran Siddharth , Pereira Felipe , Fukuda Shinichi , Nagasaka Yosuke , Apicella Ivana , Yerramothu Praveen , Marion Kenneth M. , Cai Xiaoyu , Sadda Srinivas R. , Gelfand Bradley D. , Ambati Jayakrishna
Published: November 2021

Purpose

Subretinal injection (SRI) in mice is widely used in retinal research, yet the learning curve (LC) of this surgically challenging technique is unknown.

Methods

To evaluate the LC for SRI in a murine model, we analyzed training data from 3 clinically trained ophthalmic surgeons from 2018 to 2020. Successful SRI was defined as either the absence of retinal pigment epithelium (RPE) degeneration after phosphate buffer saline injection and the presence of RPE degeneration afterAluRNA injection. Multivariable survival-time regression models were used to evaluate the association between surgeon experience and success rate, with adjustment for injection agents, and to calculate an approximate case number to achieve a 95% success rate. A Cumulative Sum (CUSUM) analysis was performed and plotted individually to monitor each surgeon’s simultaneous performance.

Results

Despite prior microsurgery experience, the combined average success rate of the first 50 cases in mice was only 27%. The predicted SRI success rate did not reach a plateau above 95% until approximately 364 prior cases. Using the 364-training case as a “cutoff” point, the predicted probability of success before and after the 364thcase was 65.38% and 99.32%, respectively (P< 0.0001). CUSUM analysis showed an initial upward slope and then remained within the decision intervals with an acceptable success rate set at 95% in the late stage.

Conclusions

This study demonstrates the complexity and substantial LC for successful SRI in mice with high confidence. A systematic training system could improve the reliability and reproducibility of SRI-related experiments and improve the interpretation of experimental results using this technique.

Translational Relevance

Our prediction model and monitor system allow objective quantification of technical proficiency in the field of subretinal drug delivery and gene therapy for the first time.
Exhaled Mycobacterium tuberculosis predicts incident infection in household contacts
Authors: Williams CML , Muhammad A , Sambou B , Bojang A , Jobe A , Daffeh G , Owolabi O , Pan D , Pareek M , Barer MR , Sutherland JS , Haldar P
Published: November 2021

Background

Halting transmission of Mycobacterium tuberculosis (Mtb) by identifying infectious individuals early is key to eradicating Tuberculosis (TB). Here we evaluate face mask sampling as a tool for stratifying infection risk in household contacts of pulmonary TB (pTB).

Methods

Forty-six sputum positive pTB patients in The Gambia (Aug 2016-Nov 2017) consented to mask sampling prior to commencing treatment. Incident Mtb infection was defined in their 181 household contacts as QuantiFERON (QFT) conversion or an increase in Interferon-ƴ release of ≥ 1IU/ml, 6 months after index diagnosis. Multilevel mixed-effects logistical regression analysis with cluster adjustment by household was used to identify predictors of incident infection.

Findings

Mtb was detected in 91% of pTB mask samples with high variation in IS6110 copies (5.3 ×102 to 1.2 ×107). A high mask Mtb level (≥20,000 IS6110 copies) was observed in 45% of cases and independently associated with increased likelihood of incident Mtb infection in contacts (AOR (95%CI) 3.20 (1.26 - 8.12), p=0.01), compared with cases having low/negative mask Mtb levels. Mask Mtb level was a better predictor of incident Mtb infection than sputum bacillary load, chest radiographic characteristics or sleeping proximity.

Interpretation

Mask sampling offers a highly sensitive and non-invasive tool to support both diagnosis of pTB and stratification of individuals who are most infectious. Our findings have the potential to revolutionise contact screening strategies and outbreak management in high TB burden settings and is of urgent public health importance.
Surgical Outcomes of Myelomeningocele Repair: a 20-Year Experience from a Single Center in a Middle-Income Country
Authors: Zoghi Sina , Feili Maryam , Mosayebi Mohammad Amin , Afifi Mohammad Amin , Feili Afrooz , Masoudi Mohammad Sadegh , Taheri Reza
Published: November 2021

Objective

Spina bifida primarily affects people of low and middle socioeconomic status. Herein, we describe the outcome of myelomeningocele surgical management in Iran and predictors of its postoperative complications and mortality.

Methods

This retrospective chart review studies the children who underwent surgical management for myelomeningocele in Shiraz, Fars province, Iran, from May 2001 to September 2020. To this end, we investigated mortality and 30-day complications and the factors that determined the operation’s outcome.

