bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Impact of LGR5, Prox1, and Notch1 Biomarkers in Stage II to III Colon Cancer
Authors: Abdelrahman Aziza E. , El-azony Ahmed , Elsebai Eman , Ibrahim Hanaa M.
Published: October 2021

The potentiation and activation of Wnt signaling pathways are now assumed to mediate the self-renewal and proliferation of colon cancer stem cells that are responsible for therapeutic resistance, tumor relapse, and metastasis. We aimed to evaluate LGR5, Prox1, and Notch1 immunohistochemical expression in stage II to III colon cancer. Their predictive role of tumor relapse, overall survival, and disease-free survival was statistically analyzed. Our results revealed that high LGR5 expression was identified in 56.7% of the patients, LGR5 expression was significantly associated with left-sided tumors (P<0.001). Moreover, its expression was significantly associated with the unfavorable tumor characteristics including high grade, deep invasion (pT), lymph node metastasis, and advanced tumor stage (P<0.001 for each). High Prox1 expression was observed in 65% of the cases, and its expression was significantly associated with tumor grade, lymph node metastasis, and the advanced tumor stage (P=0.004, 0.009, 0.016, respectively). Positive Notch1 expression was identified in 35% of patients, and it was inversely associated with high grade lymph node metastasis, deep invasion (pT), and advanced tumor stage (P<0.001 for each). During the follow-up period, the tumor relapse was significantly associated with high LGR5, high Prox1, and negative Notch1 expression. Shorter overall survival and disease-free survival were significantly associated with high LGR5, high Prox1, and negative Notch1 expression. High LGR5, high Prox1, and negative Notch1 expression are unfavorable prognostic factors in colon cancer. Prox1 is a crucial regulator of Notch-independent LGR5+ stem cells that is mostly responsible for relapse and therapeutic resistance in stage II to III colon cancer.
Review of IgG4-related Hashimoto Thyroiditis With Best Practice Recommendations for Diagnosis and Reporting
Authors: Adams Steven H. , Gitto Lorenzo , Serinelli Serenella , Curtiss Christopher
Published: October 2021

Found in virtually any organ system, immunoglobulin (Ig) G4–related disease (RD) is a recently recognized immune-mediated, systemic, a fibroinflammatory disease characterized histologically by storiform fibrosis, obliterative phlebitis, and lymphoplasmacytic infiltrate with IgG4-positive plasma cells (PCs). IgG4-related Hashimoto thyroiditis (IgG4-RHT), also called IgG4-related thyroiditis, shares many features with IgG4-RD but is distinct in several ways. A case of IgG4-RHT in a 51-year-old African American female is assembled together with a literature review which uncovered 82 cases of IgG4-RHT. The findings and criteria which the respective authors used to reach their diagnoses are analyzed. Findings common to all studies are lymphoplasmacytic infiltration and IgG4-positive staining, while most describe follicular atrophy (95.2%, 79/83). Stromal fibrosis involving >33% of thyroid architecture was reported in 74% (58/78) of cases. While few reports observed storiform fibrosis, all describe lack of obliterative phlebitis or systemic involvement. Discrepancies between reports exist in immunostaining thresholds, as well as grading systems for stromal fibrosis. Based on our review of the literature and experience, we propose a set of best practice recommendations for the diagnosis of IgG4-RHT. Our diagnostic criteria are (1) lack of extrathyroidal IgG4-RD, (2) the fibroinflammatory process should not extend beyond the thyroid capsule, (3) stromal fibrosis comprises at least 30% of the involved tissue, (4) >30% IgG4/IgG ratio, with absolute immunostaining cutoffs varying by the degree of stromal fibrosis: for >50% stromal fibrosis use >20 IgG4+PCs/HPF, for 30% to 50% fibrosis use >30 IgG4+PCs/HPF, (5) fibrosis infiltrates the interlobular/interfollicular space, (6) features of follicle injury, and (7) obliterative phlebitis is not required.
Evaluation of Venous-to-Arterial Carbon Dioxide Tension Difference as a Complementary Parameter During Pediatric Septic Shock Resuscitation
Authors: El-Nawawy Ahmed Ahmed , Hassaan Shimaa Mohammad , Hassouna Hadir Mohamed
Published: October 2021

Objectives

The aim of this study was to evaluate the venous-to-arterial carbon dioxide tension difference during early resuscitation in pediatric septic shock.

Methods

A prospective observational study was conducted in the pediatric intensive care unit of a tertiary care teaching. Children having septic shock aged from 3 to 60 months were studied within the first 24 hours of admission. Central venous and peripheral arterial blood samples for blood gases analysis at time of central venous catheter insertion and after 6 hours were obtained. Central venous carbon dioxide pressure, arterial carbon dioxide pressure, and their difference (delta Pco
2) were recorded. Patients were categorized, accordingly to delta Pco
2 after 6 hours of resuscitation, into high delta Pco
2 group (≥6 mm Hg) and low delta Pco
2 group (<6 mm Hg).

Results

Oxygen extraction ratio at 6 hours of resuscitation was significantly lower among the low delta Pco
2 group. Arterial lactate showed marked improvement in the low delta Pco
2 group to be less than 2 mmol/L at 12 hours of resuscitation. Low delta Pco
2 group showed significant higher shock reversal with shorter shock reversal time. Mortality was significantly lower among low delta Pco
2 group with shorter pediatric intensive care unit stay.

