bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative and postoperative prognostic factors of patients with stage II/III lower rectal cancer without neoadjuvant therapy in the clinical trial (JCOG0212)
Authors: Ohue Masayuki , Fujita Shin , Mizusawa Junki , Kanemitsu Yukihide , Hamaguchi Tetsuya , Tsukamoto Shunsuke , Noura Shingo , Yasui Masayoshi , Itoh Masaaki , Shiomi Akio , Komori Koji , Watanabe Jun , Akazai Yoshihiro , Shiozawa Manabu , Yamaguchi Takashi , Bandou Hiroyuki , Katsumata Kenji , Moriya Yoshihiro
Published: November 2021

Background

The JCOG0212 trial was a randomized controlled trial comparing mesorectal excision alone to mesorectal excision with lateral lymph node dissection for stage II/III lower rectal cancer patients without clinical lateral lymph node enlargement. This study aimed to identify clinicopathological prognostic factors for relapse-free survival and overall survival of lower rectal cancer in the trial.

Methods

Prospective data were selected from 663 patients with complete data. Uni and multivariable Cox regression model was applied to evaluate the preoperative and the combined preoperative and postoperative factors, respectively. Preoperative factors included age, sex, performance status, clinical T, clinical N and operative procedures. Postoperative factors included histological grade, pathological T, number of metastatic lymph nodes and number of dissected lymph nodes. No patient received neoadjuvant treatment.

Results

Regarding preoperative factors, multivariable analysis revealed that performance status 1 (vs. 0: HR 2.079, P = 0.0041) and cT4a (vs. cT2–3: HR 2.721, P = 0.0002) were independent risk factors for relapse-free survival, and those for overall survival were male (vs. female: HR 1.660, P = 0.0228) and cT4a (vs. cT2–3: HR 2.486, P = 0.0473). The only independent preoperative risk factor common for relapse-free survival and overall survival was cT4a. Taking preoperative and postoperative factors together, the number of metastatic lymph nodes was the only independent risk factor common for relapse-free survival and overall survival.

Conclusions

Clinical stage II/III lower rectal cancer patients with cT4a should be a target of therapeutic development of neoadjuvant therapy. Postoperatively, intensive chemotherapy should be investigated for patients with more metastatic lymph nodes.
Active small bowel sparing in intracavitary brachytherapy for cervical cancer
Authors: Goh Youngmoon , Kim Dohyeon , Kim Joo-Young , Kim Hak Soo , Jeong Jong Hwi , Lee Sung Uk , Youn Sang Hee , Oh Eun Sang , Ha Bo Ram , Yeo Adam Unjin , Kim Myeongsoo , Shin Dongho , Lee Se Byeong , Kim Yeon-Joo , Kim Tae Hyun , Lim Young Kyung
Published: November 2021

Objective

To propose and evaluate an active method for sparing the small bowel in the treatment field of cervical cancer brachytherapy by prone position procedure.

Methods

The prone position procedure consists of five steps: making bladder empty, prone-positioning a patient on belly board, making the small bowel move to abdomen, filling the bladder with Foley catheter and finally turning the patient into the supine position. The proposed method was applied for the treatment of seven cervical cancer patients. Its effectiveness was evaluated and a correlation between the patient characteristics and the volumetric dose reduction of small bowel was also investigated. Brachytherapy treatment plans were built before and after the proposed method, and their dose-volume histograms were compared for targets and organs-at-risk. In this comparison, all plans were normalized to satisfy the same D90% for high-risk clinical target volume.

Results

For the enrolled patients, the average dose of small bowel was significantly reduced from 75.2 ± 4.9 Gy before to 60.2 ± 4.0 Gy after the prone position procedure, while minor dosimetric changes were observed in rectum, sigmoid and bladder. The linear correlation to body mass index, thickness and width of abdominopelvic cavity and bladder volume were 76.2, 69.7, 28.8 and −36.3%, respectively.

Conclusions

The application of prone position procedure could effectively lower the volumetric dose of the small bowel. The dose reduction in the small bowel had a strong correlation with the patient’s obesity and abdominal thickness. This means the patients for whom the proposed method would be beneficial can be judiciously selected for safe brachytherapy.
Rare case of visceral myopathy
Authors: Dreyer Niloofar Sherazi , Pankratjevaite Lina , Janciauskas Dainius , Saladzinskas Zilvinas
Published: November 2021

Visceral myopathy is a rare bowel disease affecting peristalsis and causing pseudo-obstruction. There is no specific treatment for chronic intestinal pseudo-obstruction caused by visceral myopathy. We report a case of a 30-year-old woman with visceral myopathy who, due to unsuccessful conservative treatment, underwent surgery. However, few surgeries did not give the desired result and the patient still suffers from chronic constipation, abdominal distension and pain. The diagnosis of visceral myopathy is complicated. Neither conservative nor surgical treatment of visceral myopathy is associated with good results.
Herschel–ATLAS Data Release III: near-infrared counterparts in the South Galactic Pole field – another 100 000 submillimetre galaxies
Authors: Ward B A , Eales S A , Pons E , Smith M W L , McMahon R G , Dunne L , Ivison R J , Maddox S J , Negrello M
Published: November 2021