Results

256 patients were enrolled. The median age at the operation was roughly eight days (IQR: 7). The most common site of involvement of Myelomeningocele (MMC) was Lumbosacral (86%, n = 204). At the evaluation conducted prior to operation, CSF leaking was observed in 7% (n=16) of the patients. Postoperatively, 5.7% of the patients were expired in the 30 days following the operation (n = 14), while 24% needed readmission (n = 47). The most common complications leading to readmission included wound dehiscence (n = 10, 42%) and wound purulence (n = 6, 25%). No variable was significantly associated with postoperative complication except for the site of the lesion (p-value = 0.035) and the presence of the lipid content in the defect (p-value = 0.044).

Conclusions

Most patients born with MMC are referred for the neurosurgical evaluation following their birth; however, as results show there is much left to be desired compared with the 48h recommended by The Congress of Neurological Surgeons. Here, we concluded that presence of lipid compartment in the lesion and the site of the lesion are the two factor that were associated with the rate of mortality. However, further investigation into preoperative interventions and risk factors to mitigate risk of postoperational complications and mortality is highly encouraged. We highly advocate for the investigation and dissemination of the outcome of the conventional surgical management of MMC in financially restrained areas; because they can show the limitation these settings are confronted with (that are in a way unique to them and different from the resourceful settings) and provide a model for other similar areas with limited suitable care.
A connectivity signature for glioblastoma
Authors: Hai Ling , Hoffmann Dirk C , Mandelbaum Henriette , Xie Ruifan , Ito Jakob , Jung Erik , Weil Sophie , Sievers Philipp , Venkataramani Varun , Azorin Daniel Dominguez , Ernst Kati , Reibold Denise , Will Rainer , Suvà Mario L. , Herold-Mende Christel , Sahm Felix , Winkler Frank , Schlesner Matthias , Wick Wolfgang , Kessler Tobias
Published: November 2021

Tumor cell extensions called tumor microtubes (TMs) in glioma resemble neurites during neurodevelopment and connect glioma cells to a network that has considerable relevance for tumor progression and therapy resistance. The determination of interconnectivity in individual tumors has been challenging and the impact of tumor cell connectivity on patient survival remained unresolved so far. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells was established and clinically validated. Thirty-four of 40 connectivity genes were related to neurogenesis, neural tube development or glioma progression, including the TM-network-relevant GAP43 gene. Astrocytic-like and mesenchymal-like GB cells had the highest connectivity signature scores in scRNA-Seq data of patient-derived xenografts and patient samples. In 230 human GBs, high connectivity correlated with the mesenchymal expression subtype, TP53 wildtype, and with dismal patient survival. CHI3L1 was identified as a robust molecular marker of connectivity. Thus, the connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell connectivity is relevant for patients’ prognosis, and serves as a robust biomarker that can be used for future clinical trials.

Statement of significance

Integration of GB cells into functional networks drives tumor progression and resistance. Here, we established and validated a novel connectivity gene expression signature of single GB cells and whole tumors that can be easily applied to clinical and preclinical samples. It is shown that connectivity is determining prognosis combining molecular, functional and clinical insights into the disease.
Changes in transmission of Enterovirus D68 (EV-D68) in England inferred from seroprevalence data
Authors: Pons-Salort Margarita , Lambert Ben , Kamau Everlyn , Pebody Richard , Harvala Heli , Simmonds Peter , Grassly Nicholas C
Published: November 2021

The factors leading to the global emergence of enterovirus D68 (EV-D68) in 2014 as a cause of acute flaccid myelitis (AFM) in children are unknown. To investigate potential changes in virus transmissibility or population susceptibility, we measured the seroprevalence of EV-D68-specific neutralising antibodies in serum samples collected in England in 2006, 2011 and 2017. Using catalytic mathematical models, we estimate an approximately two-fold increase in the basic reproduction number over the 10-year study period, coinciding with the emergence of clade B around 2009. Despite such increase in transmission, the virus was already widely circulating before the AFM outbreaks and the increase of infections by age cannot explain the observed number of AFM cases. Therefore, the acquisition of or an increase in neuropathogenicity would be additionally required to explain the emergence of outbreaks of AFM. Our results provide evidence that changes in enterovirus phenotypes cause major changes in disease epidemiology.
Cumulative incidence of SARS-CoV-2 and associated risk factors among healthcare workers in the Eastern Cape, South Africa
Authors: Stead David , Adeniyi Oladele Vincent , Singata-Madliki Mandisa , Abrahams Shareef , Batting Joanne , Jelliman Eloise , Parrish Andrew
Published: November 2021

Objectives

This study assesses the cumulative incidence of SARS-CoV-2 infection among healthcare workers (HCWs) during South Africa’s first wave and examines the associated demographic, health-related, and occupational risk factors for infection.