Conclusions

Delta Pco
2 after 6 hours of resuscitation of <6 mm Hg indicates normalization of tissue perfusion during pediatric septic shock management. It could be used as a complementary tool to guide the resuscitation in the early phase of pediatric septic shock.
Amyotrophic Lateral Sclerosis and Noninvasive Positive Pressure Ventilatory Support
Authors: Bach John R. , Pham Hoa
Published: October 2021

Many studies suggest a brief statistical benefit on survival and quality of life by using nasal noninvasive ventilation for patients with amyotrophic lateral sclerosis and other neuromuscular conditions. Indeed, nasal noninvasive ventilation has become synonymous with continuous positive airway pressure and lo-span bilevel positive airway pressure. Nasal noninvasive ventilation, however, may not normalize CO2 levels and continuous positive airway pressure and O2 exacerbate hypercapnia and often lead to CO2 narcosis, intubation, and ultimately tracheostomy or palliative care death. However, a third option can be to offer up to continuous noninvasive ventilatory support and extubation to it. Noninvasive ventilatory support can be effective for full, definitive ventilatory support, even for people with no measurable vital capacity, and has maintained classic amyotrophic lateral sclerosis patients for up to 12 yrs without resort to tracheotomies. Nineteen centers have reported 335 amyotrophic lateral sclerosis patients using continuous noninvasive ventilatory support instead of tracheostomy mechanical ventilation for an average of 14 mos (6 mos to 14 yrs). The noninvasive ventilatory support must also be used in conjunction with mechanical insufflation-exsufflation to clear airway debris and normalize or renormalize ambient air oxyhemoglobin saturation, both to avoid intubation and to facilitate extubation. People with amyotrophic lateral sclerosis satisfying specific criteria, even when continuously dependent on tracheostomy mechanical ventilation, can be decannulated and placed on continuous noninvasive ventilatory support with mechanical insufflation-exsufflation.
Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain
Authors: Bernard Healey Shannon A. , Scholtes Ingrid , Abrahams Mark , McNaughton Peter A. , Menon David K. , Lee Michael C.
Published: October 2021

Introduction:

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels mediate repetitive action potential firing in the heart and nervous system. The HCN2 isoform is expressed in nociceptors, and preclinical studies suggest a critical role in neuropathic pain. Ivabradine is a nonselective HCN blocker currently available for prescription for cardiac indications. Mouse data suggest that ivabradine in high concentrations is equianalgesic with gabapentin. We sought to translate these findings to patients with chronic peripheral neuropathic pain.

Objectives:

We sought to translate these findings to patients with chronic peripheral neuropathic pain.

Methods:

We adopted an open-label design, administering increasing doses of ivabradine to target a heart rate of 50 to 60 BPM, up to a maximum of 7.5 mg twice daily. All participants scored their pain on an 11-point numerical rating scale (NRS).

Results:

Seven (7) participants received the drug and completed the study. There was no significant treatment effect on the primary endpoint, the difference between the mean score at baseline and at maximum dosing (mean reduction = 0.878, 95% CI = −2.07 to 0.31, P = 0.1). Exploratory analysis using linear mixed models, however, revealed a highly significant correlation between ivabradine dose and pain scores (χ2(1) = 74.6, P < 0.001), with a reduction of 0.12 ± 0.01 (SEM) NRS points per milligram. The 2 participants with painful diabetic neuropathy responded particularly well.

Conclusion:

This suggests that ivabradine may be efficacious at higher doses, particularly in patients with diabetic neuropathic pain. Importantly, participants reported no adverse effects. These data suggest that ivabradine, a peripherally restricted drug (devoid of central nervous system side effects), is well tolerated in patients with chronic neuropathic pain. Ivabradine is now off-patent, and its analgesic potential merits further investigation in clinical trials.
The Conventional Technique Versus the No-touch Isolation Technique for Primary Tumor Resection in Patients With Colon Cancer (JCOG1006)
Authors: Takii Yasumasa , Mizusawa Junki , Kanemitsu Yukihide , Komori Koji , Shiozawa Manabu , Ohue Masayuki , Ikeda Satoshi , Takiguchi Nobuhiro , Kobatake Takaya , Ike Hideyuki , Sato Toshihiko , Tomita Naohiro , Ota Mituyoshi , Masaki Tadahiko , Hamaguchi Tetsuya , Shida Dai , Katayama Hiroshi , Shimada Yasuhiro , Fukuda Haruhiko
Published: October 2021

Objective:

This phase III trial evaluated whether the no touch was superior to the conventional in patients with cT3/T4 colon cancer.

Background:

No touch involves ligating blood vessels that feed the primary tumor to limit cancer cell spreading. However, previous studies did not confirm the efficacy of the no touch.

Methods:

This open-label, randomized, phase III trial was conducted at 30 Japanese centers. The eligibility criteria were histologically proven colon cancer; clinical classification of T3–4, N0–2, andM0; and patients aged 20 to 80years. Patients were randomized (1:1) to undergo open surgery with conventional or the no touch. Patients with pathological stage III disease received adjuvant capecitabine chemotherapy. The primary endpoint was disease-free survival (DFS) according to the intention-to-treat principle.

Results:

Between January 2011 and November 2015, 853 patients were randomized to the conventional group (427 patients) or the no touch group (426 patients). The 3-year DFS were 77.3% [95% confidence interval (CI) 73.1%–81.0%] and 76.2% (95% CI 71.9%–80.0%) in the conventional and no touch groups, respectively. The superiority of no touch was not confirmed: hazard ratio for DFS = 1.029 (95% CI 0.800– 1.324; 1-sided P = 0.59). Operative morbidity was observed in 31 of 427 conventional patients (7%) and 26 of 426 no touch patients (6%). All grade adverse events were similar between the conventional and no touch groups. No in-hospital mortality occurred in either group.

