bluuebunny/crossref_metadata_2025 huggingface dataset:
Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial
Authors: Liu Dan , Zhou Jun , Wang Yongsheng , Li Mingjun , Jiang Haiping , Liu Yunpeng , Yin Xianli , Ge Minghua , Xiang Xiaojun , Ying Jieer , Huang Jian , Zhang Yan-qiao , Cheng Ying , Huang Zhigang , Yuan Xianglin , Han Weiqing , Yan Dong , Wang Xinshuai , Liu Pan , Wang Linna , Zhang Xiaojing , Luo Suxia , Liu Tianshu , Shen Lin
Published: October 2022

Background

Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701.

Methods

This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR).

Results

In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4–36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5–73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR.

Conclusions

SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration.

Trial registration

ClinicalTrials.gov, NCT03710265
Biomarkers beyond BRCA: promising combinatorial treatment strategies in overcoming resistance to PARP inhibitors
Authors: Chu Yu-Yi , Yam Clinton , Yamaguchi Hirohito , Hung Mien-Chie
Published: October 2022

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) exploit the concept of synthetic lethality and offer great promise in the treatment of tumors with deficiencies in homologous recombination (HR) repair. PARPi exert antitumor activity by blocking Poly(ADP-ribosyl)ation (PARylation) and trapping PARP1 on damaged DNA. To date, the U.S. Food and Drug Administration (FDA) has approved four PARPi for the treatment of several cancer types including ovarian, breast, pancreatic and prostate cancer. Although patients with HR-deficient tumors benefit from PARPi, majority of tumors ultimately develop acquired resistance to PARPi. Furthermore, even though BRCA1/2 mutations are commonly used as markers of PARPi sensitivity in current clinical practice, not all patients with BRCA1/2 mutations have PARPi-sensitive disease. Thus, there is an urgent need to elucidate the molecular mechanisms of PARPi resistance to support the development of rational effective treatment strategies aimed at overcoming resistance to PARPi, as well as reliable biomarkers to accurately identify patients who will most likely benefit from treatment with PARPi, either as monotherapy or in combination with other agents, so called marker-guided effective therapy (Mget). In this review, we summarize the molecular mechanisms driving the efficacy of and resistance to PARPi as well as emerging therapeutic strategies to overcome PARPi resistance. We also highlight the identification of potential markers to predict PARPi resistance and guide promising PARPi-based combination strategies.
Role of triglycerides as a predictor of autoimmune hepatitis with cirrhosis
Authors: Wang Peng , Wang Yuqi , Liu Hui , Han Xiaoxu , Yi Yunyun , Wang Xin , Li Xin
Published: October 2022

Background

Metabolism-related indicators have been suggested as possible prognostic indicators of liver disease in recent relevant studies, but their value in predicting autoimmune hepatitis (AIH) cirrhosis is unclear. This study evaluated the role of lipid levels in determining the prognosis of AIH-related cirrhosis.

Methods

We retrospectively included 345 patients with AIH who were initially diagnosed at Beijing Ditan Hospital from 2010-2019, and ultimately screened 196 patients who met the criteria. A logistic regression analysis was performed to screen factors associated with cirrhosis. Kaplan–Meier (KM) curves were constructed to analyze the effects of different triglyceride (TG) levels on the survival of patients with cirrhosis. A restricted cubic spline fitted Cox regression model was used to analyze the nonlinear relationship between serum TG levels and patient prognosis.

Results

Patients with AIH cirrhosis have lower TG levels than those without cirrhosis. Lower serum TG levels correlated with the severity of cirrhosis. The survival analysis showed that TG levels were associated with the overall survival of patients with AIH, as a lower 5-year survival rate (log-rankP<0.05) was observed for patients in the TG≤0.95 mmol/L group (hazard ratio (HR)=3.79, 95% CI: 1.528-9.423). In addition, lower TG levels were associated with a higher incidence of death in patients with AIH cirrhosis. The risk of death gradually increased for the interval of TG levels of 0.5-0.8 mmol/L (Pfor nonlinearity<0.001), and the hazard ratio per standard deviation increase in the TG level was 0.97 (95% CI: 0.94-0.99). The plot showed a U-shaped relationship between TG levels and the survival of patients with decompensated cirrhosis. The risk ratio progressively decreased with lower TG levels (Pfor nonlinearity=0.002). Below 0.6 mmol/L, the probability of TG risk per standard deviation prediction was 1.49 (95% CI: 1.00-2.24).

Conclusion

Serum TG levels are closely related to the disease severity and overall survival of patients with AIH cirrhosis and may be used as a new indicator of advanced liver disease and long-term prognosis.
Extracellular vesicles derived from endometrial epithelial cells deliver exogenous miR-92b-3p to affect the function of embryonic trophoblast cells via targeting TSC1 and DKK3
Authors: Hua Renwu , Liu Qiaorui , Lian Weisi , Kang Ting ting , Gao Dengying , Huang Cheng , Wang Yueying , Lei Minggang
Published: October 2022

Background

Extracellular vesicles (EVs) could mediate embryo-maternal communication to affect embryo implantation by delivering biology information, including microRNA (miRNA), protein, lipid. Our previous research shows that miR-92b-3p was differentially expressed in EVs of uterine flushing fluids during the embryo implantation period. However, the role of miR-92b-3p from EVs in embryo implantation remains elusive.