Methods

Multi-stage cluster sampling was used in a cross-sectional study to recruit 1,309 HCWs from two academic hospitals in the Eastern Cape, South Africa over six weeks in November and December 2020. Prior test results for SARS-CoV-2 polymerase chain reaction (PCR) and participants’ characteristics were recorded while a blood sample was drawn for detection of IgG antibodies against SARS-CoV-2 nucleocapsid protein. The primary outcome measure was the SARS-CoV-2 cumulative incidence rate, defined as the combined total of positive results for either PCR or IgG antibodies, divided by the total sample. The secondary outcome was significant risk factors associated with infection.

Results

Of the total participants included in the analysis (N=1295), the majority were female (81.5%), of black race (78.7%) and nurses (44.8%). A total of 390 (30.1%) HCWs had a positive SARS-CoV-2 PCR result and SARS-CoV-2 antibodies were detected in 488 (37.7%), yielding a cumulative incidence of 47.2% (n = 611). In the adjusted logistic regression model, being overweight (Adjusted odds ratio (AOR) = 2.15, 95% CI 1.44-3.20), obese (AOR = 1.37, 95% CI 1.02-1.85) and living with HIV (AOR = 1.78, 95% CI 1.38-were independently associated with SARS-CoV-2 infection. There was no significant difference in infection rates between high, medium and low COVID-19 exposure working environments.

Conclusions

The high SARS-CoV-2 cumulative incidence in the cohort was surprising this early in the epidemic and probably related to exposure both in and outside the hospitals. To mitigate the impact of SARS-CoV-2 among HCWs, infection prevention and control (IPC) strategies should target community transmission in addition to screening for HIV and metabolic conditions.

Strengths and limitations of this study

This is a large representative sample of the total workforce of the two hospitals, with a good spectrum of staff category.

Combining the historical SARS-CoV-2 PCR results with the Nucleocapsid IgG enabled capturing of some of the asymptomatic and missed SARS-CoV-2 infections.

This is one of the first studies to look at SARS-CoV-2 infection risk factors in a high exposure environment in Africa.

A limitation is that HIV ELISA and CD4 counts were not tested, but relied on self-report, which may likely underestimate the burden of HIV in the cohort.
Neutralisation of the SARS-CoV-2 Delta sub-lineage AY.4.2 and B.1.617.2 + E484K by BNT162b2 mRNA vaccine-elicited sera
Authors: Lassaunière Ria , Polacek Charlotta , Fonager Jannik , Bennedbæk Marc , Boding Lasse , Rasmussen Morten , Fomsgaard Anders
Published: November 2021

Several factors may account for the recent increased spread of the SARS-CoV-2 Delta sublineage AY.4.2 in the United Kingdom, Romania, Poland, and Denmark. Here, we evaluate the sensitivity of AY.4.2 to neutralisation by sera from Pfizer/BioNTech (BNT162b2) vaccine recipients. AY.4.2 neutralisation was comparable to other circulating Delta lineages or sublineages. In contrast, the more rare B.1.617.2+E484K variant showed a significant >4-fold reduction in neutralisation that warrants surveillance of strains with the acquired E484K mutation.
Interchromosomal interaction of homologous Stat92E alleles regulates transcriptional switch during stem-cell differentiation
Authors: Antel Matthew , Masoud Madona , Raj Romir , Pan Ziwei , Li Sheng , Mellone Barbara G. , Inaba Mayu
Published: November 2021