Conclusion:

The present study failed to confirm the superiority of the no touch.
The Long Road to Parenthood
Authors: Atkinson Rachel B. , Castillo-Angeles Manuel , Kim Eugene S. , Hu Yue-Yung , Gosain Ankush , Easter Sarah Rae , Dupree James M. , Cooper Zara , Rangel Erika L.
Published: October 2021

Objective:

We sought to characterize demographics, costs, and workplace support for surgeons using assisted reproductive technology (ART), adoption, and surrogacy to build their families.

Summary Background Data:

As the surgical workforce diversifies, the needs of surgeons building a family are changing. ART, adoption, and surrogacy may be used with greater frequency among female surgeons who delay childbearing and surgeons in same-sex relationships. Little is known about costs and workplace support for these endeavors.

Methods:

An electronic survey was distributed to surgeons through surgical societies and social media. Rates of ART use were compared between partners of male surgeons and female surgeons and multivariate analysis used to assess risk factors. Surgeons using ART, adoption, or surrogacy were asked to describe costs and time off work to pursue these options.

Results:

Eight hundred and fifty-nine surgeons participated. Compared to male surgeons, female surgeons were more likely to report delaying children due to surgical training (64.9% vs. 43.5%, P < 0.001), have fewer children (1.9 vs. 2.4, p < 0.001), and use ART (25.2% vs. 17.4%, P = 0.035). Compared to non-surgeon partners of male surgeons, female surgeons were older at first pregnancy (33 vs 31 years, P < 0.001) with age > 35 years associated with greater odds of ART use (odds ratio 3.90; 95% confidence interval 2.74–5.55, P < 0.001). One-third of surgeons using ART spent >$40,000; most took minimal time off work for treatments. Forty-five percent of same-sex couples used adoption or surrogacy. 60% of surgeons using adoption or surrogacy spent >$40,000 and most took minimal paid parental leave.

Conclusions:

ART, adoption, or surrogacy is costly and lacks strong workplace support in surgery, disproportionately impacting women and same-sex couples. Equitable and inclusive environments supporting all routes to parenthood ensure recruitment and retention of a diverse workforce. Surgical leaders must enact policies and practices to normalize childbearing as part of an early surgical career, including financial support and equitable parental leave for a growing group of surgeons pursuing ART, surrogacy, or adoption to become parents.
Palliative care in COVID-19
Authors: Janssen Daisy J.A.
Published: October 2021

Purpose of review

The purpose of this paper is (1) to provide insight in the palliative care needs of patients with COVID-19; (2) to highlight the challenges of COVID-19 for palliative care; and (3) to highlight developments in COVID-19 palliative care.

Recent findings

Patients with serious COVID-19 have palliative care needs in all domains: physical, psychological, social and spiritual. COVID-19 palliative care is confronted with many challenges, including: the uncertain prognosis, resource limitations, challenges regarding advance care planning, lack of guidance, limited multidisciplinary collaboration, need for remote communication, restrictions in family visits, and burden for clinicians. Palliative care responded with many developments: development of services; integration of palliative care with other services; tools to support advance care planning, (remote) communication with patients and families, or spiritual care; and care for team members.

Palliative care has an important role in this pandemic. Palliative care rapidly developed services and opportunities were found to support patients, families and clinicians. Further developments are warranted to face future demands of a pandemic, including integrated palliative care and education in palliative care skills across all specialties. Intervention studies are needed to enable evidence-based recommendations for palliative care in COVID-19.
The upregulation of Nur77 decreases ketamine-induced hippocampal neurons toxicity in rats
Authors: Li Min , Xue Yufeng
Published: October 2021

Ketamine is clinically used as a narcotic. However, ketamine has certain deficits and produces toxicity to neurons. As a member of the NR4A receptor subfamily, Nur77 decreases neurodegenerative disorders. The study aims to investigate the effects of upregulated Nur77 on ketamine-induced rat hippocampal neurons damage and the active mechanism. Neurons were obtained from rat hippocampal and identified by immunofluorescence assays. The treatment groups contained ketamine group, Nur77 group, ketamine + Nur77 group and ketamine + L-cam group. Neurons apoptosis and reactive oxygen species (ROS) were determined by a related kit using flow cytometry. Enzyme NAD(P)H quinone oxidoreductase 1 (NQO1), enzyme heme oxygenase 1 (HO1), Nur77, the expression of Bax, Bcl-2 and cleaved-caspase-3 and inflammatory cytokines were measured using western blot assays and reverse transcription-quantitative PCR (RT-qPCR) assays. Ketamine-induced neurons apoptosis; however, Nur77 decreased ketamine-induced neurons apoptosis. A low level of ROS was observed in two combination groups. Neurons treated by ketamine only had the lowest levels of Nur77, NQO1 and HO1, compared with other treatment groups. The levels of Bax and cleaved-caspase-3 in two combination groups were lower than those in the ketamine group. Furthermore, the ketamine group had higher levels of tumor necrosis factor alpha, IL-1β and IL-6 but the lowest level of IL-4. Upregulated Nur77 reduced the ketamine-induced toxicity in neurons. The mechanism of Nur77 involved antioxidation, apoptosis signaling pathway and inflammation signaling pathway. Our study provides a novel therapy that could attenuate ketamine-induced toxicity.
Flying bats use serial sampling to locate odour sources
Authors: Brokaw Alyson F. , Davis Evynn , Page Rachel A. , Smotherman Michael
Published: October 2021