Materials and methods

EVs were isolated from porcine endometrial epithelial cells (EECs) by ultracentrifugation. MiR-92b-3p mimics and EVs were used to regulate the expression of miR-92b-3p in porcine trophoblast cells (PTr2 cells). Cell proliferation, migration and adhesion analyses were used to observe the phenotype. RT-qPCR, western blot and dual-luciferase reporter assay were used to assess the targets of miR-92b-3p.

Results

In this study, EVs derived from porcine EECs were identified and could be taken up by PTr2 cells. We found that the EVs derived from EECs transfected with miR-92b-3p mimic (EVs-miR-92b-3p) significantly promoted the proliferation, migration and adhesion of PTr2 cells. We verified thatTuberous sclerosis complex subunit(TSC1) andDickkopf 3(DKK3) were the target genes of miR-92b-3p. Moreover, our study showed that miR-92b-3p plays a vital role in PTr2 cells via targetingTSC1andDKK3.Furthermore, the 3'UTR vectors of TSC1 and DKK3 can rescue the effect of miR-92b-3p on PTr2 cells.

Conclusions

Taken together, this study reveals a novel mechanism that EVs derived from porcine EECs treated with miR-92b-3p crosstalk with trophoblasts by targetingTSC1andDKK3, leading to an enhanced ability for implantation.
Metformin alleviates bone loss in ovariectomized mice through inhibition of autophagy of osteoclast precursors mediated by E2F1
Authors: Xie Xudong , Hu Liangcong , Mi Bobin , Xue Hang , Hu Yiqiang , Panayi Adriana C. , Endo Yori , Chen Lang , Yan Chenchen , Lin Ze , Li Hui , Zhou Wu , Liu Guohui
Published: October 2022

Background

Postmenopausal bone loss, mainly caused by excessive bone resorption mediated by osteoclasts, has become a global public health burden. Metformin, a hypoglycemic drug, has been reported to have beneficial effects on maintaining bone health. However, the role and underlying mechanism of metformin in ovariectomized (OVX)-induced bone loss is still vague.

Results

In this study, we demonstrated for the first time that metformin administration alleviated bone loss in postmenopausal women and ovariectomized mice, based on reduced bone resorption markers, increased bone mineral density (BMD) and improvement of bone microstructure. Then, osteoclast precursors administered metformin in vitro and in vivo were collected to examine the differentiation potential and autophagical level. The mechanism was investigated by infection with lentivirus-mediated BNIP3 or E2F1 overexpression. We observed a dramatical inhibition of autophagosome synthesis and osteoclast formation and activity. Treatment with RAPA, an autophagy activator, abrogated the metformin-mediated autophagy downregulation and inhibition of osteoclastogenesis. Additionally, overexpression of E2F1 demonstrated that reduction of OVX-upregulated autophagy mediated by metformin was E2F1 dependent. Mechanistically, metformin-mediated downregulation of E2F1 in ovariectomized mice could downregulate BECN1 and BNIP3 levels, which subsequently perturbed the binding of BECN1 to BCL2. Furthermore, the disconnect between BECN1 and BCL2 was shown by BNIP3 overexpression.

Conclusion

In summary, we demonstrated the effect and underlying mechanism of metformin on OVX-induced bone loss, which could be, at least in part, ascribed to its role in downregulating autophagy during osteoclastogenesis via E2F1-dependent BECN1 and BCL2 downregulation, suggesting that metformin or E2F1 inhibitor is a potential agent against postmenopausal bone loss.
Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy
Authors: Zhao Binghao , Li Huanzhang , Xia Yu , Wang Yaning , Wang Yuekun , Shi Yixin , Xing Hao , Qu Tian , Wang Yu , Ma Wenbin
Published: October 2022

Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.
Virtual and augmented reality in critical care medicine: the patient’s, clinician’s, and researcher’s perspective
Authors: Bruno Raphael Romano , Wolff Georg , Wernly Bernhard , Masyuk Maryna , Piayda Kerstin , Leaver Susannah , Erkens Ralf , Oehler Daniel , Afzal Shazia , Heidari Houtan , Kelm Malte , Jung Christian
Published: October 2022

Virtual reality (VR) and augmented reality (AR) are aspiring, new technologies with increasing use in critical care medicine. While VR fully immerses the user into a virtual three-dimensional space, AR adds overlaid virtual elements into a real-world environment. VR and AR offer great potential to improve critical care medicine for patients, relatives and health care providers. VR may help to ameliorate anxiety, stress, fear, and pain for the patient. It may assist patients in mobilisation and rehabilitation and can improve communication between all those involved in the patient’s care. AR can be an effective tool to support continuous education of intensive care medicine providers, and may complement traditional learning methods to acquire key practical competences such as central venous line placement, cardiopulmonary resuscitation, extracorporeal membrane oxygenation device management or endotracheal intubation. Currently, technical, human, and ethical challenges remain. The adaptation and integration of VR/AR modalities into useful clinical applications that can be used routinely on the ICU is challenging. Users may experience unwanted side effects (so-called “cybersickness”) during VR/AR sessions, which may limit its applicability. Furthermore, critically ill patients are one of the most vulnerable patient groups and warrant special ethical considerations if new technologies are to be introduced into their daily care. To date, most studies involving AR/VR in critical care medicine provide only a low level of evidence due to their research design. Here we summarise background information, current developments, and key considerations that should be taken into account for future scientific investigations in this field.

