Tracking tumor alteration in glioma through serum fibroblast activation protein combined with image.

PURPOSE: Detecting tumor progression of glioma continues to pose a formidable challenge. The role of fibroblast activation protein (FAP) in gliomas has been demonstrated to facilitate tumor progression. Glioma-circulating biomarkers have not yet been used in clinical practice. This study seeks to evaluate the feasibility of glioma detection through the utilization of a serum FAP marker. METHODS: We adopted enzyme-linked immunosorbent assay (ELISA) technique to quantify the relative FAP level of serum autoantibodies in a cohort of 87 gliomas. The correlation between preoperative serum autoantibody relative FAP levels and postoperative pathology, including molecular pathology was investigated. A series of FAP tests were conducted on 33 cases of malignant gliomas in order to ascertain their efficacy in monitoring the progression of the disease in relation to imaging observations. To validate the presence of FAP expression in tumors, immunohistochemistry was conducted on four gliomas employing a FAP-specific antibody. Additionally, the investigation encompassed the correlation between postoperative tumor burden, as assessed through volumetric analysis, and the relative FAP level of serum autoantibodies. RESULTS: A considerable proportion of gliomas exhibited a significantly increased level of serum autoantibody relative FAP level. This elevation was closely associated with both histopathology and molecular pathology, and demonstrated longitudinal fluctuations and variations corresponding to the progression of the disease The correlation between the rise in serum autoantibody relative FAP level and tumor progression and/or exacerbation of symptoms was observed. CONCLUSIONS: The measurement of serum autoantibody relative FAP level can be used to detect the disease as a valuable biomarker. The combined utilization of its detection alongside MR imaging has the potential to facilitate a more accurate and prompt diagnosis.

AKTeO2(CO3) (A = Li, Na): The First Carbonatotellurites Featuring a Zero-Dimensional [Te2C2O10]4- Cluster and a Wide Band Gap.

The first carbonatotellurites, AKTeO2(CO3) (A = Li, Na), have been successfully synthesized by using boric acid as the mineralizer. AKTeO2(CO3) (A = Li, Na) crystallize in the monoclinic space group P21/n (no. 14), and their structures exhibit the novel zero-dimensional (0D) [Te2C2O10]4- clusters, in which two [TeO4]4- groups form a [Te2O6]4- dimer via edge-sharing, with each side of the dimer attached by a [CO3]2- group via a Te-O-C bridge. The alkali metal cations occupy the voids between the 0D clusters and maintain the charge balance. The ultraviolet-visible-near-infrared diffuse reflectance spectra show that the short absorption cut-off edges of LiKTeO2(CO3) (LKTC) and NaKTeO2(CO3) (NKTC) are 248 and 240 nm, respectively, and LKTC exhibits the largest experimental band gap (4.58 eV) among all of the tellurites containing the π-conjugated anionic groups reported. Theoretical calculations revealed that they exhibit moderate birefringences of 0.029 and 0.040@1064 nm, respectively.

Data transmission with up to 100 orbital angular momentum modes via commercial multi-mode fiber and parallel neural networks.

This work presents an artificial intelligence enhanced orbital angular momentum (OAM) data transmission system. This system enables encoded data retrieval from speckle patterns generated by an incident beam carrying different topological charges (TCs) at the distal end of a multi-mode fiber. An appropriately trained network is shown to support up to 100 different fractional TCs in parallel with TC intervals as small as 0.01, thus overcoming the problems with previous methods that only supported a few modes and could not use small TC intervals. Additionally, an approach using multiple parallel neural networks is proposed that can increase the system's channel capacity without increasing individual network complexity. When compared with a single network, multiple parallel networks can achieve the better performance with reduced training data requirements, which is beneficial in saving computational capacity while also expanding the network bandwidth. Finally, we demonstrate high-fidelity image transmission using a 16-bit system and four parallel 14-bit systems via OAM mode multiplexing through a 1-km-long commercial multi-mode fiber (MMF).

A Standardized Step-by-Step Approach for the Diagnosis and Treatment of Sepsis.