The strength of pairing of homologous chromosomes differs in a locus-specific manner and is correlated to gene expression states. However, the functional impact of homolog pairing on local transcriptional activity is still unclear. Drosophila male germline stem cells (GSCs) constantly divide asymmetrically to produce one GSC and one differentiating gonialblast (GB). The GB then enters the differentiation program in which stem cell specific genes are quickly downregulated. Here we demonstrate that a change in local pairing state of the Stat92E locus is required for the downregulation of the Stat92E gene during differentiation. Using OligoPaint fluorescent in situ hybridization (FISH), we show that the interaction between homologous regions of Stat92E is always tight in GSCs and immediately loosened in GBs. When one of the Stat92E locus was absent or relocated to another chromosome, Stat92E did not pair and failed to downregulate, suggesting that the pairing is required for switching of transcriptional activity. The defect in downregulation of Stat92E was also observed upon knockdown of global pairing or anti-pairing factors. Moreover, the Stat92E enhancer element, but not cis-transcription, is required for the change in pairing state, indicating that it is not a consequence of transcriptional changes. GSCs are known to inherit pre-existing histones H3 and H4, while newly synthesized histones are distributed in GBs. When this histone inheritance was compromised, the change in Stat92E pairing did not occur, suggesting that it is an intrinsically programmed process during asymmetric stem cell division. We propose that the change of local pairing state may be a common process to reprogram gene activity during cell-differentiation.
In vitro reconstitution of divisome activation
Authors: Radler Philipp , Baranova Natalia , Caldas Paulo , Sommer Christoph , López-Pelegrín Mar , Michalik David , Loose Martin
Published: November 2021

Bacterial cell division is coordinated by the Z-ring, a cytoskeletal structure of treadmilling filaments of FtsZ and their membrane anchors, FtsA and ZipA. For divisome maturation and initiation of constriction, the widely conserved actin-homolog FtsA plays a central role, as it links downstream cell division proteins in the membrane to the Z-ring in the cytoplasm. According to the current model, FtsA initiates cell constriction by switching from an inactive polymeric conformation to an active monomeric form, which then stabilizes the Z-ring and recruits downstream proteins such as FtsN. However, direct biochemical evidence for this mechanism is missing so far. Here, we used biochemical reconstitution experiments in combination with quantitative fluorescence microscopy to study the mechanism of divisome activation in vitro. By comparing the properties of wildtype FtsA and FtsA R286W, a gain-of-function mutant thought to mimic its active state, we found that active FtsA outperforms the wildtype protein in replicating FtsZ treadmilling dynamics, filament stabilization and FtsN recruitment. We could attribute these differences to a faster membrane exchange of FtsA R286W as well as its higher packing density below FtsZ filaments. Using FRET microscopy, we also show that binding of FtsN does not compete with, but promotes FtsA self-interaction. Together, our findings shed new light on the assembly and activation of the bacterial cell division machinery and the mechanism of how FtsA initiates cell constriction.
CRISPR-Cas9 mediated nuclear transport and genomic integration of nanostructured genes in human primary cells
Authors: Lin-Shiao Enrique , Pfeifer Wolfgang G. , Shy Brian R. , Doost Mohammad Saffari , Chen Evelyn , Vykunta Vivasvan S. , Hamilton Jennifer R. , Stahl Elizabeth C. , Lopez Diana M. , Espinoza Cindy R. Sandoval , Dejanov Alexander E. , Lew Rachel J. , Poirer Michael G. , Marson Alexander , Castro Carlos E. , Doudna Jennifer A.
Published: November 2021

DNA nanostructures are a promising tool for delivery of a variety of molecular payloads to cells. DNA origami structures, where 1000’s of bases are folded into a compact nanostructure, present an attractive approach to package genes; however, effective delivery of genetic material into cell nuclei has remained a critical challenge. Here we describe the use of DNA nanostructures encoding an intact human gene and a fluorescent-protein encoding gene as compact templates for gene integration by CRISPR-mediated homology-directed repair (HDR). Our design includes CRISPR-Cas9 ribonucleoprotein (RNP) binding sites on the DNA nanostructures to increase shuttling of structures into the nucleus. We demonstrate efficient shuttling and genomic integration of DNA nanostructures using transfection and electroporation. These nanostructured templates display lower toxicity and higher insertion efficiency compared to unstructured double-stranded DNA (dsDNA) templates in human primary cells. Furthermore, our study validates virus-like particles (VLPs) as an efficient method of DNA nanostructure delivery, opening the possibility of delivering DNA nanostructures in vivo to specific cell types. Together these results provide new approaches to gene delivery with DNA nanostructures and establish their use as large HDR templates, exploiting both their design features and their ability to encode genetic information. This work also opens a door to translate other DNA nanodevice functions, such as measuring biophysical properties, into cell nuclei.