In this paper, we present the third data release (DR3) of the Herschel Astrophysical Terahertz Large Area Survey (H-ATLAS). We identify likely near-infrared counterparts to submillimetre sources in the South Galactic Pole (SGP) field using the VISTA VIKING survey. We search for the most probable counterparts within 15 arcsec of each Herschel source using a probability measure based on the ratio between the likelihood the true counterpart is found close to the submillimetre source and the likelihood that an unrelated object is found in the same location. For 110 374 (57.0 per cent) sources, we find galaxies on the near-infrared images where the probability that the galaxy is associated to the source is greater than 0.8. We estimate the false identification rate to be 4.8 per cent, with a probability that the source has an associated counterpart on the VIKING images of 0.835 ± 0.009. We investigate the effects of gravitational lensing and present 41 (0.14 deg−2) candidate lensed systems with observed flux densities >100 mJy at 500 μm. We include in the data release a probability that each source is gravitationally lensed and discover an additional 5923 sources below 100 mJy that have a probability greater than 0.94 of being gravitationally lensed. We estimate that ∼400–1 000 sources have multiple true identifications in VIKING based on the similarity of redshift estimates for multiple counterparts close to a Herschel source. The data described in this paper can be found at the H-ATLAS website.
Hunting wide-area optical surveys for high proper motion isolated neutron stars
Authors: Toyouchi Daisuke , Hotokezaka Kenta , Takada Masahiro
Published: November 2021

High-velocity neutron stars (HVNSs) that were kicked out from their birth location can be potentially identified with their large proper motions, and possibly with large parallax, when they come across the solar neighborhood. In this paper, we study the feasibility of hunting isolated HVNSs in wide-area optical surveys by modelling the evolution of NS luminosity taking into account spin-down and thermal radiation. Assuming the upcoming 10-yr Vera C. Rubin Observatory’s LSST observation, our model calculations predict that about 10 HVNSs mainly consisting of pulsars with ages of 104–$10^5\, \rm yr$ and thermally emitting NSs with 105–$10^6\, \rm yr$ are detectable. We find that a few NSs with effective temperature $\lt 5 \times 10^5\, \rm K$, which are likely missed in the current and future X-ray surveys, are also detectable, and the detectability highly depends on NS cooling models. In particular, if considering dark matter heating in NS cores, we find that such cold NSs would account for $70{{\ \rm per\ cent}}$ of the whole detectable sample, and they are typically older than $10^6\, \rm yr$ and tend to have slow transverse velocities, $\lesssim 100\, \rm km\, s^{-1}$, compared to already known pulsars. Thus, the future optical observation will give a unique NS sample, which can provide essential constraints on the NS cooling and heating mechanisms. Moreover, we suggest that providing HVNS samples with optical surveys is helpful for understanding the intrinsic kick-velocity distribution of NSs.
Why do black holes trace bulges (& central surface densities), instead of galaxies as a whole?
Authors: Hopkins Philip F , Wellons Sarah , Anglés-Alcázar Daniel , Faucher-Giguère Claude-André , Grudić Michael Y
Published: November 2021

Previous studies of fueling black holes in galactic nuclei have argued (on scales ${\sim}0.01{-}1000\,$pc) accretion is dynamical with inflow rates $\dot{M}\sim \eta \, M_{\rm gas}/t_{\rm dyn}$ in terms of gas mass Mgas, dynamical time tdyn, and some η. But these models generally neglected expulsion of gas by stellar feedback, or considered extremely high densities where expulsion is inefficient. Studies of star formation, however, have shown on sub-kpc scales the expulsion efficiency fwind = Mejected/Mtotal scales with the gravitational acceleration as $(1-f_{\rm wind})/f_{\rm wind}\sim \bar{a}_{\rm grav}/\langle \dot{p}/m_{\ast }\rangle \sim \Sigma _{\rm eff}/\Sigma _{\rm crit}$ where $\bar{a}_{\rm grav}\equiv G\, M_{\rm tot}(\lt r)/r^{2}$ and $\langle \dot{p}/m_{\ast }\rangle$ is the momentum injection rate from young stars. Adopting this as the simplest correction for stellar feedback, $\eta \rightarrow \eta \, (1-f_{\rm wind})$, we show this provides a more accurate description of simulations with stellar feedback at low densities. This has immediate consequences, predicting the slope and normalization of the MBH − σ and MBH − Mbulge relation, LAGN −SFR relations, and explanations for outliers in compact Es. Most strikingly, because star formation simulations show expulsion is efficient (fwind ∼ 1) below total-mass surface density $M_{\rm tot}/\pi \, r^{2}\lt \Sigma _{\rm crit}\sim 3\times 10^{9}\, \mathrm{M}_{\odot }\, {\rm kpc^{-2}}$ (where $\Sigma _{\rm crit}=\langle \dot{p}/m_{\ast }\rangle /(\pi \, G)$), BH mass is predicted to specifically trace host galaxy properties above a critical surface brightness Σcrit (B-band $\mu _{\rm B}^{\rm crit}\sim 19\, {\rm mag\, arcsec^{-2}}$). This naturally explains why BH masses preferentially reflect bulge properties or central surface densities (e.g. $\Sigma _{1\, {\rm kpc}}$), not ‘total’ galaxy properties.
Multiplexed activation in mammalian cells using a split-intein CRISPR/Cas12a based synthetic transcription factor
Authors: Bryson James W , Auxillos Jamie Y , Rosser Susan J
Published: November 2021