Graphical abstract
Effects of mosquito resting site temperatures on the estimation of pathogen development rates in near-natural habitats in Germany
Authors: Sauer Felix Gregor , Kiel Ellen , Lühken Renke
Published: October 2022

Background

Environmental temperature is a key driver for the transmission risk of mosquito-borne pathogens. Epidemiological models usually relate to temperature data from standardized weather stations, but these data may not capture the relevant scale where mosquitoes experience environmental temperatures. As mosquitoes are assumed to spend most of their lifetime in resting sites, we analysed mosquito resting site patterns and the associated temperatures in dependence on the resting site type, resting site height and the surrounding land use.

Methods

The study was conducted in 20 areas in near-natural habitats in Germany. Ten areas were studied in 2017, and another 10 in 2018. Each study area consisted of three sampling sites, where we collected mosquitoes and microclimatic data in artificial (= garden pop-up bags) and natural resting sites at three height levels between 0 and 6 m. Land use of the study sites was characterized as forest and meadows based on reclassified information of the CORINE (Coordination of Information on the Environment) Land Cover categories. The hourly resting site temperatures and the data from the nearest weather station of the German meteorological service were used to model the duration of the extrinsic incubation period (EIP) of mosquito-borne pathogens.

Results

Anopheles, Culex and Culiseta preferred artificial resting sites, while Aedes were predominantly collect in natural resting sites. Around 90% of the mosquitoes were collected from resting sites below 2 m. The mosquito species composition did not differ significantly between forest and meadow sites. Mean resting site temperatures near the ground were approximately 0.8 °C lower than at a height of 4–6 m, which changed the predicted mean EIP up to 5 days at meadow and 2 days at forest sites. Compared with temperature data from standardized weather stations, the resting site temperatures near the ground would prolong the mean estimated EIP 4 days at forest sites and 2 days at meadow sites.

Conclusions

The microclimate of mosquito resting sites differs from standardized meteorological data, which can influence the transmission of mosquito-borne pathogens. In a near-natural environment, colder temperatures at mosquitoes’ preferred resting sites near the ground would prolong the EIP of mosquito-borne pathogens relative to data from weather stations.

Graphical Abstract
Postoperative weakness and anesthetic-associated rhabdomyolysis in a pediatric patient: a case report and review of the literature
Authors: Floridis John , Barbour Ruth
Published: October 2022

Background

Anesthesia-associated rhabdomyolysis is a rare complication of surgery that causes postoperative myalgia, weakness, and potential renal failure if not managed promptly. Predisposing conditions that may lead to this complication include muscular dystrophies and myopathies.

Case presentation

This rare case describes a pediatric non-Indigenous Australian patient developing this complication, with no known predisposing risk factors, and no clear etiology. A 9-year-old child with a background of asthma underwent an elective removal of keloid scar on her chest wall. The procedure was brief and uncomplicated, with an uneventful induction of anesthesia. During the emergence period, she developed acutely raised airway pressures with bronchospasm and laryngospasm requiring the use of salbutamol and suxamethonium with good effect. In the initial postoperative period, the patient complained of generalized myalgia and muscle weakness and was unable to mobilize independently. There was transient recovery to normal function; however, a recurrence of symptoms the following day with associated myalgias warranted admission to hospital. She was found to have rhabdomyolysis that was managed conservatively with a full recovery of several weeks. She was thoroughly investigated for any underlying cause, including genetic testing for malignant hyperthermia susceptibility (she had a variant of unknown significance but was negative for the known genetic abnormalities that cause malignant hyperthermia).

Conclusion

This case report demonstrates the importance of considering anesthesia-associated rhabdomyolysis as a differential for acute postoperative weakness, and outlines an investigative approach. To the best of our knowledge, it is the first case described in the pediatric literature to report biphasic progression of symptoms.
Efficiency, and economies of scale and scope in Japanese agricultural cooperatives
Authors: Harimaya Kozo , Kagitani Koichi
Published: October 2022