Teaser Sentence

CRISPR-Cas9 mediates nuclear transport and integration of nanostructured genes in human primary cells
Central and peripheral delivery of AAV9-SMN target different pathomechanisms in a mouse model of spinal muscular atrophy
Authors: Reilly Aoife , Deguise Marc-Olivier , Beauvais Ariane , Yaworski Rebecca , Thebault Simon , Tessier Daniel R. , Tabard-Cossa Vincent , Hensel Niko , Schneider Bernard L. , Kothary Rashmi
Published: November 2021

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the SMN1 gene. Although lower motor neurons are a primary target, there is evidence that peripheral organ defects contribute to SMA. Current SMA gene therapy uses a single, high titre intravenous bolus of AAV9-SMN resulting in impressive, yet limited amelioration of the clinical phenotype. However, risks of this treatment include liver toxicity. Intrathecal administration is under clinical trial but was interrupted due to safety concerns in a concomitant animal study. As there is no direct comparison between the different delivery strategies while avoiding high dose toxicity, we injected SMA mice with low dose scAAV9-cba-SMN either intravenously (IV) for peripheral SMN restoration or intracerebroventricularly (ICV) for CNS-focused SMN restoration. Here, IV injections restored SMN in peripheral tissues but not CNS, while ICV injections mildly increased SMN in the periphery and the CNS. Consequently, only ICV treatment rescued motor neuron degeneration. Surprisingly, both treatments resulted in an impressive rescue of survival, weight, motor function, and peripheral phenotypes including liver and pancreas pathology. Our work highlights independent contributions of peripheral organs to SMA pathology and suggests that treatments should not be restricted to the motor neuron.

Graphical Abstract
Input-specific induction of cerebellar long-term depression does not require presynaptic alteration.
Authors: Linden D J
Published: November 2021

In cerebellar long-term depression (LTD), conjunctive stimulation of parallel fiber (PF) and climbing fiber (CF) inputs to a Purkinje neuron result in a selective depression of PF-Purkinje neuron synaptic strength. This system is attractive for the study of neuronal information storage, both because of its duration and because it demonstrates input specificity. The mechanisms underlying input specificity in this system are not known, but they could involve presynaptic alterations, postsynaptic alterations, or some combination of both. To allow for an unambiguous analysis of postsynaptic processes, an LTD induction protocol has been developed using cultured cerebellar cells in which pulses of quisqualate and direct Purkinje neuron depolarization replace PF and CF stimulation, respectively. Input specificity is retained in this reduced system. When multiple, nonoverlapping quisqualate application sites are used, LTD is confined to those sites that are stimulated during depolarization. This property of LTD induction is also preserved under conditions where both spontaneous and evoked neurotransmitter releases are reduced or eliminated, indicating that postsynaptic alterations are sufficient to confer input specificity. Input-specific LTD may also be induced by local application of a protein kinase C (PKC) activator (1-oleoyl-2-acetylglycerol) together with direct Purkinje neuron depolarization, suggesting that input-specific LTD results from the conjunction of a spatially broad Ca signal mediated by Purkinje neuron depolarization, together with a spatially constrained PKC-activating signal mediated by quisqualate application.
Neuronal tuning and associative mechanisms in form representation.
Authors: Sakai K , Naya Y , Miyashita Y
Published: November 2021

We examine the hypothesis that the form representation in the anterior inferotemporal (AIT) cortex is acquired through learning. According to this hypothesis, perceptual aspects of the temporal association area are closely related to its visual representation, in that the response selectivity of AIT neurons can be influenced by visual experience. On the basis of the neurophysiological evidence, we summarize two neuronal mechanisms that subserve the acquisition of form selectivity in AIT neurons. The first mechanism is neuronal tuning to particular stimuli that were learned in a cognitive task. The second mechanism is association, with which relevant information can be retrieved from other stored memories. On the grounds that long-term memory of objects is acquired and organized by at least these two neuronal mechanisms in the temporal association area, we further present a model of the cognitive memory system that unifies perception and imagery.
Parallel brain systems for learning with and without awareness.
Authors: Reber P J , Squire L R
Published: November 2021