The adoption of CRISPR systems for the generation of synthetic transcription factors has greatly simplified the process for upregulating endogenous gene expression, with a plethora of applications in cell biology, bioproduction and cell reprogramming. The recently discovered CRISPR/Cas12a (Cas12a) systems offer extended potential, as Cas12a is capable of processing its own crRNA array, to provide multiple individual crRNAs for subsequent targeting from a single transcript. Here we show the application of dFnCas12a-VPR in mammalian cells, with the Francisella novicida Cas12a (FnCas12a) possessing a shorter PAM sequence than Acidaminococcus sp. (As) or Lachnospiraceae bacterium (Lb) variants, enabling denser targeting of genomic loci, while performing just as well or even better than the other variants. We observe that synergistic activation and multiplexing can be achieved using crRNA arrays but also show that crRNAs expressed towards the 5′ of 6-crRNA arrays show evidence of enhanced activity. This not only represents a more flexible tool for transcriptional modulation but further expands our understanding of the design capabilities and limitations when considering longer crRNA arrays for multiplexed targeting.
Recognition of G-quadruplex RNA by a crucial RNA methyltransferase component, METTL14
Authors: Yoshida Atsuhiro , Oyoshi Takanori , Suda Akiyo , Futaki Shiroh , Imanishi Miki
Published: November 2021

N6-methyladenosine (m6A) is an important epitranscriptomic chemical modification that is mainly catalyzed by the METTL3/METTL14 RNA methyltransferase heterodimer. Although m6A is found at the consensus sequence of 5′-DRACH-3′ in various transcripts, the mechanism by which METTL3/METTL14 determines its target is unclear. This study aimed to clarify the RNA binding property of METTL3/METTL14. We found that the methyltransferase heterodimer itself has a binding preference for RNA G-quadruplex (rG4) structures, which are non-canonical four-stranded structures formed by G-rich sequences, via the METTL14 RGG repeats. Additionally, the methyltransferase heterodimer selectively methylated adenosines close to the rG4 sequences. These results suggest a possible process for direct recruitment of METTL3/METTL14 to specific methylation sites, especially near the G4-forming regions. This study is the first to report the RNA binding preference of the m6A writer complex for the rG4 structure and provides insights into the role of rG4 in epitranscriptomic regulation.
Rational design and construction of multi-copy biomanufacturing islands in mammalian cells
Authors: Altamura Raffaele , Doshi Jiten , Benenson Yaakov
Published: November 2021

Cell line development is a critical step in the establishment of a biopharmaceutical manufacturing process. Current protocols rely on random transgene integration and amplification. Due to considerable variability in transgene integration profiles, this workflow results in laborious screening campaigns before stable producers can be identified. Alternative approaches for transgene dosage increase and integration are therefore highly desirable. In this study, we present a novel strategy for the rapid design, construction, and genomic integration of engineered multiple-copy gene constructs consisting of up to 10 gene expression cassettes. Key to this strategy is the diversification, at the sequence level, of the individual gene cassettes without altering their protein products. We show a computational workflow for coding and regulatory sequence diversification and optimization followed by experimental assembly of up to nine gene copies and a sentinel reporter on a contiguous scaffold. Transient transfections in CHO cells indicates that protein expression increases with the gene copy number on the scaffold. Further, we stably integrate these cassettes into a pre-validated genomic locus. Altogether, our findings point to the feasibility of engineering a fully mapped multi-copy recombinant protein ‘production island’ in a mammalian cell line with greatly reduced screening effort, improved stability, and predictable product titers.
Reshaping UK/Ireland relations: Brexit’s cross-border and bilateral impact
Authors: Murphy Mary C
Published: November 2021

This article considers the implications of Brexit for UK–Irish relations. It examines how Brexit has altered the terms of the British–Irish relationship by considering the impact on bilateral and cross-border economic and trade patterns. The article focuses on two primary economic effects. First, the short-term impact of Brexit and the Ireland/Northern Ireland Protocol on the Northern Ireland economy, and on trade relations between Great Britain and Ireland and across the Irish border; and second, how Brexit has spurred a discussion about the (economic) appropriateness of partition on the island of Ireland in the post-Brexit period, the extent to which it has led to increased calls for a border poll, and how any future unification process might be economically managed. This includes some provisional evaluation of the economic costs and challenges in relation to future constitutional change for the island of Ireland and the UK. The discussion here connects with wider British constitutional issues including calls for Scottish independence and the possible break-up of the UK.
Globalizing the Second World War
Authors: Buchanan Andrew
Published: November 2021

Entrenched within national histories, the Second World War has largely resisted the ‘global turn’ despite its eminent globality. The broad reconceptualization presented here views the Second World War as a paroxysm of worldwide war (December 1941−September 1945) embedded within a capacious cycle of regional wars and revolutions beginning with the Japanese invasion of Manchuria in 1931 and ending in Korea in 1953. This expanded temporal frame is intertwined with a broadening of spatial horizons that allows the assimilation of world regions from Latin America to sub-Saharan Africa, facilitates the integration of transnational flows of matériel, people and ideas, and underscores hybridity and popular agency. These conceptual shifts challenge the reified imaginary of the war of 1939–45, blurring ‘war’ and ‘post-war’ and allowing us to picture an American-led world order emerging directly from the war while illuminating the fighting that continued uninterrupted by Hiroshima and Nagasaki. This approach explores the tension between global and national histories — itself a reflection of the contradiction between capitalism’s push for worldwide markets and the nation states within which it is organized — and views American hegemony as the primary outcome of the long war while highlighting the qualifications posed by the Chinese Revolution, the strengthening of the USSR, and the rise of anti-colonial struggles.
Patience and Comparative Development
Authors: Sunde Uwe , Dohmen Thomas , Enke Benjamin , Falk Armin , Huffman David , Meyerheim Gerrit
Published: November 2021