The purpose of this study is to investigate regional differences in the business characteristics of Japanese agricultural cooperatives (JAs), which have been widely criticized for depending on non-agricultural activities, contradictory to cooperative principles. We construct a panel data set over 2004–2019 from the financial statements of JAs’ prefectural-level federations and use a stochastic meta-frontier cost function model, which enables the decomposition of meta-frontier efficiency into two components: technical efficiency and technology gap ratios. The operational differences between JAs in urban and rural areas are investigated by comparing their efficiency and economies of scale and scope. The main results are summarized as follows: first, the meta-cost efficiency scores of JAs in urban areas are, on average, larger than those in rural areas, which reflects the differences in technology gap ratios. Second, JAs exhibit overall economies of scale in both areas; however, the product-specific economies of scale differ between financial and nonfinancial outputs. Finally, JAs in rural areas exhibit relatively larger economies of scope than those in urban areas. These findings indicate clear distinctions between urban and rural areas in cost-reduction effects. Finally, financial activities bring higher efficiency for JAs in urban areas, while benefits from simultaneous production are larger for those in rural areas.
Effects of different temperatures of carbohydrate-protein-containing drinks on gastric emptying rate after exercise in healthy young men: randomized crossover trial
Authors: Fujihira Kyoko , Takahashi Masaki , Shimamura Kei , Hayashi Naoyuki
Published: October 2022

Background

The present study examined the effects of different temperatures of carbohydrate-protein-containing drinks after exercise on the subsequent gastric emptying rate in healthy young men.

Methods

Twelve healthy young men completed two, 1-day trials in random order. In both trials, the participants completed intermittent cycling exercise for 20 min, consisting of a 120% heart rate peak for 20 s, followed by 25 W for 40 s. Participants consumed 400 mL of carbohydrate-protein-containing drink (0.85 MJ) at 4 °C (EX + 4 °C) or 60 °C (EX + 60 °C) over a 5-min period after exercise. The participants sat on a chair for 2.5 h to measure their gastric emptying rate using the 13C-sodium acetate breath test. Subjective feelings of gastrointestinal discomfort and appetite were measured using a visual analog scale. Interstitial fluid glucose levels after drinking were measured using a continuous glucose-monitoring device.

Results

The percentage excretion of 13CO2 tended to be higher at EX + 60 °C than at EX + 4 °C from the start of the test until 30 min after drink ingestion (5.7 ± 0.5 vs. 6.5 ± 0.4%dose/h for the EX + 4 °C and EX + 60 °C trials, respectively; effect sizes [ES] = 0.277, p = 0.065). The time of maximum 13CO2 emissions per hour (Tmax-calc) and the time of half 13CO2 emissions per hour (T1/2) did not differ between trials. Subjective gastrointestinal discomfort was lower at EX + 60 °C compared to EX + 4 °C (ES = 0.328, p = 0.041). There were no significant differences in interstitial fluid glucose levels between the different temperatures of carbohydrate-protein-containing drinks after exercise (p = 0.698).

Conclusions

Consumption of warm carbohydrate-protein-containing drinks after exercise may accelerate gastric emptying in the very early phase and may reduce gastric discomfort.

Trial registration

University Hospital Medical Information Network, UMIN000045626. Registered on June 10, 2021.
Extracellular vesicles from oviductal and uterine fluids supplementation in sequential in vitro culture improves bovine embryo quality
Authors: Leal Cláudia Lima Verde , Cañón-Beltrán Karina , Cajas Yulia N. , Hamdi Meriem , Yaryes Aracelli , Millán de la Blanca María Gemma , Beltrán-Breña Paula , Mazzarella Rosane , da Silveira Juliano Coelho , Gutiérrez-Adán Alfonso , González Encina M , Rizos Dimitrios
Published: October 2022

Background

In vitro production of bovine embryos is a well-established technology, but the in vitro culture (IVC) system still warrants improvements, especially regarding embryo quality. This study aimed to evaluate the effect of extracellular vesicles (EVs) isolated from oviductal (OF) and uterine fluid (UF) in sequential IVC on the development and quality of bovine embryos. Zygotes were cultured in SOF supplemented with either BSA or EVs-depleted fetal calf serum (dFCS) in the presence (BSA-EV and dFCS-EV) or absence of EVs from OF (D1 to D4) and UF (D5 to D8), mimicking in vivo conditions. EVs from oviducts (early luteal phase) and uterine horns (mid-luteal phase) from slaughtered heifers were isolated by size exclusion chromatography. Blastocyst rate was recorded on days 7–8 and their quality was assessed based on lipid contents, mitochondrial activity and total cell numbers, as well as survival rate after vitrification. Relative mRNA abundance for lipid metabolism-related transcripts and levels of phosphorylated hormone-sensitive lipase (pHSL) proteins were also determined. Additionally, the expression levels of 383 miRNA in OF- and UF-EVs were assessed by qRT-PCR.

Results

Blastocyst yield was lower (P < 0.05) in BSA treatments compared with dFCS treatments. Survival rates after vitrification/warming were improved in dFCS-EVs (P < 0.05). EVs increased (P < 0.05) blastocysts total cell number in dFCS-EV and BSA-EV compared with respective controls (dFCS and BSA), while lipid content was decreased in dFCS-EV (P < 0.05) and mitochondrial activity did not change (P > 0.05). Lipid metabolism transcripts were affected by EVs and showed interaction with type of protein source in medium (PPARGC1B, LDLR, CD36, FASN and PNPLA2, P < 0.05). Levels of pHSL were lower in dFCS (P < 0.05). Twenty miRNA were differentially expressed between OF- and UF-EVs and only bta-miR-148b was increased in OF-EVs (P < 0.05).