A fundamental issue about memory and its different forms is whether learning can occur without the development of conscious knowledge of what is learned. Amnesic patients and control subjects performed a serial reaction time task, exhibiting equivalent learning of an imbedded repeating sequence as measured by gradually improving reaction times. In contrast, four tests of declarative (explicit) knowledge indicated that the amnesic patients were unaware of their knowledge. Moreover, after taking the tests of declarative memory, all subjects continued to demonstrate tacit knowledge of the repeating sequence. This dissociation between declarative and nondeclarative knowledge indicates that the parallel brain systems supporting learning and memory differ in their capacity for affording awareness of what is learned.
Activity-dependent enhancement of presynaptic facilitation provides a cellular mechanism for the temporal specificity of classical conditioning in Aplysia.
Authors: Clark G A , Hawkins R D , Kandel E R
Published: November 2021

A hallmark of many forms of classical conditioning is a precise temporal specificity: Learning is optimal when the conditioned stimulus (CS) slightly precedes the unconditioned stimulus (US), but the learning is degraded at longer or backward intervals, consistent with the notion that conditioning involves learning about predictive relationships in the environment. To further examine the cellular mechanisms contributing to the temporal specificity of classical conditioning of the siphon-withdrawal response in Aplysia, we paired action potential activity in siphon sensory neurons (the neural CS) with tail nerve shock (the US) at three critical time points. We found that CS-US pairings at short (0.5 sec) forward intervals produced greater synaptic facilitation at sensorimotor connections than did either 0.5-sec backward pairings or longer (5 sec) forward pairings, as reflected in a differential increase in both the amplitude and rate of rise of the synaptic potential. In the same preparations, forward pairings also differentially reduced the sensory neuron afterhyperpolarization relative to backward pairings, suggesting that changes in synaptic efficacy were accompanied by temporally specific changes in ionic currents in the sensory neurons. Additional experiments demonstrated that short forward pairings of sensory cell activity and restricted applications of the neuromodulatory transmitter serotonin (normally released by the US) differentially enhanced action potential broadening in siphon sensory neurons, relative to backward pairings. Taken together, these results suggest that temporally specific synaptic enhancement engages both spike-width-dependent and spike-width-independent facilitatory processes and that activity-dependent enhancement of presynaptic facilitation may contribute to both the CS-US sequence and proximity requirements of conditioning.
Supply chain resilience and business responses to disruptions of the COVID-19 pandemic
Authors: Ramanathan Usha , Aluko Olu , Ramanathan Ramakrishnan
Published: November 2021

Purpose

At its peak, the COVID-19 pandemic has created disruption to food supply chains in the UK and for the entire world. Although societal changes created some resilience within the supply chains, high volatility in demand creates supply, logistics and distribution issues. This is reflected in the economic instability of businesses and small and medium enterprises (SMEs). In this paper, the authors explore factors behind this initial disruption in the supply chains and offer suggestions to businesses based on the established practices and theories.

Design/methodology/approach

The authors use mixed methods research. First, the authors conducted an exploratory study by collecting data from published online sources. Then, the authors analysed possible scenarios from the available information using regression. The authors then conducted two interviews with UK retail sector representatives. These scenarios have been compared and contrasted to provide decision-making points to businesses and supply chain players to tackle current and any future potential disruptions.

Findings

The findings from the current exploratory study inform the volatility of supply chains. The authors suggested some possible responses from businesses, during and after the pandemic.

Originality/value

The regression model provides a decision-making approach to help supply chain businesses during the pandemic outbreak. Once a complete data set of COVID-19 is available, the authors can create a resilience model that can help businesses and supply chains.
The positive aspects of fire use: a grounded theory of the experiences of non-criminalised fire users
Authors: Horsley Faye K.
Published: November 2021

Purpose

Psychological research on fire has focussed primarily on its misuse in the form of arson and firesetting, which reflects a tradition in forensic psychology for focussing on risk and pathological behaviour. However, this is inconsistent with the strengths-based approach because it fails to account for positive aspects of fire and law-abiding/ healthy interactions with fire. This study aims to explore the psychology of non-criminalised forms of fire use. It is predicated on a novel, dimensional, conceptualisation of fire-related behaviour – the continuum of fire use (CoFU; Horsley, 2020, 2021).

Design/methodology/approach

Semi-structured interviews were conducted with 12 adults who use fire in law-abiding forms. Data were analysed using techniques informed by grounded theory. Steps were taken to ensure reliability and validity, including a Cohen’s Kappa calculation, which indicated an agreement level of 0.8 between two raters.

Findings

Four core themes were identified relating to the benefits of fire on psychological well-being, namely, immediate gratification; hope and empowerment; self-concept and emotional security.