This article studies the relationship between patience and comparative development through a combination of reduced-form analyses and model estimations. Based on a globally representative dataset on time preference in 76 countries, we document two sets of stylized facts. First, patience is strongly correlated with per capita income and the accumulation of physical capital, human capital, and productivity. These correlations hold across countries, sub-national regions, and individuals. Second, the magnitude of the patience elasticity strongly increases in the level of aggregation. To provide an interpretive lens for these patterns, we analyse an overlapping generations model in which savings and education decisions are endogenous to patience, aggregate production is characterized by capital-skill complementarities, and productivity implicitly depends on patience through a human capital externality. In our model estimations, general equilibrium effects alone account for a non-trivial share of the observed amplification effects, and an extension to human capital externalities can quantitatively match the empirical evidence.
Crassaminicella thermophila sp. nov., a moderately thermophilic bacterium isolated from a deep-sea hydrothermal vent chimney and emended description of the genus Crassaminicella
Authors: Li Xue-Gong , Lin Jin , Bai Shi-Jie , Dai Jie , Jiao Ze-Xi , Tang Hong-Zhi , Qi Xiao-Qing , Zhang Wei-Jia , Liu Min , Xu Jian-Sheng , Wu Long-Fei
Published: November 2021

A novel moderately thermophilic, anaerobic, heterotrophic bacterium (strain SY095T) was isolated from a hydrothermal vent chimney located on the Southwest Indian Ridge at a depth of 2730 m. Cells were Gram-stain-positive, motile, straight to slightly curved rods forming terminal endospores. SY095Twas grown at 45–60 °C (optimum 50–55 °C), pH 6.0–7.5 (optimum 7.0), and in a salinity of 1–4.5 % (w/v) NaCl (optimum 2.5 %). Substrates utilized by SY095Tincluded fructose, glucose, maltose,N-acetyl glucosamine and tryptone. Casamino acid and amino acids (glutamate, glutamine, lysine, methionine, serine and histidine) were also utilized. The main end products from glucose fermentation were acetate, H2and CO2. Elemental sulphur, sulphate, thiosulphate, sulphite, fumarate, nitrate, nitrite and Fe(III) were not used as terminal electron acceptors. The predominant cellular fatty acids were C14 : 0(60.5%) and C16 : 0(7.6 %). The main polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, five unidentified phospholipids and two unidentified aminophospholipids. No respiratory quinones were detected. The chromosomal DNA G+C content was 30.8 mol%. The results of phylogenetic analysis of the 16S rRNA gene sequences indicated that SY095Twas closely related toCrassaminicella profundaRa1766HT(95.8 % 16S rRNA gene sequence identity). SY095Texhibited 78.1 % average nucleotide identity (ANI) toC. profundaRa1766HT. Thein silicoDNA–DNA hybridization (DDH) value indicated that SY095Tshared 22.7 % DNA relatedness withC. profundaRa1766HT. On the basis of its phenotypic, genotypic and phylogenetic characteristics, SY095Tis suggested to represent a novel species of the genusCrassaminicella, for which the nameCrassaminicella thermophilasp. nov. is proposed. The type strain is SY095T(=JCM 34213=MCCC 1K04191). An emended description of the genusCrassaminicellais also proposed.
Key carboxylate residues for iron transit through the prokaryotic ferritin SynFtn
Authors: Bradley Justin M. , Fair Joshua , Hemmings Andrew M. , Le Brun Nick E.
Published: November 2021

Ferritins are proteins forming 24meric rhombic dodecahedral cages that play a key role in iron storage and detoxification in all cell types. Their function requires the transport of Fe2+ from the exterior of the protein to buried di-iron catalytic sites, known as ferroxidase centres, where Fe2+ is oxidized to form Fe3+-oxo precursors of the ferritin mineral core. The route of iron transit through animal ferritins is well understood: the Fe2+ substrate enters the protein via channels at the threefold axes and conserved carboxylates on the inner surface of the protein cage have been shown to contribute to transient binding sites that guide Fe2+ to the ferroxidase centres. The routes of iron transit through prokaryotic ferritins are less well studied but for some, at least, there is evidence that channels at the twofold axes are the major route for Fe2+ uptake. SynFtn, isolated from the cyanobacterium

Synechococcus

CC9311, is an atypical prokaryotic ferritin that was recently shown to take up Fe2+ via its threefold channels. However, the transfer site carboxylate residues conserved in animal ferritins are absent, meaning that the route taken from the site of iron entry into SynFtn to the catalytic centre is yet to be defined. Here, we report the use of a combination of site-directed mutagenesis, absorbance-monitored activity assays and protein crystallography to probe the effect of substitution of two residues potentially involved in this pathway. Both Glu141 and Asp65 play a role in guiding the Fe2+ substrate to the ferroxidase centre. In the absence of Asp65, routes for Fe2+ to, and Fe3+ exit from, the ferroxidase centre are affected resulting in inefficient formation of the mineral core. These observations further define the iron transit route in what may be the first characterized example of a new class of ferritins peculiar to cyanobacteria.
Influence of tissue and geographic locality on culturable endophytic bacteria of Atractylodes macrocephala
Authors: Wu Wei , Wang Shiyu , Wu Jianjun , He Bingqian , Zhu Bo , Qin Luping
Published: November 2021