Sepsis is the major culprit of death among critically ill patients who are hospitalized in intensive care units (ICUs). Although sepsis-related mortality is steadily declining year-by-year due to the continuous understanding of the pathophysiological mechanism on sepsis and improvement of the bundle treatment, sepsis-associated hospitalization is rising worldwide. Surviving Sepsis Campaign (SSC) guidelines are continuously updating, while their content is extremely complex and comprehensive for a precisely implementation in clinical practice. As a consequence, a standardized step-by-step approach for the diagnosis and treatment of sepsis is particularly important. In the present study, we proposed a standardized step-by-step approach for the diagnosis and treatment of sepsis using our daily clinical experience and the latest researches, which is close to clinical practice and is easy to implement. The proposed approach may assist clinicians to more effectively diagnose and treat septic patients and avoid the emergence of adverse clinical outcomes.

Brønsted Acid Catalyzed Dearomatization by Intramolecular Hydroalkoxylation/Claisen Rearrangement: Diastereo- and Enantioselective Synthesis of Spirolactams.

Described herein is a novel Brønsted acid catalyzed intramolecular hydroalkoxylation/Claisen rearrangement, allowing the practical and atom-economic synthesis of a range of valuable spirolactams from readily available ynamides in generally good to excellent yields with excellent diastereoselectivities and broad substrate scope. Importantly, an unexpected dearomatization of nonactivated arenes and heteroaromatic compounds is involved in this tandem sequence. Moreover, an asymmetric version of this tandem cyclization was also achieved by efficient kinetic resolution by chiral phosphoric acid catalysis. In addition, the [3,3]-rearrangement is shown to be kinetically preferred over the related [1,3]-rearrangement by theoretical calculations.

Post-Procedural Anticoagulation After Primary Percutaneous Coronary Intervention for Anterior Acute Myocardial Infarction With Severe Left Ventricular Dysfunction.

BACKGROUND: Patients with anterior acute myocardial infarction (AMI) and left ventricular (LV) dysfunction have an increased risk of LV thrombus (LVT). In the thrombolytic era, short-term anticoagulation using low-molecular-weight heparin during hospitalization proved to significantly reduce LVT formation, but, the effect of this prophylactic approach remains unclear in the current era. Therefore, we conducted a study to evaluate the effects of post-procedural anticoagulation (PPAC) using enoxaparin in addition to dual antiplatelet therapy (DAPT) after primary percutaneous coronary intervention (PCI) in such patients.Methods and Results:A total of 426 anterior AMI patients with LV ejection fraction ≤40% were retrospectively enrolled and classified into 2 groups based on whether they received PPAC (enoxaparin SC for at least 7 days). All patients received primary PCI and DAPT. The primary endpoint was definite LVT at 30 days diagnosed by echocardiography. The secondary endpoints were 30-day mortality, embolic events, and major bleeding events. PPAC was independently associated with a lower incidence of LVT (odds ratio 0.139, 95% confidence interval 0.032-0.606, P=0.009). The 30-day mortality, embolic events, and major bleeding events were not statistically different between groups. CONCLUSIONS: Short-term PPAC using enoxaparin after primary PCI may be an effective and safe way to prevent LVT in patients with anterior AMI and LV dysfunction.

A 4-gene prognostic signature predicting survival in hepatocellular carcinoma.

OBJECTIVE: To develop an independent prognostic signature for patients with hepatocellular carcinoma (HCC). METHODS: HCC gene expression profile the cancer genome atlas-liver hepatocellular carcinoma and GSE14520 were used as discovery and test set, respectively. Differentially expressed genes (DEGs) were identified between HCC tissues and adjacent normal liver tissues. Univariate Cox proportional hazards regression analysis was performed to identify DEGs correlated with survival of HCC patients. A 4-gene-based signature was constructed based on a least absolute shrinkage and selection operator Cox penalized regression model. The predictive value of the signature was analyzed and validated. RESULTS: Two hundred sixty-three DEGs were identified between HCC and adjacent liver tissues. After univariate survival analysis, 90 DEGs were found to be significantly correlated with the overall survival (OS) of HCC patients, of which 4 genes (KPNA2, CDC20, SPP1, and TOP2A) with non-zero coefficient were used to construct a prognostic signature. The 4-gene signature was significantly associated with the age (P = 0.046), grade ( P = 0.022), and T stage ( P = 0.023) of HCC patients in the discovery set and it also significantly associated with TNM stage ( P = 0.033), and serum alpha-fetoprotein lever ( P = 0.034). Patients in the 4-gene low-risk group were associated with better OS and recurrence-free survival (RFS) than those in the high-risk group in the discovery and test set. Meanwhile, the 4-gene signature is an independent prognostic factor regarding OS and RFS in the discovery and test set. CONCLUSION: We developed a 4-gene-based signature, which could be a candidate prognostic factor for patients with HCC.