Olfactory tracking generally sacrifices speed for sensitivity, but some fast-moving animals appear surprisingly efficient at foraging by smell. Here, we analysed the olfactory tracking strategies of flying bats foraging for fruit. Fruit- and nectar-feeding bats use odour cues to find food despite the sensory challenges derived from fast flight speeds and echolocation. We trained Jamaican fruit-eating bats (Artibeus jamaicensis) to locate an odour reward and reconstructed their flight paths in three-dimensional space. Results confirmed that bats relied upon olfactory cues to locate a reward. Flight paths revealed a combination of odour- and memory-guided search strategies. During ‘inspection flights’, bats significantly reduced flight speeds and flew within approximately 6 cm of possible targets to evaluate the presence or absence of the odour cue. This behaviour combined with echolocation explains how bats maximize foraging efficiency while compensating for trade-offs associated with olfactory detection and locomotion.
Rational solutions of the defocusing non-local nonlinear Schrödinger equation: asymptotic analysis and soliton interactions
Authors: Xu Tao , Li Lingling , Li Min , Li Chunxia , Zhang Xuefeng
Published: October 2021

In this paper, we obtain the

N

th-order rational solutions for the defocusing non-local nonlinear Schrödinger equation by the Darboux transformation and some limit technique. Then, via an improved asymptotic analysis method relying on the balance between different algebraic terms, we derive the explicit expressions of all asymptotic solitons of the rational solutions with the order

1
≤
N
≤
4

. It turns out that the asymptotic solitons are localized in the straight lines or algebraic curves, and the exact solutions approach the curved asymptotic solitons with a slower rate than the straight ones. Moreover, we find that all the rational solutions exhibit just five different types of soliton interactions, and the interacting solitons are divided into two halves with each having the same amplitudes. Particularly for the curved asymptotic solitons, there may exist a slight difference for their velocities between at

t

and

−
t

with certain parametric conditions. In addition, we reveal that the soliton interactions in the rational solutions with

N
≥
2

are stronger than those in the exponential and exponential-and-rational solutions.
Modeling brings additional insights into the kinetics of SARS-CoV-2 neutralizing antibody
Authors: Mélanie Prague , Clairon Quentin , Guedj Jérémie , Thiébaut Rodolphe
Published: October 2021

Following the paper by Seow et al. published in Nature Microbiology, we reanalyzed the publicly available data using dynamical models of humoral response. The main conclusion is that, from available data, we can demonstrate that the decline of neutralizing antibodies (as measured with ID50) is biphasic, which is compatible with two types of antibody secreting cells (short lived and long lived). We found that lower bound of half life of the long-lived antibody secreting cells is 450 days. Moreover, our model predicts that the neutralizing antibody response could be more durable than suggested (up to 129 days for individuals with no requirement of supplemental oxygen and up to 175 days for others). A result which adds insight on the longevity of immune response.
Longitudinal and comparative analysis of humoral response upon COVID-19 vaccination
Authors: Romero-Pinedo Salvador , Quesada Marina , Álvarez-Fernández Stela , Olmo Asunción , Abia David , Alarcón Balbino , Delgado Pilar
Published: October 2021

The emergence of COVID-19 has led to a worldwide challenge for the rapid development of vaccines. Several types of safe and effective vaccines have been available in a time frame never seen before. Comparative studies to know the extent of protection and the immune response elicited by the different vaccines are of outstanding utility. Here, as a correlate for protection, we perform a comparative study of the humoral response to three vaccines, ChAdOx1 (Oxford-AstraZeneca), mRNA-1273 (Moderna), and BNT162b2 (Pfizer-BioNTech) by applying a flow cytometry-based highly sensitive method that we had previously developed. We have found that mRNA vaccines (mRNA-1273 and BNT162b2) induce a stronger humoral response that lasts for at least 6 months after vaccination. We also show that only one dose of BNT162b2 is enough to achieve the maximum response in seropositive pre-vaccination donors.
δ1 variant of SARS-COV-2 acquires spike V1176F and yields a highly mutated subvariant in Europe
Authors: Yang Xiang-Jiao
Published: October 2021

Genomic surveillance of SARS-COV-2 has revealed that in addition to many variants of interests, this virus has yielded four variants of concern, α, β, γ and δ, as designated by the World Health Organization. δ variant has recently become the predominant pandemic driver around the world and yielded four different subvariants (δ1, δ2, δ3 and δ4). Among them, δ1 has emerged as the key subvariant that drives the pandemic in India, Europe and the USA. A relevant question is whether δ1 subvariant continues to evolve and acquires additional mutations. Related to this, this subvariant has acquired spike V1176F, a signature substitution of γ variant, and yielded a new sublineage, δ1F. The substitution alters heptad repeat 2 of spike protein and is expected to improve interaction with heptad repeat 1 and enhance virus entry. Moreover, there are δ1F sublineages encoding spike N501Y, A783S, Q836E and V1264L. While N501Y is a signature substitution shared by α, β and γ variants, V1264L is a key substitution in a δ1 sublineage that is a major pandemic driver in Southeast Asia. The Q836E-encoding lineage carries an average of 50 mutations per genome, making it the most mutated variant identified so far. Similar to δ1 subvariant, δ2 subvariant has also acquired spike V1176F and yielded new sublineages. Together, these results suggest that V1176F is a recurrent spike substitution that is frequently acquired by SARS-COV-2 variants to improve viral fitness. It is thus important to track the evolutionary trajectory of related variants for considering and instituting the most effective public health measures.
Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression
Authors: Milaneschi Yuri , Arnold Matthias , Kastenmüller Gabi , Dehkordi Siamak Mahmoudian , Krishnan Ranga R. , Dunlop Boadie W. , Rush A. John , Penninx Brenda W. J. H. , Kaddurah-Daouk Rima ,   for the Mood Disorders Precision Medicine Consortium (MDPMC)
Published: October 2021

Background

Altered metabolism of acylcarnitines – transporting fatty acids to mitochondria – may link cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization.