The endophytic bacterial community and their diversity are closely related to the host’s growth and development. This paper explores the culturable endophytic bacteria in the stems, leaves, roots and rhizomes of Atractylodes macrocephala (AM) of four localities (Yuqian, Wenxian, Pan’an and Pingjiang) and the potential correlation between the bacteria and plant bioactive compounds. A total of 118 endophytic bacteria belonging to 3 phyla, 5 classes, 11 orders, 26 families and 48 genera were isolated and identified from the four AM tissues. Among them,

Bacillus

was the dominant genus. In AM, the tissue type and locality influenced the endophytic bacterial community. Approximately 29.7 and 28.8% of the endophytic bacteria exhibited tissue specificity and geographic specificity, respectively. Furthermore, high-performance liquid chromatography revealed that the sesquiterpenoid (atractylenolide I, atractylenolide Ⅱ and atractylon) content was more in the rhizomes of Wenxian than in those of Pingjiang, Yuqian and Pan’an. The multiple linear regression was used to screen the bacterial strains related to the bioactive compounds of AM. The relative frequency of

Microbacterium

positively correlated with atractylenolide I and atractylon content in AM but negatively correlated with atractylenolide Ⅱ content. The study also provides a theoretical framework for future research on endophytic bacteria as alternative sources of secondary plant metabolites.
Determining the Impact of Ethnicity on the Accuracy of Measurements of Oxygen Saturations. A Retrospective Cohort Study
Authors: Bangash Mansoor N , Hodson James , Evison Felicity , Patel Jaimin M , Johnston Andrew McD , Gallier Suzy , Sapey Elizabeth , Parekh Dhruv
Published: November 2021

Background

Pulse oximeters are routinely used in community and hospital settings worldwide as a rapid, non-invasive, and readily available bedside tool to approximate blood oxygenation. Potential racial biases in SpO2 measurements may influence the accuracy of pulse oximetry readings and impact clinical decision making. We aimed to assess whether the accuracy of oxygen saturation measured by peripheral pulse oximetry (SpO2), relative to arterial blood gas (SaO2), varies by ethnicity.

Methods

In this large retrospective observational cohort study covering four NHS Hospitals serving a large urban population in Birmingham, consecutive patients admitted to hospital requiring oxygen therapy were identified by electronic patient records. For each spell, the first available pair of SpO2 and SaO2 measurements taken within an interval of less than 20 minutes were identified and included in the analysis. The differences between SpO2 and SaO2 measurements, were compared across self-identified groups of ethnicities. These differences were subsequently adjusted for age, sex, bilirubin, systolic blood pressure, carboxyhaemaglobin saturations and the time interval between SpO2 and SaO2 measurements.

Findings

Paired O2 saturation measurements from 16818 inpatient spells between 1st January 2017 and 18th February 2021, were analysed. The cohort self-identified as being of White (81.2%), Asian (11.7%), Black (4.0%), or Other (3.2%) ethnicities. Across the cohort, SpO2 was significantly higher than SaO2 (median: 98% vs. 97%, p<0.001), with a median difference of 0.5 percentage points (pps). However, the size of this difference varied considerably with the magnitude of SaO2, with SpO2 overestimation by a median of 3.8pp for SaO2 values <90% but underestimating by a median of 0.4pp for an SaO2 of 95%. The differences between SpO2 and SaO2 were also found to vary significantly by ethnicity, with this difference being 0.8pp (95% confidence interval: 0.6-1.0) greater in those of Black vs. White ethnicity. These differences resulted in 6.1% vs. 8.7% of White vs. Black patients classified as normoxic on SpO2 who were hypoxic on the gold standard SaO2 reading (p=0.007).

Interpretation

Pulse oximetry tends to overestimate O2 saturation, and this is more pronounced in patients of Black ethnicity. Prospective studies are urgently warranted to assess the impact of ethnicity on the accuracy of pulse oximetry, to ensure care is optimised for all.

Funding

This work was supported by PIONEER, the Health Data Research UK (HDR-UK) Health Data Research Hub in acute care. HDR-UK is an initiative funded by the UK Research and Innovation, Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities.
High Burden of COVID-19 among Unvaccinated Law Enforcement Officers and Firefighters
Authors: Caban-Martinez Alberto J. , Gaglani Manjusha , Olsho Lauren E.W. , Grant Lauren , Schaefer-Solle Natasha , Louzado-Feliciano Paola , Tyner Harmony L. , Yoon Sarang K. , Naleway Allison L. , Smith Michael , Sokol Brian E. , Lutrick Karen , Fowlkes Ashley L. , Meece Jennifer , Noriega Roger , Odean Marilyn , Phillips Andrew L. , Groom Holly C. , Murthy Kempapura , Edwards Laura J. , Ellingson Katherine D. , M.Yoo Young , Cruz Alexandra , Respet Karley , Thiese Matthew S. , Kuntz Jennifer L. , Rose Spencer , Hadden Louise S. , Gerald Joe K. , Mak Josephine , Gallimore-Wilson Damena , Lundgren Jessica , Hegmann Kurt T. , Dunnigan Kayan , Wesley Meredith G. , Bedrick Edward J. , Lamberte Julie Mayo , Jones John M. , Hunt Angela , Bruner Matthew M. , Groover Kimberly , Kutty Preeta K. , Testoff Addison C. , LeClair Lindsay B. , Etolue Jini M. , Thompson Mark G. , Burgess Jefferey L.
Published: November 2021