Conclusions

Mimicking physiological conditions using EVs from OF and UF in sequential IVC does not affect embryo development but improves blastocyst quality regarding survival rate after vitrification/warming, total cell number, lipid content, and relative changes in expression of lipid metabolism transcripts and lipase activation. Finally, EVs miRNA contents may contribute to the observed effects.
Low-abundance populations distinguish microbiome performance in plant cell wall deconstruction
Authors: Tom Lauren M. , Aulitto Martina , Wu Yu-Wei , Deng Kai , Gao Yu , Xiao Naijia , Rodriguez Beatrice Garcia , Louime Clifford , Northen Trent R. , Eudes Aymerick , Mortimer Jenny C. , Adams Paul D. , Scheller Henrik V. , Simmons Blake A. , Ceja-Navarro Javier A. , Singer Steven W.
Published: October 2022

Background

Plant cell walls are interwoven structures recalcitrant to degradation. Native and adapted microbiomes can be particularly effective at plant cell wall deconstruction. Although most understanding of biological cell wall deconstruction has been obtained from isolates, cultivated microbiomes that break down cell walls have emerged as new sources for biotechnologically relevant microbes and enzymes. These microbiomes provide a unique resource to identify key interacting functional microbial groups and to guide the design of specialized synthetic microbial communities.

Results

To establish a system assessing comparative microbiome performance, parallel microbiomes were cultivated on sorghum (Sorghum bicolor L. Moench) from compost inocula. Biomass loss and biochemical assays indicated that these microbiomes diverged in their ability to deconstruct biomass. Network reconstructions from gene expression dynamics identified key groups and potential interactions within the adapted sorghum-degrading communities, including Actinotalea, Filomicrobium, and Gemmatimonadetes populations. Functional analysis demonstrated that the microbiomes proceeded through successive stages that are linked to enzymes that deconstruct plant cell wall polymers. The combination of network and functional analysis highlighted the importance of cellulose-degrading Actinobacteria in differentiating the performance of these microbiomes.

Conclusions

The two-tier cultivation of compost-derived microbiomes on sorghum led to the establishment of microbiomes for which community structure and performance could be assessed. The work reinforces the observation that subtle differences in community composition and the genomic content of strains may lead to significant differences in community performance.
CRISPR-Cas9-mediated functional dissection of the foxc1 genomic region in zebrafish identifies critical conserved cis-regulatory elements
Authors: Ferre-Fernández Jesús-José , Muheisen Sanaa , Thompson Samuel , Semina Elena V.
Published: October 2022

FOXC1 encodes a forkhead-domain transcription factor associated with several ocular disorders. Correct FOXC1 dosage is critical to normal development, yet the mechanisms controlling its expression remain unknown. Together with FOXQ1 and FOXF2, FOXC1 is part of a cluster of FOX genes conserved in vertebrates. CRISPR-Cas9-mediated dissection of genomic sequences surrounding two zebrafish orthologs of FOXC1 was performed. This included five zebrafish–human conserved regions, three downstream of foxc1a and two remotely upstream of foxf2a/foxc1a or foxf2b/foxc1b clusters, as well as two intergenic regions between foxc1a/b and foxf2a/b lacking sequence conservation but positionally corresponding to the area encompassing a previously reported glaucoma-associated SNP in humans. Removal of downstream sequences altered foxc1a expression; moreover, zebrafish carrying deletions of two or three downstream elements demonstrated abnormal phenotypes including enlargement of the anterior chamber of the eye reminiscent of human congenital glaucoma. Deletions of distant upstream conserved elements influenced the expression of foxf2a/b or foxq1a/b but not foxc1a/b within each cluster. Removal of either intergenic sequence reduced foxc1a or foxc1b expression during late development, suggesting a role in transcriptional regulation despite the lack of conservation at the nucleotide level. Further studies of the identified regions in human patients may explain additional individuals with developmental ocular disorders.
Source characteristics of the 16 June 2020 ML 5.4 earthquake and its significant aftershock sequences, northern Red Sea, Egypt
Authors: Saadalla Hamada , Hamed Ahmad
Published: October 2022

The northern Red Sea in eastern Egypt is one of the world’s newest marine basins. The northern Red Sea is a very active seismic region and poses a significant hazard to the nearest cities on the Red Sea coast. On June 16, 2020, a moderate earthquake (ML = 5.4), as published by the Egyptian National Seismic Network (ENSN), occurred in the northern Red Sea followed by several aftershocks, ranging in magnitude from 2.0 to 3.4. The best-fitting double-couple movement obtained using the full waveform moment tensor inversion of the main earthquake indicated strike-slip movement, with a minor normal component. The two nodal main shock planes were oriented NNE–SSW and ESE–WNW, respectively. The aftershocks sequences distribution did not coincide with the 16 Jun, 2020 main earthquake, neither in map view nor with respect to depth which may pointed to a secondary fault plane activation and stress triggered by the mainshock. The aftershocks clustered at the north western side of the main earthquakes and extend in the north western direction, which supported that the ESE–WNW plane is the fault plane. The spectral parameters of the S-wave displacement spectra of the main earthquake and its significant aftershock sequences were determined using the spectral inversion method and Brune’s$$\omega^{2}$$ω2modulation. The obtained spectra are flat in the frequency range from 0.8 Hz to each corner frequency, and they decreased rapidly at frequencies of < 10 Hz. The calculated seismic moment, moment magnitude, corner frequency, source radius, and stress drop vary from 8.293E+18 to 7.541E+22 dyn·cm, 2.4 to 5.0, 2.2 to 8.2 Hz, 171 to 633 m, and 0.02 to 13 MPa, respectively. The moment magnitude is equal to or slightly higher than the local magnitude reported by ENSN. The calculated stress drops for the earthquakes increased with increasing earthquake size.
Metabolic Power in Team and Racquet Sports: A Systematic Review with Best-Evidence Synthesis
Authors: Brochhagen Joana , Hoppe Matthias Wilhelm
Published: October 2022