Sucrose is involved in the regulation of iron deficiency responses in rice (Oryza sativa L.).

KEY MESSAGE: Sucrose signaling pathways were rapidly induced in response to early iron deficiency in rice plants, and the change of sucrose contents in plants was essential for the activation of iron deficiency responses. Sucrose is the main product of photosynthesis in plants, and it functions not only as an energy metabolite but also a signal molecule. However, a few studies have examined the involvement of sucrose in mediating iron deficiency responses in rice. In this study, we found that the decrease in photosynthesis and total chlorophyll concentration (SPAD values) in leaves occurred at a very early stage under iron deficiency. In addition, the sucrose was increased in leaves but decreased in roots of rice plants under iron deficiency, and also the sucrose transporter (SUT) encoded genes' expression levels in leaves were all inhibited, including OsSUT1, OsSUT2, OsSUT3, OsSUT4, and OsSUT5. The carbohydrate distribution was changed under iron deficiency and sucrose might be involved in the iron deficiency responses of rice plants. Furthermore, exogenous application of sucrose or dark treatment experiments were used to test the hypothesis; we found that the increased endogenous sucrose would cause the repression of iron acquisition-related genes in roots, while further stimulated iron transport-related genes in leaves. Compared to the exogenous application of sucrose, the dark treatment had the opposite effects. All the above results highlighted the important role of sucrose in regulating the responses of rice plants to iron deficiency.

Efficacy and safety of probiotic-supplemented triple therapy for eradication of Helicobacter pylori in children: a systematic review and network meta-analysis.

AIM: The aim of this study was to identify the best probiotic supplementation in triple therapy for pediatric population with Helicobacter pylori infection. METHODS: Eligible trials were identified by comprehensive searches. Relative risks with 95% confidence intervals and relative ranks with P scores were assessed. RESULTS: Twenty-nine trials (3122 participants) involving 17 probiotic regimens were identified. Compared with placebo, probiotic-supplemented triple therapy significantly increased H. pylori eradication rates (relative ratio (RR) 1.19, 95% CI 1.13-1.25) and reduced the incidence of total side effects (RR 0.49, 95% CI 0.38-0.65). Furthermore, to supplemented triple therapy, Lactobacillus casei was identified the best for H. pylori eradication rates (P score = 0.84), and multi-strain of Lactobacillus acidophilus and Lactobacillus rhamnosus for total side effects (P score = 0.93). As for the subtypes of side effects, multi-strain of Bifidobacterium infantis, Bifidobacterium longum, L. acidophilus, L. casei, Lactobacillus plantarum, Lactobacillus reuteri, L. rhamnosus, Lactobacillus salivarius, Lactobacillus sporogenes, and Streptococcus thermophilus was the best to reduce the incidence of diarrhea; multi-strain of Bacillus mesentericus, Clostridium butyricum, and Streptococcus faecalis for loss of appetite; multi-strain of B. longum, Lactobacillus bulgaricus, and S. thermophilus for constipation; multi-strain of Bifidobacterium bifidum, B. infantis, L. acidophilus, L. bulgaricus, L. casei, L. reuteri, and Streptococcus for taste disturbance; Saccharomyces boulardii for bloating; and multi-strain of Bifidobacterium breve, B. infantis, L. acidophilus, L. bulgaricus, L. casei, L. rhamnosus, and S. thermophilus for nausea/vomiting. CONCLUSIONS: Probiotics are recommended to supplement triple therapy in pediatrics, and the effectiveness of triple therapy is associated with specific probiotic supplementation.

Urgent transcatheter arterial embolization for the treatment of ruptured renal angiomyolipoma with spontaneous hemorrhage.