Methods

Summary statistics were obtained from large GWAS: the Fenland Study (N= 9,363), and the Psychiatric Genomics Consortium (246,363 depression cases and 561,190 controls). Two-sample Mendelian randomization analyses tested the potential causal link of 15 endogenous acylcarnitines with depression.

Results

In univariable analyses, genetically-predicted lower levels of short-chain acylcarnitines C2 (Odds Ratio [OR] 0.97, 95% Confidence Intervals [CIs] 0.95-1.00) and C3 (OR 0.97, 95%CIs 0.96-0.99) and higher levels of medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.01-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06) were associated with increased depression risk. No reverse potential causal role of depression genetic liability on acylcarnitines levels was found. Multivariable analyses showed that the association with depression was driven by the medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.02-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06), suggesting a potential causal role in the risk of depression. Causal estimates for C8 (OR=1.05, 95%CIs=1.02-1.07) and C10 (OR=1.05, 95%CIs=1.02-1.08) were confirmed in follow-up analyses using genetic instruments derived from a GWAS meta-analysis including up to 16,841 samples.

Discussion

Accumulation of medium-chain acylcarnitines is a signature of inborn errors of fatty acid metabolism and age-related metabolic conditions. Our findings point to a link between altered mitochondrial energy production and depression pathogenesis. Acylcarnitine metabolism represents a promising access point for the development of novel therapeutic approaches for depression.
Proteomic and clinical biomarkers for acute mountain sickness diagnosis, prognosis, protection, and pathogenesis in a longitudinal cohort
Authors: Yang Jing , Jia Zhilong , Song Xinyu , Shi Jinlong , Zhao Xiaojing , He Kunlun
Published: October 2021

Acute mountain sickness (AMS) is frequently experienced by non-high-altitude natives at high altitudes, which affects the quality of health and productivity of humans. The diagnosis of the disease mainly depends on a self-questionnaire, which reveals our insufficient understanding of AMS and the necessity of developing reliable biomarkers for AMS. In addition to 65 clinical indexes and 22 AMS symptom phenotypes, we profiled the plasma proteomic profiles of AMS via a combination of proximity extension assay with multiple reaction monitoring for a longitudinal cohort of 53 individuals divided into discovery and validation stages. Through differential analysis, machine learning models with high accuracy and protein-symptom-clinical index functional network analysis, we identified proteomic and clinical biomarkers for AMS diagnosis, prognosis, protection, and pathogenesis. RET, a top-weighted protein in the pathogenesis model, showed opposite regulations between individuals with AMS and those without AMS ascending to a high altitude. The downregulation of ADAM15 may play a protective role at high altitude in individuals without AMS. These results suggest that RET and ADAM15 could be promising therapeutic targets for AMS. Moreover, PHGDH and TRAF2 could be candidate predictive and diagnostic biomarkers for AMS, respectively. Additionally, C-peptide was found to be actively involved in the pathogenesis and could aid the assistant diagnosis of AMS. Notably, individuals with AMS showed higher gluconeogenesis activity at the plain than those without AMS. Our findings shed light on the proteomic and clinical biomarkers of AMS, provide a wealth of biological insights into AMS, and thereby promote precision medicine for AMS.
In vivo single cell transcriptomics reveals Klebsiella pneumoniae rewiring of lung macrophages to promote infection
Authors: Dumigan Amy , Cappa Oisin , Morris Brenda , sa-Pessoa Graca Santos Joana , Calderon-Gonzalez Ricardo , Mills Grant , Lancaster Rebecca , Simpson David , Kissenpfennig Adrien , Bengoechea Jose A
Published: October 2021

The strategies deployed by antibiotic resistant bacteria to counteract host defences are poorly understood. Here, we elucidate a novel host-pathogen interaction that results in the control of lung macrophage polarisation by the human pathogen Klebsiella pneumoniae. We identify interstitial macrophages (IMs) as the main population of lung macrophages associated with Klebsiella. Single cell transcriptomics and trajectory analysis of cells uncover that type I IFN and IL10 signalling, and macrophage polarization are characteristic of infected IMs, whereas Toll-like receptor (TLR) and Nod-like receptor signalling are features of infected alveolar macrophages. Klebsiella-induced macrophage polarization is a singular M2-type we termed M(Kp). To rewire macrophages towards M(Kp), K. pneumoniae hijacks a hitherto unknown TLR-type I IFN-IL10-STAT6 innate axis. Absence of STAT6 limits the intracellular survival of Klebsiella whereas the inhibition of STAT6 facilitates the clearance of the pathogen in vivo. Glycolysis characterises M(Kp) metabolism, and inhibition of glycolysis results in clearance of intracellular Klebsiella. We demonstrate the capsule polysaccharide is the Klebsiella factor governing M(Kp). Klebsiella also skews human macrophage polarization towards M(Kp) in a type I IFN-IL10-STAT6-dependent manner. Altogether, our work demonstrates that Klebsiella induction of M(Kp) represents a hitherto unknown strategy to overcome host restriction during pneumonia.
Demographic model and biological adaptation inferred from the genome-wide SNP data reveal tripartite origins of southernmost Chinese Huis
Authors: He Guanglin , Fan Zhi-Quan , Zou Xing , Deng Xiaohui , Yeh Hui-Yuan , Wang Zheng , Liu Jing , Xu Quyi , Chen Ling , Deng Xiao-Hua , Wang Chuan-Chao , Liu Changhui , Wang Mengge , Liu Chao
Published: October 2021