Background

In intermittent team and racquet sports, metabolic loads are rarely investigated as they are difficult to examine, e.g., by portable metabolic carts and lactate measures. However, determining the instantaneous metabolic power of intermittent running from acceleration and speed data is possible. Recently, this potential has gained more interest in research and practice due to the development of player tracking technologies that allow easy access to the required data. The aim of this review was to systematically investigate the validity and point out the evidence of this new approach for estimating metabolic loads in intermittent sports. To provide an in-depth understanding of this approach and its validity, the fundamental aspects of the underlying concept were also considered.

Methods

PubMed®, Cochrane Library, Web of Science™, and BISp-surf databases were included in the search conducted on March 1, 2021. Studies assessing physiological and methodological validation as well as conceptual studies of the metabolic power approach in intermittent sports players without diseases or injuries were deemed eligible. The quality assessment was implemented using a modified 12-item version of the Downs and Black checklist. Additionally, a best-evidence synthesis of the validation studies was performed to clarify the direction and strength of the evidence.

Results

Of 947 studies that were identified, 31 met the eligibility criteria of which 7 were physiological, 13 methodological validation, and 11 conceptual studies. Gold standards for validating the metabolic power approach were predominantly oxygen uptake with 6 and traditional running speed analysis with 8 studies for physiological and methodological validation, respectively. The best-evidence synthesis showed conflicting to strong and moderate to strong evidence for physiological and methodological validity of the approach, respectively. The conceptual studies revealed several modifications regarding the approach that need to be considered. Otherwise, incorrect implementation can occur.

Conclusions

Evidence of the physiological validity of the metabolic power approach ranged from conflicting to strong. However, this should be treated with caution as the validation studies were often partially implemented incorrectly as shown by the underlying concept studies. Moreover, strong evidence indicated that the approach is valid from a methodological perspective. Future studies must consider what the metabolic power approach can and cannot actually display.
Accuracy of digital surgical guides for dental implants
Authors: Kim Myoung-Ju , Jeong Jun Young , Ryu Jaeyoung , Jung Seunggon , Park Hong-Ju , Oh Hee-Kyun , Kook Min-Suk
Published: October 2022

Background

Recently developed imaging techniques, such as cone beam computed tomography (CBCT) and CAD/CAM technology, have facilitated reliable implant planning and implant surgical guide production by 3D printing. This study compared the accuracy of implant-guided surgery using the R2GATE®program with CBCT before and after surgery.

Patients and methods

The study included patients who visited the Department of Oral and Maxillofacial Surgery at Chonnam National University Hospital from September 2021 to March 2022. Twenty-four implants were placed in eleven patients. Using R2GATE®Windows (Megagen implant, Daegu, Korea) software, implant placement was planned. The difference was measured by the CBCT before and after surgery. The cervical and apical distance and angular deviation of the implants were measured. Statistical analysis was performed using an independent t-test, Pearson correlation, and multiple regression analyses.

Results

The three-dimensional linear distance difference between the planned implant and the placed implant was 0.97 ± 0.37 mm at the cervical and 1.13 ± 0.36 mm at the apical. The difference in angle deviation between the planned implant and the placed implant was 3.42 ± 2.12°. Among the variables affecting the accuracy of implant placement, a statistically significant difference was found when using a tissue-supported implant guide, implant diameter and implant length.

Conclusion

Based on these results, using the R2GATE®program is useful to use an implant digital surgical guide, and it will be used in various clinic.
A social cognitive perspective on occupational identity development in college students
Authors: Vautero Jaisso , Silva Ana Daniela
Published: October 2022

Occupational identity is a central concept of career development, by providing a sense of direction and meaning across career development. This study aimed to examine how this concept can be associated with career processes through model formed by a set of socio-cognitive factors. The participants were 358 college students at a Brazilian university who completed measures of occupational identity, environmental supports and barriers, self-efficacy, goal progress, and academic satisfaction. Analysis indicates that the occupational identity status was partially well predicted by the combination of self-efficacy to cope with barriers, supports, academic satisfaction, and goal progress. These results highlight that students with a positive sense of competencies to deal with barriers and adequate levels of academic satisfaction would easily establish an occupational identity.
Compound fermentation supernatants of antagonistic bacteria control Rhizoctonia cerealis and promote wheat growth
Authors: Yi Yanjie , Liu Yang , Luan Pengyu , Hou Zhipeng , Yang Yanhui , Li Ruifang , Liang Zhenpu , Zhang Xiaoxia , Liu Shulei
Published: October 2022

Background

Wheat sheath blight, caused by Rhizoctonia cerealis, is a popular fungal disease that causes serious harm to wheat production. Biological control can offer the safe and effective method to control wheat diseases.