Background The rich neovascularization of renal angiomyolipoma (AML) has a tendency for spontaneous rupture with subsequent hemorrhage. Nephrectomy or nephron-sparing surgery has rarely been used as a primary treatment in urgent situations. Purpose To evaluate the safety and long-term outcomes for patients treated by urgent transcatheter arterial embolization (TAE) for spontaneous ruptured renal AML with severe hemorrhage. Material and Methods A retrospective evaluation was performed of 25 renal AML cases with spontaneous hemorrhage confirmed by imaging. Polyvinyl alcohol (PVA) particles and coils of multiple sizes were used to embolize the spontaneous renal AML ruptures. Results The technical success rate of TAE was 96% (24/25). One week post-TAE, 1 patient with recurrent hemorrhage underwent emergency nephrectomy. Minor complications affected 16 patients with post-embolization syndrome; 15 patients resolved using conservative measures and one patient received nephrectomy post TAE 1 week later. All patients were followed up for 24-72 months (median, 50.2 months). Surgical treatment was avoided for 92% (23/25) of patients, and the re-embolization rate was 0% at 2 years post TAE. In the 23 patients without surgical treatment, the mean maximum diameter of renal AML was reduced from 12.4 ± 5.5 cm to 6.3 ± 2.5 cm and no hemorrhage occurred during follow-up. Conclusion Urgent TAE is a technically feasible and minimally invasive procedure for controlling severe hemorrhage and preservation of renal function following spontaneous ruptured renal AML.

[An automatic peak detection method for LIBS spectrum based on continuous wavelet transform].

Spectrum peak detection in the laser-induced breakdown spectroscopy (LIBS) is an essential step, but the presence of background and noise seriously disturb the accuracy of peak position. The present paper proposed a method applied to automatic peak detection for LIBS spectrum in order to enhance the ability of overlapping peaks searching and adaptivity. We introduced the ridge peak detection method based on continuous wavelet transform to LIBS, and discussed the choice of the mother wavelet and optimized the scale factor and the shift factor. This method also improved the ridge peak detection method with a correcting ridge method. The experimental results show that compared with other peak detection methods (the direct comparison method, derivative method and ridge peak search method), our method had a significant advantage on the ability to distinguish overlapping peaks and the precision of peak detection, and could be be applied to data processing in LIBS.

2-Isopropylthioxanthone-Catalyzed Divergent Functionalization of Bicyclo[1.1.0]butanes under Visible-Light Irradiation.

1,3-Functionalized cyclobutane structural motifs are ubiquitous in natural products and pharmaceuticals. Photoinduced alkylation of bicyclo[1.1.0]butanes (BCBs) offers a step-economical strategy for accessing 1,3-functionalized cyclobutane motifs. Herein, we disclose a general and mild photocatalytic protocol of bromoallylation and alkylation of BCBs in a metal, additive-free manner by using the same photocatalyst, 2-isopropylthioxanthone, in different catalytic roles. Furthermore, the synthetic utility of these products was illustrated in the synthesis of various valuable and complex cyclobutane derivatives.

Successful treatment of near-fatal pulmonary embolism and cardiac arrest in an adult patient with fulminant psittacosis-induced severe acute respiratory distress syndrome after veno-venous extracorporeal membrane oxygenation rescue: A case report and follow-up.

Background: Veno-venous extracorporeal membrane oxygenation (ECMO) was successfully performed for the rescue of an adult patient with severe acute respiratory distress syndrome (ARDS) induced by fulminant psittacosis, and then a near-fatal pulmonary embolism (PE) and cardiac arrest (CA) of the same patient was cured through catheter-directed thrombolysis. Case presentation: A 51-year-old female patient was admitted to the hospital on September 10, 2021 due to slurred speech, weakness in lower limbs, dizziness, and nausea. Subsequently, she developed confusion and was transferred to the intensive care unit (ICU), where she received anti-shock, antibiotics, invasive mechanical ventilation (IMV), and veno-venous ECMO due to the diagnosis of severe pneumonia, severe ARDS, and septic shock based on comprehensive physical examination, laboratory tests, and imaging findings. The metagenomic next-gengeration sequencing (m-NGS) in the bronchoalveolar lavage fluid (BALF) suggested that the pathogen was chlamydia psittaci, so the antibiotics were adjusted to doxycycline combined with azithromycin. After withdrawal from ECMO, ultrasound (US) re-examination of the left lower limb revealed inter-muscular vein thrombosis, following which heparin was replaced by subcutaneous injection of 0.4ml enoxaparin sodium twice daily for anti-coagulation therapy. After withdrawal from IMV, the patient suffered sudden CA and successful cardiopulmonary resuscitation (CPR), and emergency pulmonary angiography (PA) was performed to show bilateral main pulmonary artery embolism. After immediate catheter-directed thrombolysis and placement of an inferior vena cava filter, the patient's condition gradually stabilized. Conclusions: Veno-venous ECMO can be successfully performed as an emergency life-saving treatment for patients with severe ARDS induced by fulminant psittacosis, and during ECMO regular examinations should be conducted to detect and manage thrombosis in time, thereby avoiding the occurrence of near-fatal PE and CA.