The culturally unique Sanya Hui (SYH) people are regarded as the descendants of ancient Cham people in Central Vietnam (CV) and exhibit a scenario of complex migration and admixture history, who were likely to first migrate from Central and South Asia (CSA) to CV and then to South Hainan and finally assimilated with indigenous populations and resided in the tropical island environments since then. A long-standing hypothesis posits that SYH derives from different genetic and cultural origins, which hypothesizes that SYH people are different from the genetically attested admixture history of northern Hui people possessing major Han-related ancestry and minor western Eurasian ancestry. However, the effect of the cultural admixture from CSA and East Asia (EA) on the genetic admixture of SYH people remains unclear. Here, we reported the first batch of genome-wide SNP data from 94 SYH people from Hainan and comprehensively characterized their genetic structure, origin, and admixture history. Our results found that SYH people were genetically different from the northern Chinese Hui people and harbored a close genomic affinity with indigenous Vietnamese but a distinct relationship with Cham, which confirmed the hypothesis of documented recent historical migration from CV and assimilation with Hainan indigenous people. The fitted admixture models and reconstructed demographic frameworks revealed an additional influx of CSA and EA ancestries during the historical period, consisting of the frequent cultural communication along the Southern Maritime Silk Road and extensive interaction with EA. Analyses focused on natural-selected signatures of SYH people revealed a similar pattern with mainland East Asians, which further confirmed the possibility of admixture-induced biological adaptation of island environments. Generally, three genetically attested ancestries from CV, EA, and CSA in modern SYH people supported their tripartite model of genomic origins.
Theta-band phase locking during encoding leads to coordinated entorhinal-hippocampal replay
Authors: Santos-Pata Diogo , Barry Caswell , Freyja Ólafsdóttir H.
Published: October 2021

Precisely timed interactions between hippocampal and cortical neurons during replay epochs are thought to support memory consolidation. Indeed, research has shown replay is associated with heightened hippocampal-cortical synchrony. Yet, many caveats remain in our understanding. Namely, it remains unclearhowthis offline synchrony comes about, whether it is specific to particular behavioural states and how - if at all - it relates to learning. In this study, we sought to address these questions by analysing coordination between CA1 cells and neurons of the deep layers of the medial entorhinal cortex (dMEC) while rats learned a novel spatial task. During movement, we found a subset of dMEC cell which were particularly locked to hippocampal LFP theta-band oscillations and which were preferentially coordinated with hippocampal replay during offline periods. Further, dMEC synchrony with CA1 replay peaked ∼10ms after replay initiation in CA1, suggesting the distributed replay reflects extra-hippocampal information propagation, and was specific to ‘offline’ periods.

Finally, theta-modulated dMEC cells only became coordinated with replay after an animal’s first encounter with a novel spatial environment and then showed a striking experience-dependent increase in synchronisation with hippocampal replay trajectories, mirroring the animals’ acquisition of the novel task and coupling to the hippocampal local field. Together, these findings provide strong support for the hypothesis that synergistic hippocampal-cortical replay supports the consolidation of new memories and highlights phase locking to hippocampal theta oscillations as a potential mechanism by which such cross-structural synchrony comes about. Importantly, as CA1 phase-locking to theta is implicated in the generation of theta sequences, thought to be required for replay expression, we speculate the dMEC theta phase-locking reflects the emergence of distributed hippocampal-dMEC theta sequences and that these may support the commission of memories to long-term cortical storage.
Identification of Significant Gene Expression Changes in Multiple Perturbation Experiments using Knockoffs
Authors: Zhao Tingting , Zhu Guangyu , Flaherty Patrick
Published: October 2021

Motivation

Large-scale multiple perturbation experiments have the potential to reveal a more detailed understanding of the molecular pathways that respond to genetic and environmental changes. A key question in these studies is which gene expression changes are important for the response to the perturbation.

Results

We present here a method based on the model-X knockoffs framework to identify significant gene expression changes in multiple perturbation experiments. This approach makes no assumptions on the functional form of the dependence between the responses and the perturbations and provides finite sample false discovery rate control for the set of important gene expression responses. In a large-scale multiple perturbation gene expression data set from the Library of Integrated Network-Based Cellular Signature (LINCS) NIH program, we identified important genes whose expression is modulated in response to perturbation with anthracycline, vorinostat, trichostatin-a, geldanamycin, and sirolimus. Furthermore, we compared the set of important genes that respond to these small molecules to identify co-responsive pathways.