Results

In this study, antagonistic bacteria XZ20-1 and XZ38-3 were isolated and identified as Bacillus amyloliquefaciens and Bacillus velezensis, respectively, and all produced cellulase, protease, amylase and siderophore. To improve antifungal activity, fermentation supernatants of antagonistic bacteria Pseudomonas fluorescens RB5 (previously isolated and stored in the laboratory), B. amyloliquefaciensns XZ20-1 and B. velezensis XZ38-3 were combined and the optimal compound ratio (2:6:4) was quickly screened out through the improved triangle coordinate diagram method. The inhibition rate of compound fermentation supernatants (CFS) reached 61.01%, which was 22.51, 17.05 and 21.42% higher than that of single strain, respectively. The further stability analysis showed that compound fermentation supernatants were relatively stable to pH, temperature, ultraviolet and light. Effect of CFS on pathogen cells through fluorescent microscopy using different stains revealed the mechanism, which CFS can cause cell membrane permeability changed, accumulation of ROS and DNA fragmentation. In the pot experiments, the control efficacy of CFS was 83.05%. Moreover, plant height, root length and fresh weight, chlorophyll and soluble protein of wheat seedlings in CFS treatment groups were more than those in the control group.

Conclusions

This work screened out the optimal compound ratio of fermentation supernatants by the improved triangular coordinate diagram method firstly and revealed the action mechanism and provides an effective microbial agent for controlling R. cerealis and promoting wheat growth.
Single-color peripheral photoinhibition lithography of nanophotonic structures
Authors: He Minfei , Zhang Zhimin , Cao Chun , Qiu Yiwei , Shen Xiaoming , Zhou Guozun , Cai Zixin , Sun Xinjie , He Xin , Xu Liang , Liu Xi , Ding Chenliang , Cao Yaoyu , Kuang Cuifang , Liu Xu
Published: October 2022

Advances in direct laser writing to attain super-resolution are required to improve fabrication performance and develop potential applications for nanophotonics. In this study, a novel technique using single-color peripheral photoinhibition lithography was developed to improve the resolution of direct laser writing while preventing the chromatic aberration characteristics of conventional multicolor photoinhibition lithography, thus offering a robust tool for fabricating 2D and 3D nanophotonic structures. A minimal feature size of 36 nm and a resolution of 140 nm were achieved with a writing speed that was at least 10 times faster than existing photoinhibition lithography. Super-resolution and fast scanning enable the fabrication of spin-decoupled metasurfaces in the visible range within a printing duration of a few minutes. Finally, a subwavelength photonic crystal with a near-ultraviolet structural color was fabricated to demonstrate the potential of 3D printing. This technique is a flexible and reliable tool for fabricating ultracompact optical devices.
ENT manifestation CCs in tuberculosis: a descriptive study
Authors: Chavan Reshma P. , Ingole Shivraj M. , Parokaran Anish Anto , Desai Wilson V. , Damodhar Ajay P.
Published: October 2022

Background

An attempt was made to study ENT manifestations in tuberculosis.

Material and methods

A descriptive study was carried out among 200 patients with ENT manifestations of tuberculosis attending various departments at a government medical college hospital. Patients will be evaluated and followed up according to protocol. All patients diagnosed with tuberculosis were treated, according to the recent RNTCP guidelines using the CBNAAT testing.

Results

In the present study, 66% of patients with tuberculosis of the ear, nose, and throat region were females. Seventy-five percent of patients with tuberculosis of ENT and neck region were between the age group of 11 and 40 years. Cases of tubercular lymphadenitis (89.5%), tubercular laryngitis (4.5%), tubercular otitis media (3%), TB of the oral cavity (2%), and TB of the nose (1%) were seen. Painless lymph node enlargement was found in 91.62% of cases. Lymph node enlargement, hoarseness of voice, painless profuse otorrhoea, hearing loss, nasal obstruction, rhinorrhea, odynophagia, ulcers in the oral cavity, and tonsil enlargement were seen in patients of respective ENT tuberculosis. Concomitant pulmonary TB was found in 8.37% of cases of cervical TB, 100% of cases of laryngeal TB, 50% of cases of TB otitis media, 75% of cases of oral TB, and 50% of cases of nasal TB. Biopsy and CBNAAT have a promising role in tuberculosis management.