Role and Mechanism of PKC-δ for Cardiovascular Disease: Current Status and Perspective.

Protein kinase C (PKC) is a protein kinase with important cellular functions. PKC-δ, a member of the novel PKC subfamily, has been well-documented over the years. Activation of PKC-δ plays an important regulatory role in myocardial ischemia/reperfusion (IRI) injury and myocardial fibrosis, and its activity and expression levels can regulate pathological cardiovascular diseases such as atherosclerosis, hypertension, cardiac hypertrophy, and heart failure. This article aims to review the structure and function of PKC-δ, summarize the current research regarding its activation mechanism and its role in cardiovascular disease, and provide novel insight into further research on the role of PKC-δ in cardiovascular diseases.

Microbial composition and nitrogen removal pathways in a novel sequencing batch reactor integrated with semi-fixed biofilm carrier: evidence from a pilot study for low- and high-strength sewage treatment.

The sequencing batch reactor (SBR) activated sludge process is a well-established technology for sewage treatment. One of the drawbacks of SBRs, however, total nitrogen (TN) removals is insufficient. By means of introducing four improvements, including semi-fixed biofilm carrier, sludge elevation mixing and change for the mode of influent and effluent, compliant standard for TN discharge was obtained in this novel SBR configuration during low- and high-strength sewage load. To illustrate the microbial compositions and functions of the attached biofilm on semi-fixed carrier and the suspended aggregates, as well as the nitrogen removal pathway, high throughput 16S rRNA gene amplicon sequencing, PICRUSt2 algorithm, and KEGG database were applied. The results revealed that (i) the microbial communities from suspended aggregates and biofilm samples were significantly different from each other; (ii) during low-strength sewage loads, TN removal was mainly by nitrification-denitrification. The suspended aggregates was responsible for denitrification, while the biofilm was focused on ammonium oxidation; (iii) during high-strength sewage loads, function of nitrate reductase from suspended aggregates was faded, and anammox and N assimilation by biofilm became dominant. Meanwhile, TN removal referring to the formation of L-glutamine via assimilation was the main pathway.

Lymphocyte-C-reactive protein ratio can differentiate disease severity of COVID-19 patients and serve as an assistant screening tool for hospital and ICU admission.

In this study, we aimed to explore whether lymphocyte-C-reactive protein ratio (LCR) can differentiate disease severity of coronavirus disease 2019 (COVID-19) patients and its value as an assistant screening tool for admission to hospital and intensive care unit (ICU). A total of 184 adult COVID-19 patients from the COVID-19 Treatment Center in Heilongjiang Province at the First Affiliated Hospital of Harbin Medical University between January 2020 and March 2021 were included in this study. Patients were divided into asymptomatic infection group, mild group, moderate group, severe group, and critical group according to the Diagnosis and Treatment of New Coronavirus Pneumonia (ninth edition). Demographic and clinical data including gender, age, comorbidities, severity of COVID-19, white blood cell count (WBC), neutrophil proportion (NEUT%), lymphocyte count (LYMPH), lymphocyte percentage (LYM%), red blood cell distribution width (RDW), platelet (PLT), C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (SCr), albumin (ALB), total bilirubin (TB), direct bilirubin (DBIL), indirect bilirubin (IBIL), and D-dimer were obtained and collated from medical records at admission, from which sequential organ failure assessment (SOFA) score and LCR were calculated, and all the above indicators were compared among the groups. Multiple clinical parameters, including LYMPH, CRP, and LCR, showed significant differences among the groups. The related factors to classify COVID-19 patients into moderate, severe, and critical groups included age, number of comorbidities, WBC, LCR, and AST. Among these factors, the number of comorbidities showed the greatest effect, and only WBC and LCR were protective factors. The area under the receiver operating characteristic (ROC) curve of LCR to classify COVID-19 patients into moderate, severe, and critical groups was 0.176. The cutoff value of LCR and the sensitivity and specificity of the ROC curve were 1,780.7050 and 84.6% and 66.2%, respectively. The related factors to classify COVID-19 patients into severe and critical groups included the number of comorbidities, PLT, LCR, and SOFA score. Among these factors, SOFA score showed the greatest effect, and LCR was the only protective factor. The area under the ROC curve of LCR to classify COVID-19 patients into severe and critical groups was 0.106. The cutoff value of LCR and the sensitivity and specificity of the ROC curve were 571.2200 and 81.3% and 90.0%, respectively. In summary, LCR can differentiate disease severity of COVID-19 patients and serve as a simple and objective assistant screening tool for hospital and ICU admission.