Availability and Implementation

https://github.com/flahertylab/deepYknockoff

Contact

pflaherty@umass.eduandzhaott0416@gmail.com

Supplementary information

Supplementary data are available atBioinformaticsonline.
High Resolution Nanostructure with Two-stages of Exponential Energy Dissipation at the Ultrathin Osteochondral Interface Tissue of Human Knee Joint
Authors: Wang Xiaozhao , Lin Junxin , Li Zonghao , Ma Yuanzhu , Zhang Xianzhu , He Qiulin , Wu Qin , Wei Wei , Yao Xudong , Li Chenglin , Li Wenyue , Xie Shaofang , Hu Yejun , Zhang Shufang , Hong Yi , Li Xu , Chen Weiqiu , Duan Wangping , Ouyang Hongwei
Published: October 2021

Cartilage adheres to subchondral bone via a specific osteochondral interface tissue where forces are transferred from soft cartilage to hard bone without fatigue damage over a lifetime of load cycles. However, the fine structure and mechanical properties of osteochondral interface tissue remain unclear. Here, we identified an ultrathin ∼20-30 μm calcified region with two-layered micro-nano structures of osteochondral interface tissue in human knee joint, which exhibited characteristic biomolecular compositions and complex nanocrystals assembly. Within this region, an exponential increase of modulus (3 orders of magnitude) was conducive to the force transmission which was verified by finite element simulations. The nanoscale heterogeneity of hydroxyapatite, along with enrichment of elastic-responsive protein-titin which is usually present in muscle, endowed the osteochondral tissue with excellent energy dissipation and fatigue resistance properties. Our results provide potential design for high-performance interface materials for osteochondral interface regeneration and functional coatings.
Monoclonal Antibody Treatment of Breakthrough COVID-19 in Fully Vaccinated Individuals with High-Risk Comorbidities
Authors: Bierle Dennis M. , Ganesh Ravindra , Tulledge-Scheitel Sidna , Hanson Sara N. , Arndt Lori L. , Wilker Caroline G. , Razonable Raymund R.
Published: October 2021

Breakthrough COVID-19 may occur in fully vaccinated persons. In this cohort of 1395 persons (mean age, 54.3 years; 60% female; median body mass index, 30.7) who developed breakthrough COVID-19, there were 107 (7.7%) who required hospitalization by day 28. Hospitalization was significantly associated with the number of medical comorbidities. Anti-spike monoclonal antibody treatment was significantly associated with a lower risk of hospitalization (Odds Ratio: 0.227; 95% confidence interval, 0.128 - 0.403; p<0.001). The number needed to treat to prevent one hospitalization was 225 among the lowest-risk patient group compared to 4 among the groups with highest numbers of medical comorbidity.

summary

Breakthrough COVID-19 may occur among vaccinated individuals with a high number of medical comorbidities, especially during the surge of SARS-CoV-2 Delta variant. Treatment with anti-spike monoclonal antibody was associated with significantly lower rates of hospitalization and oxygen supplementation.
ZipHiC: a novel Bayesian framework to identify enriched interactions and experimental biases in Hi-C data
Authors: Osuntoki Itunu G. , Harrison Andrew , Dai Hongsheng , Bao Yanchun , Zabet Nicolae Radu
Published: October 2021

Several computational and statistical methods have been developed to analyse data generated through the 3C-based methods, especially the Hi-C. Most of existing methods do not account for dependency in Hi-C data. Here, we present ZipHiC, a novel statistical method to explore Hi-C data focusing on detection of enriched contacts. ZipHiC implements a Bayesian method based on a hidden Markov random field (HMRF) model and the Approximate Bayesian Computation (ABC) to detect interactions in two-dimensional space based on Hi-C contact frequency matrix. ZipHiC uses data on the sources of biases related to contact frequency matrix, allows borrowing information from neighbours using the Potts model and improves computation speed by using the ABC model. In addition to outperforming existing tools on both simulated and real data, our model also provides insights into different sources of biases that affects Hi-C data. We show that some datasets display higher biases from DNA accessibility or Transposable Elements content. Furthermore, approximately half of the detected significant interactions connect promoters with other parts of the genome indicating a functional biological role. Finally, we found that the micro-C datasets display higher biases from DNA accessibility compared to a similar Hi-C experiment, but this can be corrected by ZipHiC.
Identification of bacterial drug-resistant cells by the convolutional neural network in transmission electron microscope images
Authors: Hayashi-Nishino Mitsuko , Aoki Kota , Kishimoto Akihiro , Takeuchi Yuna , Fukushima Aiko , Uchida Kazushi , Echigo Tomio , Yagi Yasushi , Hirose Mika , Iwasaki Kenji , Shin’ya Eitaro , Washio Takashi , Furusawa Chikara , Nishino Kunihiko
Published: October 2021

The emergence of bacteria that are resistant to antibiotics is common in areas where antibiotics are used widely. The current standard procedure for detecting bacterial drug resistance is based on bacterial growth under antibiotic treatments. Here we describe the morphological changes in enoxacin-resistant Escherichia coli cells and the computational method used to identify these resistant cells in transmission electron microscopy (TEM) images without using antibiotics. Our approach was to create patches from TEM images of enoxacin-sensitive and enoxacin-resistant E. coli strains, use a convolutional neural network for patch classification, and identify the strains on the basis of the classification results. The proposed method was highly accurate in classifying cells, achieving an accuracy rate of 0.94. Using a gradient-weighted class activation mapping to visualize the region of interest, enoxacin-resistant and enoxacin-sensitive cells were characterized by comparing differences in the envelope. Moreover, Pearson’s correlation coefficients suggested that four genes, including lpp, the gene encoding the major outer membrane lipoprotein, were strongly associated with the image features of enoxacin-resistant cells.
Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis
Authors: Wang Runci , Singaraju Anvita , Marks Kathryne E. , Shakib Lorien , Dunlap Garrett , Cunningham-Bussel Amy , Chen Lin , Tirpack Aidan , Fein Miriam R. , Todd Derrick J. , MacFarlane Lindsey , Goodman Susan M. , DiCarlo Edward F. , Massarotti Elena M. , Sparks Jeffrey A. , Hamnvik Ole-Petter R. , Min Le , Jonsson A. Helena , Brenner Michael B. , Chan Karmela K. , Bass Anne R. , Donlin Laura T. , Rao Deepak A.
Published: October 2021