Law Enforcement Officers (LEOs), firefighters, and other first responders are at increased risk of SARS-CoV-2 infection compared to healthcare personnel but have relatively low COVID-19 vaccine uptake. Resistance to COVID-19 vaccine mandates among first responders has the potential to disrupt essential public services and threaten public health and safety. Using data from the HEROES-RECOVER prospective cohorts, we report on the increased illness burden of COVID-19 among unvaccinated first responders. From January to September 2021, first responders contributed to weekly active surveillance for COVID-19-like illness (CLI). Self-collected respiratory specimens collected weekly, irrespective of symptoms, and at the onset CLI were tested by Reverse Transcription Polymerase Chain Reaction (RT-PCR) assay for SARS-CoV-2. Among 1415 first responders, 17% were LEOs, 68% firefighters, and 15% had other first responder occupations. Unvaccinated (41%) compared to fully vaccinated (59%) first responders were less likely to believe COVID-19 vaccines are very or extremely effective (17% versus 54%) or very or extremely safe (15% versus 54%). From January through September 2021, among unvaccinated LEOs, the incidence of COVID-19 was 11.9 per 1,000 person-weeks (95%CI=7.0-20.1) compared to only 0.6 (95%CI=0.2-2.5) among vaccinated LEOs. Incidence of COVID-19 was also higher among unvaccinated firefighters (9.0 per 1,000 person-weeks; 95%CI=6.4-12.7) compared to those vaccinated (1.8 per 1,000; 95%CI=1.1-2.8). Once they had laboratory-confirmed COVID-19, unvaccinated first responders were sick for a mean±SD of 14.7±21.7 days and missed a mean of 38.0±46.0 hours of work. These findings suggest that state and local governments with large numbers of unvaccinated first responders may face major disruptions in their workforce due to COVID-19 illness.
Circulating microRNAs from early childhood and adolescence are associated with pre-diabetes at 18 years of age in women from the PMNS cohort
Authors: Joglekar Mugdha V. , Kunte Pooja S. , Wong Wilson K.M. , Bhat D. S. , Satoor Sarang N. , Patil Rohan R. , Karandikar Mahesh S. , Fall Caroline H.D. , Yajnik Chittaranjan S. , Hardikar Anandwardhan A.
Published: November 2021

A high (20%) prevalence of glucose intolerance at 18-years was seen in women from the Pune Maternal Nutrition Study (PMNS) birth cohort. Here, we provide preliminary longitudinal analyses of circulating microRNAs in normal glucose tolerant (NGT@18y, N=10) and glucose intolerant (N=8) women (ADA criteria) at 6-, 12- and 17-years of their age using discovery analysis (OpenArray™ platform). Machine-learning workflows involving Lasso with bootstrapping/leave-one-out cross-validation (LOOCV) identified microRNAs associated with glucose intolerance at 18-years of age. Several microRNAs, including miR-212-3p, miR-30e-3p and miR-638, stratified glucose-intolerant women from NGT at childhood. Our results suggest that circulating microRNAs in childhood could predict pre-diabetes at 18-years of age. Validation of these findings in males and remaining participants from the PMNS birth cohort will provide a unique opportunity to study novel epigenetic mechanisms in the life-course progression of glucose intolerance and enhance current clinical risk prediction of pre-diabetes and progression to type 2 diabetes.
Resting-state fMRI-based screening of deschloroclozapine in rhesus macaques predicts dosage-dependent behavioral effects
Authors: Fujimoto Atsushi , Elorette Catherine , Fredericks J. Megan , Fujimoto Satoka H. , Fleysher Lazar , Rudebeck Peter H. , Russ Brian E.
Published: November 2021

Chemogenetic techniques such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable transient, reversible, and minimally invasive manipulation of neural activity in vivo. Their development in non-human primates is essential for uncovering neural circuits contributing to cognitive functions and their translation to humans. One key issue that has delayed the development of chemogenetic techniques in primates is the lack of an accessible drug-screening method. Here, we utilize resting-state functional MRI (rs-fMRI), a non-invasive neuroimaging tool, to assess the impact of deschloroclozapine (DCZ) on brain-wide resting-state functional connectivity in seven rhesus macaques without DREADDs. We found that systemic administration of 0.1 mg/kg DCZ did not alter the resting-state functional connectivity. Conversely, 0.3 mg/kg of DCZ was associated with a prominent increase in functional connectivity that was mainly confined to the connections of frontal regions. Additional behavioral tests confirmed a negligible impact of 0.1 mg/kg DCZ on socio-emotional behaviors as well as on reaction time in a probabilistic learning task. 0.3 mg/kg DCZ did, however, slow responses in the probabilistic learning task, suggesting attentional or motivational deficits associated with hyperconnectivity in fronto-temporo-parietal networks. Our study highlights both the excellent selectivity of DCZ as a DREADD actuator, and the side-effects of its excess dosage. The results demonstrate the translational value of rs-fMRI as a drug-screening tool to accelerate the development of chemogenetics in primates.
Dual Effects of Nanoviricides Platform Technology Based NV-CoV-2 Biomimetic Polymer Against COVID-19
Authors: Diwan Anil , Chakraborty Ashok , Chiniga Vijetha , Arora Vinod , Holkar Preetam , Thakur Yogesh , Tatake Jay , Barton Randall , Holkar Neelam , Pond Bethany
Published: November 2021

Remdesivir (RDV) is the only antiviral drug so far approved for COVID-19 therapy by the FDA. However its efficacy is limited in vivo due to its low stability in presence of plasma. This paper compared the stability of RDV encapsulated with our platform technology based polymer NV-387 (NV-CoV-2), in presence of plasma in vitro and in vivo. Furthermore, a non- clinical pharmacology studies of NV-CoV-2 (Polymer) and NV-CoV-2-R (Polymer encapsulated Remdesivir) in both NL-63 infected and uninfected rats were done. In an in vitro cell culture model experiment, antiviral activity of NV-CoV-2 and NV-CoV-2-R are also compared with RDV.