Comparison of demographic features and laboratory parameters between COVID-19 deceased patients and surviving severe and critically ill cases.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been far more devastating than expected, showing no signs of slowing down at present. Heilongjiang Province is the most northeastern province of China, and has cold weather for nearly half a year and an annual temperature difference of more than 60ºC, which increases the underlying morbidity associated with pulmonary diseases, and thus leads to lung dysfunction. The demographic features and laboratory parameters of COVID-19 deceased patients in Heilongjiang Province, China with such climatic characteristics are still not clearly illustrated. AIM: To illustrate the demographic features and laboratory parameters of COVID-19 deceased patients in Heilongjiang Province by comparing with those of surviving severe and critically ill cases. METHODS: COVID-19 deceased patients from different hospitals in Heilongjiang Province were included in this retrospective study and compared their characteristics with those of surviving severe and critically ill cases in the COVID-19 treatment center of the First Affiliated Hospital of Harbin Medical University. The surviving patients were divided into severe group and critically ill group according to the Diagnosis and Treatment of New Coronavirus Pneumonia (the seventh edition). Demographic data were collected and recorded upon admission. Laboratory parameters were obtained from the medical records, and then compared among the groups. RESULTS: Twelve COVID-19 deceased patients, 27 severe cases and 26 critically ill cases were enrolled in this retrospective study. No differences in age, gender, and number of comorbidities between groups were found. Neutrophil percentage (NEUT%), platelet (PLT), C-reactive protein (CRP), creatine kinase isoenzyme (CK-MB), serum troponin I (TNI) and brain natriuretic peptides (BNP) showed significant differences among the groups (P = 0.020, P = 0.001, P < 0.001, P = 0.001, P < 0.001, P < 0.001, respectively). The increase of CRP, D-dimer and NEUT% levels, as well as the decrease of lymphocyte count (LYMPH) and PLT counts, showed significant correlation with death of COVID-19 patients (P = 0.023, P = 0.008, P = 0.045, P = 0.020, P = 0.015, respectively). CONCLUSION: Compared with surviving severe and critically ill cases, no special demographic features of COVID-19 deceased patients were observed, while some laboratory parameters including NEUT%, PLT, CRP, CK-MB, TNI and BNP showed significant differences. COVID-19 deceased patients had higher CRP, D-dimer and NEUT% levels and lower LYMPH and PLT counts.

Effects of ultrasound on invasive golden mussel Limnoperna fortunei mortality and tissue lesions.

Biofouling by the invasive golden mussel Limnoperna fortunei deleteriously affects artificial water systems, but few effective, environmentally friendly antifouling strategies exist. We propose ultrasound for control of this invasive mussel and report minimum exposure times to kill juveniles and adults at ultrasonic powers ranging 300-600 W from a fixed distance of 8.5 cm. Analysis using a PMA + RT-qPCR assay revealed the formation of tissue lesions in response to ultrasound, with gill tissue more prone to injury than adductor muscle tissue. Shell microstructure determined using scanning electron microscopy (SEM) + energy dispersive X-ray spectroscopy (EDS) is plywood-like, with a thicker shell and increased numbers of prism and nacre layers in adult mussels that provide greater resistance to ultrasound, reducing mortality and tissue lesions. Our results suggest L. fortunei biomass could be effectively reduced by ultrasound, especially for early life-history stages without, or with only immature shells.