Conclusion

Early diagnosis of tuberculosis in ENT requires a high index of suspicion for patients non-responding to routine treatment
Exploring the association between brain-derived neurotrophic factor levels and longitudinal psychopathological and cognitive changes in Sardinian psychotic patients
Authors: Isayeva Ulker , Manchia Mirko , Collu Roberto , Primavera Diego , Deriu Luca , Caboni Edoardo , Iaselli Novella , Sundas Davide , Tusconi Massimo , Pinna Federica , Paribello Pasquale , Scherma Maria , Pisanu Claudia , Meloni Anna , Zai Clement C. , Congiu Donatella , Squassina Alessio , Fratta Walter , Fadda Paola , Carpiniello Bernardo
Published: October 2022

Background and hypothesis

Schizophrenia spectrum disorders are among the most debilitating mental disorders and has complex pathophysiological underpinnings. There is growing evidence that brain-derived neurotrophic factor (BDNF) can play a role in its pathogenesis. The present study investigated the longitudinal variation of serum BDNF levels in a 24-month observational prospective cohort study of Sardinian psychotic patients and its relationship with psychopathological and cognitive changes. Furthermore, we examined whether genetic variation within theBDNFgene could moderate these relationships.

Study design

Every 6 months, 105 patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and social measures. We performed a targeted analysis of four tag single nucleotide polymorphisms within theBDNFgene that were selected and analyzed using polymerase chain reaction. Longitudinal data were analyzed using mixed-effects linear regression models.

Study results

We observed a declining longitudinal trajectory of BDNF levels in psychotic patients in general, and in relation to the severity of depressive and negative symptoms. BDNF serum levels also declined in patients scoring lower in cognitive measures such as attention and speed of information processing and verbal fluency. The rs7934165 polymorphism moderated the significant association between verbal fluency and BDNF levels.

Conclusions

These findings in patients from real-world settings suggest a plausible role of peripheral BDNF levels as a marker of illness burden in schizophrenia spectrum disorders.
Opposing Effects of EGF Receptor Signaling on Proliferation and Differentiation Initiated by EGF or TSH/EGF Receptor Transactivation
Authors: Boutin Alisa , Marcus-Samuels Bernice , Eliseeva Elena , Neumann Susanne , Gershengorn Marvin C
Published: October 2022

Regulation of thyroid cells by thyrotropin (TSH) and epidermal growth factor (EGF) has been known but different effects of these regulators on proliferation and differentiation have been reported. We studied these responses in primary cultures of human thyroid cells to determine whether TSH receptor (TSHR) signaling may involve EGF receptor (EGFR) transactivation. We confirm that EGF stimulates proliferation and de-differentiation whereas TSH causes differentiation in the absence of other growth factors. We show that TSH/TSHR transactivates EGFR and characterize it as follows: (1) TSH-induced upregulation of thyroid-specific genes is inhibited by 2 inhibitors of EGFR kinase activity, AG1478 and erlotinib; (2) the mechanism of transactivation is independent of an extracellular EGFR ligand by showing that 2 antibodies, cetuximab and panitumumab, that completely inhibited binding of EGFR ligands to EGFR had no effect on transactivation, and by demonstrating that no EGF was detected in media conditioned by thyrocytes incubated with TSH; (3) TSH/TSHR transactivation of EGFR is different than EGFR activation by EGF by showing that EGF led to rapid phosphorylation of EGFR whereas transactivation occurred in the absence of receptor phosphorylation; (4) EGF caused downregulation of EGFR whereas transactivation had no effect on EGFR level; (5) EGF and TSH stimulation converged on the protein kinase B (AKT) pathway, because TSH, like EGF, stimulated phosphorylation of AKT that was inhibited by EGFR inhibitors; and (6) TSH-induced upregulation of thyroid genes was inhibited by the AKT inhibitor MK2206. Thus, TSH/TSHR causes EGFR transactivation that is independent of extracellular EGFR ligand and in part mediates TSH regulation of thyroid hormone biosynthetic genes.
Gut and Breast Microbiota as Endocrine Regulators of Hormone Receptor-positive Breast Cancer Risk and Therapy Response
Authors: Arnone Alana A , Cook Katherine L
Published: October 2022

Despite advances in treatment strategies, breast cancer (BC) remains one of the most prevalent cancers worldwide. Recent studies implicate the gut microbiome as a potential risk factor for BC development. Alterations in gut microbial diversity resulting in dysbiosis have been linked to breast carcinogenesis by modulating host immune responses and inflammatory pathways, favoring tumorigenesis and progression. Moreover, gut microbiota populations are different between women with BC vs those that are cancer free, further implicating the role of the gut microbiome in cancer development. This alteration in gut microbiota is also associated with changes in estrogen metabolism, which strongly correlates with BC development. Gut microbiota that express the enzyme β-glucuronidase (GUS) may increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties enabling reabsorption into circulation. Increased circulating estrogens may, in turn, drive estrogen receptor–positive BC. GUS-expressing microbiota also affect cancer therapy efficacy and toxicity by modifying glucuronide-conjugated drug metabolites. Therefore, GUS inhibitors have emerged as a potential antitumor treatment. However, the effectiveness of GUS inhibitors is still exploratory. Further studies are needed to determine how oral endocrine-targeting therapies may influence or be influenced by the microbiota and how that may affect carcinogenesis initiation and tumor recurrence.