Research limitations/implications

Drawing on findings from this study, a theoretical framework of the psychology of non-criminalised fire use is presented. This is a preliminary conceptualisation and more work is needed to address this under-researched topic.

Practical implications

The findings can inform the work of forensic practitioners. They highlight the importance of considering service users' positive interactions with fire, alongside maladaptive/ criminal use. This has implications for the assessment of fire setters, as well as rehabilitative approaches.

Social implications

It is argued in this paper that a society-wide approach is key to firesetting reduction. More specifically, findings can inform the development and refinement of early intervention programmes, which focus on supporting young people to develop a healthy relationship with fire.

Originality/value

To the best of the authors’ knowledge, this study is the first to explore the psychology of non-criminalised forms of fire use. It is predicated on a novel, dimensional, conceptualisation of fire-related behaviour – the continuum of fire use (CoFU; Horsley, 2020, 2021a, 2021b).
Case study: Central States Manufacturing, Inc
Authors: Scharf Adria L.
Published: November 2021

Purpose

This case study examines employee share ownership at Central States Manufacturing, where the employee stock ownership plan (ESOP) shares stunning sums of wealth with employees. Central States designs its ESOP to allow participants to access a portion of their ownership wealth while they are still employed at the company, through hardship and in-service withdrawals. This may make the “wealth benefit” of employee ownership more meaningful to lower-wage workers navigating economic challenges. The case study adds to the discussion about how employee ownership can benefit low- and moderate-wage workers and close the wealth gap.

Design/methodology/approach

Data were collected via: (1) published accounts, (2) structured qualitative interview with the chief financial officer (CFO), (3) follow-up emails and phone communication with company contact and (4) review of plan document language.

Findings

Workers at Central States Manufacturing – including truck drivers and production workers – build large sums of wealth through the ESOP. Central States innovates in its ESOP by permitting workers to access a portion of their ownership wealth while they are still working through hardship and service withdrawals.

Research limitations/implications

This is a mini-case study heavily reliant on the information provided by the CFO, in combination with background publications, and plan document language. It does not include employee interviews.

Originality/value

This paper lifts up an innovative company whose success and innovative ESOP plan design benefit frontline workers.
The impact of emerging technologies on accounting curriculum and the accounting profession
Authors: Wang Tawei
Published: November 2021

Purpose

In this commentary, the author uses the development of data analytics curriculum at DePaul University as an example to highlight possible challenges and share the experience. In addition, seven different possible future research directions are identified so the readers are able to understand more about the impact of emerging technologies on the accounting profession and accounting curriculum.

Findings

Challenges and experience when developing data analytics curriculum at DePaul University are discussed. In addition, seven different possible future research directions are identified so the readers are able to understand more about the impact of emerging technologies on the accounting profession and accounting curriculum.

Originality/value

This paper expresses the author’s viewpoints regarding the impact of emerging technologies on accounting curriculum and the accounting profession.
Effects of different polymerisation conditions using hybrid polymer on high turbidity suspensions
Authors: Ishak Siti Aisyah , Murshed Mohamad Fared , Sabtu Nuridah , Mokhtar Hamizah
Published: November 2021

Purpose

In this study, new hybrid polymers composed of Zinc chloride (ZnCl2), acrylamide and chitosan were prepared at different ratios and temperatures. The effects of pH and polymer dosage were examined for different polymers to observe their efficiency in the removal of turbid water. The polymers’ zeta potential, morphology, elemental composition and functional groups were also identified and studied.

Design/methodology/approach

The free-radical polymerisation process was executed in the presence of N, N’-Methylene bis-acrylamide and potassium persulphate in one molar acrylamide solution. ZnCl2 and chitosan (CO) were later introduced into the suspension under nitrogen gas flow. Ratio and temperature were varied during polymerisation. The hybrid polymer produced, termed Polyacrylamide + chitosan oligosaccharide + zinc chloride (PAMCOZ), was analysed using Fourier transform infra-red spectroscopy attenuated total reflectance and scanning electron microscope with energy dispersive X-ray. The hybrid PAMCOZ was experimented with in high turbid kaolin suspension using jar testing analysis to see its ability as a coagulant.

Findings

The coagulation process using PAMCOZ with a ratio of 11 (3:2) at 70°C surrounding temperature showed a 100% reduction at pH 4 with 50 mg/L of the polymer. The functional groups present in ratio 11 polymer were hydroxyl, carbonyl, amide and methyl groups. In addition, several elements were spotted on the surface of PAMCOZ, such as zinc (Zn), carbon (C), chlorine (Cl), nitrogen (N) and oxygen (O). The effect of pH also demonstrated that PAMCOZ was unfavourable in an alkaline turbid water environment.