The results are (i) NV-CoV-2 polymer encapsulation protects RDV from plasma- mediated catabolism in vitro and in vivo, too. (ii) Body weight measurements of the normal (uninfected) rats after administration of the test materials (NV-CoV-2, and NV-CoV-2-R) show no toxic effects on them. (iii) NL-63 infected rats body weights and their survival length were like uninfected rats after treatment with NV-CoV-2 and NV-CoV-2-R, and the efficacy as an antiviral regimen were found in the order as below: NV-CoV-2-R > NV-CoV-2 > RDV.

In brief, our platform technology based NV-387-encapsulated-RDV (NV-CoV-2-R) drug has a dual effect on coronaviruses. First, NV-CoV-2 itself as an antiviral regimen. Secondly, RDV is protected from plasma-mediated degradation in transit, rendering altogether the safest and an efficient regimen against COVID-19.
Figbird: A probabilistic method for filling gaps in genome assemblies
Authors: Tarafder Sumit , Islam Mazharul , Shatabda Swakkhar , Rahman Atif
Published: November 2021

Motivation

Advances in sequencing technologies have led to sequencing of genomes of a multitude of organisms. However, draft genomes of many of these organisms contain a large number of gaps due to repeats in genomes, low sequencing coverage and limitations in sequencing technologies. Although there exist several tools for filling gaps, many of these do not utilize all information relevant to gap filling.

Results

Here, we present a probabilistic method for filling gaps in draft genome assemblies using second generation reads based on a generative model for sequencing that takes into account information on insert sizes and sequencing errors. Our method is based on the expectation-maximization (EM) algorithm unlike the graph based methods adopted in the literature. Experiments on real biological datasets show that this novel approach can fill up large portions of gaps with small number of errors and misassemblies compared to other state of the art gap filling tools.

Availability and Implementation

The method is implemented using C++ in a software named “Filling Gaps by Iterative Read Distribution (Figbird)”, which is available at: https://github.com/SumitTarafder/Figbird.

Contact

atif@cse.buet.ac.bd

Supplementary information

Supplementary data are available at Bioinformatics online.
A dysmorphic mouse model reveals developmental interactions of chondrocranium and dermatocranium
Authors: Motch Perrine Susan M. , Pitirri M. Kathleen , Durham Emily L. , Kawasaki Mizuho , Zheng Hao , Chen Danny Z. , Kawasaki Kazuhiko , Richtsmeier Joan T.
Published: November 2021

The cranial endo- and dermal skeletons, which comprise the vertebrate skull, evolved independently over 470 million years ago and form separately during embryogenesis. In mammals, much of the cartilaginous chondrocranium is transient, undergoing endochondral ossification or disappearing, so its role in skull morphogenesis is not well studied and it remains an enigmatic structure. We provide complete three-dimensional (3D) reconstructions of the laboratory mouse chondrocranium from embryonic day 13.5 through 17.5 using a novel methodology of uncertainty-guided segmentation of phosphotungstic enhanced 3D microcomputed tomography images with sparse annotation. We evaluate the embryonic mouse chondrocranium and dermatocranium in 3D and delineate the effects of a Fgfr2 variant on embryonic chondrocranial cartilages and on the association with forming dermal bones using the Fgfr2cC342Y/+ Crouzon syndrome mouse. We show that the dermatocranium develops outside of and in shapes that conform to the chondrocranium. Results reveal direct effects of the Fgfr2 variant on embryonic cartilage, on chondrocranium morphology, and on the association between chondrocranium and dermatocranium development. Histologically we observe a trend of relatively more chondrocytes, larger chondrocytes, and/or more matrix in the Fgfr2cC342Y/+ embryos at all timepoints before the chondrocranium begins to disintegrate at E16.5. The chondrocrania and forming dermatocrania of Fgfr2cC342Y/+ embryos are relatively large, but a contrasting trend begins at E16.5 and continues into early postnatal (P0 and P2) timepoints, with the skulls of older Fgfr2cC342Y/+ mice reduced in most dimensions compared to Fgfr2c+/+ littermates. Our findings have implications for the study and treatment of human craniofacial disease, for understanding the impact of chondrocranial morphology on skull growth, and potentially on the evolution of skull morphology.
A fully automated FAIMS-DIA proteomic pipeline for high-throughput characterization of iPSC-derived neurons
Authors: Reilly Luke , Peng Lirong , Lara Erika , Ramos Daniel , Fernandopulle Michael , Pantazis Caroline B. , Stadler Julia , Santiana Marianita , Dadu Anant , Iben James , Faghri Faraz , Nalls Mike A. , Coon Steven L. , Narayan Priyanka , Singleton Andrew B. , Cookson Mark R. , Ward Michael E. , Qi Yue A.
Published: November 2021