Immune checkpoint inhibitor (ICI) therapies that promote T cell activation have improved outcomes for advanced malignancies yet also elicit harmful autoimmune reactions. The T cell mechanisms mediating these iatrogenic autoimmune events remain unclear. Here we assayed T cells from joints of patients affected by ICI-induced inflammatory arthritis (ICI-arthritis), which can present clinically indistinguishable from rheumatoid arthritis (RA). Compared to the autoimmune arthritides RA and psoriatic arthritis (PsA), ICI-arthritis joints contained an expanded CD38hi CD127− CD8+ T cell subset that displays cytotoxic, effector, and interferon (IFN) response signatures. The abundance of CD38hi CD8 T cells in ICI-arthritis resulted from a limited number of clones that could be found proliferating in the joint. Exposure of synovial T cells to Type I IFN, more so than IFN-γ, induces the CD38hi cytotoxic phenotype. Relative to other CD8+ T cell subsets in the joints, the CD38hi population is distinct from a dysfunctional population and clonally most related to TCF7+ memory populations. Examination of synovial tissue from bilateral knee arthroplasty demonstrated considerable sharing of TCR clonotypes in the CD38hi CD8 T cell fraction from both knees. These results define a distinct CD8 T cell subset that may be directly activated by ICI therapy and mediate a tissue-specific autoimmune cellular reaction in patient joints.
VSS-Hi-C: Variance-stabilized signals for chromatin contacts
Authors: Kenari Neda Shokraneh , Bayat Faezeh , Libbrecht Maxwell
Published: October 2021

Motivation

The genome-wide chromosome conformation capture assay Hi-C is widely used to study chromatin 3D structures and their functional implications. Read counts from Hi-C indicate the strength of chromatin contact between each pair of genomic loci. These read counts are heteroskedastic: that is, a difference between the interaction frequency of 0 and 100 is much more significant than a difference between the interaction frequency of 1000 and 1100. This property impedes visualization and downstream analysis because it violates the Gaussian variable assumption of many computational tools. Thus heuristic transformations aimed at stabilizing the variance of signals like the shifted-log transformation are typically applied to data before its visualization and inputting to models with Gaussian assumption. However, such heuristic transformations cannot fully stabilize the variance because of their restrictive assumptions about the mean-variance relationship in the data.

Results

Here we present VSS-Hi-C, a data-driven variance stabilization method for Hi-C data. We show that VSS-Hi-C signals have a unit variance improving visualization of Hi-C, for example in heatmap contact maps. VSS-Hi-C signals also improve the performance of subcompartment callers relying on Gaussian observations. VSS-Hi-C is implemented as an R package and can be used for variance stabilization of different genomic and epigenomic data types with two replicates available.

Availability

https://github.com/nedashokraneh/vssHiC

Contact

maxwl@sfu.ca
Immunogenicity of BNT162b2 Vaccine in Patients with Inflammatory Bowel Disease on Infliximab Combination Therapy: A Multicenter Prospective Study
Authors: Shehab Mohammad , Abu-Farha Mohamed , Alrashed Fatema , Alfadhli Ahmad , AlOtaibi Khazna , AlSahli Abdulla , Thanaraj Thangavel Alphonse , Channanath Arshad , Ali Hamad , Abubaker Jehad , Al-Mulla Fahd
Published: October 2021

Background

Vaccination is a promising strategy to protect vulnerable groups like inflammatory bowel disease (IBD) patients against COVID-19 and associated severe outcomes. COVID-19 Vaccines clinical trials excluded IBD patients taking infliximab with azathioprine or 6-mercaptopurine (infliximab combination). Therefore, we sought to evaluate serologic responses to COVID-19 vaccination with the mRNA vaccine, BNT162b2 in IBD patients receiving infliximab combination therapy compared to healthy participants.

Methods

This is a multicenter prospective study. IBD patients were recruited at the time of attendance at infusion center between August 1st, 2021, and September 15th, 2021. Our primary outcome was the concentrations of SARS-CoV-2 antibodies 4-10 weeks after vaccination with two doses of BNT162b2 vaccine in IBD patients taking infliximab combination therapy (study group) compared to healthy participants group (control group). Both study and healthy participants groups were matched for age, sex and time-since-last-vaccine-dose using optimal pair matching method.

Results

In total 116 participants were recruited in the study, 58 patients in the study group and 58 in the control group. Median (IQR) IgG concentrations were lower in the study group [99 BAU/mL (40, 177)] than the control group [139 BAU/mL (120, 188)], following vaccination (p = 0.0032). Neutralizing antibodies was also lower in the study group compared to the control group [64% (23, 94) vs 91% (85, 94), p <0.001]. The median IgA levels in the study group was also significantly lower when compared to the control group [6 U/ml (3, 34) vs 13 U/ml (7, 30), p =0.0097]. In the study group, the percentage of patients who achieved positive IgG, neutralizing antibody and IgA levels were 81%, 75% and 40% respectively. In the control group, all participants (100%) had positive IgG and neutralizing antibody levels while 62% had positive IgA levels.

Conclusion

In patients with IBD receiving infliximab combination therapy, IgG, IgA and neutralizing antibody levels after BNT162b2 vaccine were lower compared to healthy participants. However, most patients treated with infliximab combination therapy seroconverted after two doses of the vaccine.