Research limitations/implications

Due to the research methodology approach, the research results may lack actual wastewater application. Therefore, researchers are encouraged to test the hybrid coagulant on raw wastewater, such as pulp and paper mill effluent with a high turbidity value similar to this study.

Originality/value

The polymerisation between zinc chloride, acrylamide and chitosan has not yet been applied. The different ratios and effects of temperature were analysed on PAMCOZ to see the turbidity removal. PAMCOZ showed better turbidity removal in acidic conditions.
Cultivation of a vampire: ‘Candidatus Absconditicoccus praedator’
Authors: Yakimov Michail M. , Merkel Alexander Y. , Gaisin Vasil A. , Pilhofer Martin , Messina Enzo , Hallsworth John E. , Klyukina Alexandra A. , Tikhonova Ekaterina N. , Gorlenko Vladimir M.
Published: November 2021

Halorhodospira halophila, one of the most‐xerophilic halophiles, inhabits biophysically stressful and energetically expensive, salt‐saturated alkaline brines. Here, we report an additional stress factor that is biotic: a diminutive Candidate‐Phyla‐Radiation bacterium, that we named ‘Ca. Absconditicoccus praedator’ M39‐6, which predates H. halophila M39‐5, an obligately photosynthetic, anaerobic purple‐sulfur bacterium. We cultivated this association (isolated from the hypersaline alkaline Lake Hotontyn Nur, Mongolia) and characterized their biology. ‘Ca. Absconditicoccus praedator’ is the first stably cultivated species from the candidate class‐level lineage Gracilibacteria (order‐level lineage Absconditabacterales). Its closed‐and‐curated genome lacks genes for the glycolytic, pentose phosphate‐ and Entner–Doudoroff pathways which would generate energy/reducing equivalents and produce central carbon currencies. Therefore, ‘Ca. Absconditicoccus praedator’ is dependent on host‐derived building blocks for nucleic acid‐, protein‐, and peptidoglycan synthesis. It shares traits with (the uncultured) ‘Ca. Vampirococcus lugosii’, which is also of the Gracilibacteria lineage. These are obligate parasitic lifestyle, feeding on photosynthetic anoxygenic Gammaproteobacteria, and absorption of host cytoplasm. Commonalities in their genomic composition and structure suggest that the entire Absconditabacterales lineage consists of predatory species which act to cull the populations of their respective host bacteria. Cultivation of vampire : host associations can shed light on unresolved aspects of their metabolism and ecosystem dynamics at life‐limiting extremes.
Emergency intubation practices in a tertiary teaching hospital in Jakarta, Indonesia: A prospective observational study
Authors: Sulistio Septo , Habib Hadiki , Mulyana Radi Muharris , Albar Imamul Aziz
Published: November 2021

Objective

Intubation is an important competency for emergency doctors. Emergency patients are often unstable, with undifferentiated conditions. There is little time to prepare these patients prior to intubation and so ED intubation may differ from intubation in intensive care units and operating theatres. The present study aims to describe the characteristics of emergency intubation after an administrative policy change within a tertiary teaching hospital in Jakarta, allowing non‐anaesthetists to perform intubation in the ED.

Methods

Prospective data were collected regarding patients of all age groups who were intubated at the ED of Cipto Mangunkusumo General Hospital, Jakarta, from February 2018 to January 2019. Patient characteristics, intubation attempts, medications used, complications, and disposition were recorded in a self‐reported airway registry based on the Australian and New Zealand Emergency Department Airway Registry (ANZEDAR) form.

Results

During the 12‐month study period, 231 patients, or 41.5% of ED intubated patients were enrolled in the study, and there were 268 intubation attempts on these enrolled patients. The first‐pass success rate was 207 out of 231 patients, or 89.6%, with anaesthetist (88.9%), better than emergency doctors (55.4%). Complications were reported in 51 patients, or 22.0%, with desaturation and hypotension being the most common. Thirty‐three patients, or 14.3%, died in the ED before being transferred to another unit.

Conclusions

The first‐pass success rate is comparable with international data. Non‐anaesthetic physicians must improve their experience to achieve a favourable success rate. The data on complications highlight the need for improvement in Indonesian ED intubation practices.