Fully automated proteomic pipelines have the potential to achieve deep coverage of cellular proteomes with high throughput and scalability. However, it is important to evaluate performance, including both reproducibility and ability to provide meaningful levels of biological insight. Here, we present an approach combining high field asymmetric waveform ion mobility spectrometer (FAIMS) interface and data independent acquisition (DIA) proteomics approach developed as part of the induced pluripotent stem cell (iPSC) Neurodegenerative Disease Initiative (iNDI), a large-scale effort to understand how inherited diseases may manifest in neuronal cells. Our FAIMS-DIA approach identified more than 8000 proteins per mass spectrometry (MS) acquisition as well as superior total identification, reproducibility, and accuracy compared to other existing DIA methods. Next, we applied this approach to perform a longitudinal proteomic profiling of the differentiation of iPSC-derived neurons from the KOLF2.1J parental line used in iNDI. This analysis demonstrated a steady increase in expression of mature cortical neuron markers over the course of neuron differentiation. We validated the performance of our proteomics pipeline by comparing it to single cell RNA-Seq datasets obtained in parallel, confirming expression of key markers and cell type annotations. An interactive webapp of this temporal data is available for aligned-UMAP visualization and data browsing (https://share.streamlit.io/anant-droid/singlecellumap). In summary, we report an extensively optimized and validated proteomic pipeline that will be suitable for large-scale studies such as iNDI.
Spectral organ fingerprints for intraoperative tissue classification with hyperspectral imaging
Authors: Studier-Fischer A. , Seidlitz S. , Sellner J. , Wiesenfarth M. , Ayala L. , Özdemir B. , Odenthal J. , Knödler S. , Kowalewski K.F. , Haney C.M. , Camplisson I. , Dietrich M. , Schmidt K. , Salg G.A. , Kenngott H.G. , Adler T.J. , Schreck N. , Kopp-Schneider A. , Maier-Hein K. , Maier-Hein L. , Müller-Stich B.P. , Nickel F.
Published: November 2021

Visual discrimination of tissue during surgery can be challenging since different tissues appear similar to the human eye. Hyperspectral imaging (HSI) removes this limitation by associating each pixel with high-dimensional spectral information. While previous work has shown its general potential to discriminate tissue, clinical translation has been limited due to the method’s current lack of robustness and generalizability. Specifically, it had been unknown whether variability in spectral reflectance is primarily explained by tissue type rather than the recorded individual or specific acquisition conditions. The contribution of this work is threefold: (1) Based on an annotated medical HSI data set (9,059 images from 46 pigs), we present a tissue atlas featuring spectral fingerprints of 20 different porcine organs and tissue types. (2) Using the principle of mixed model analysis, we show that the greatest source of variability related to HSI images is the organ under observation. (3) We show that HSI-based fully-automatic tissue differentiation of 20 organ classes with deep neural networks is possible with high accuracy (> 95 %). We conclude from our study that automatic tissue discrimination based on HSI data is feasible and could thus aid in intraoperative decision making and pave the way for context-aware computer-assisted surgery systems and autonomous robotics.
Secondary DNA transfer on denim using a human blood analogue
Authors: Ridings Rebecca , Gabriel Alon , Elliott Colin I. , Shafer Aaron B.A.
Published: November 2021

DNA quantification technology has increased in accuracy and sensitivity, now allowing for detection and profiling of trace DNA. Secondary DNA transfer occurs when DNA is deposited via an intermediary source (e.g. clothing, tools, utensils). Multiple courtrooms have now seen secondary transfer introduced as an explanation for DNA being present at a crime scene, but sparse experimental studies mean expert opinions are often limited. Here, we used bovine blood and indigo denim substrates to quantify the amount of secondary DNA transfer and quality of STRs under three different physical contact scenarios: passive, pressure, and friction. We showed that the DNA transfer was highest under a friction scenario, followed by pressure and passive treatments. The STR profiles showed a similar, albeit less pronounced trend, with correctly scored alleles and genotype completeness being highest under a friction scenario, followed by pressure and passive. DNA on the primary substrate showed a decrease in concentration and genotype completeness both immediately and at 24 hours, suggestive of a loss of DNA during the primary transfer. The majority of secondary transfer samples amplified less than 50% of STR loci regardless of contact type. This study showed that while DNA transfer is common between denim, this is not manifested in full STR profiles. We discuss the possible technical solutions to partial profiles from trace DNA, and more broadly the ubiquity of secondary DNA transfer.
Genetic perturbation enhances functional heterogeneity in alkaline phosphatase
Authors: Sakuma Morito , Honda Shingo , Ueno Hiroshi , Miyazaki Kentaro , Tokuriki Nobuhiko , Noji Hiroyuki
Published: November 2021

Enzymes inherently exhibit molecule-to-molecule heterogeneity in catalytic activity or function, which underlies the acquisition of new functions in evolutionary processes. However, correlations between the functional heterogeneity of an enzyme and its multi-functionality or promiscuity remain elusive. In addition, the modulation of functional heterogeneity upon genetic perturbation is currently unexplored. Here, we quantitatively analyzed functional heterogeneity in the wild-type and 69 single-point mutants of Escherichia coli alkaline phosphatase (AP) by employing single-molecule assay with a femtoliter reactor array device. Most mutant enzymes exhibited higher functional heterogeneity than the wild-type enzyme, irrespective of catalytic activity. These results indicated that the wild-type AP minimizes functional heterogeneity, and single-point mutations can significantly expand the span of functional heterogeneity in AP. Moreover, we identified a clear correlation between functional heterogeneity and promiscuous activities. These findings suggest that enzymes can acquire greater functional heterogeneity following marginal genetic perturbations that concomitantly promote catalytic promiscuity.