This paper presents the design and testing of a one-axis piezoelectric accelerometer made from cellulose paper and piezoelectric zinc oxide nanowires (ZnO NWs) hydrothermally grown on paper. The accelerometer adopts a cantilever-based configuration with two parallel cantilever beams attached with a paper proof mass. A piece of U-shaped, ZnO-NW-coated paper is attached on top of the parallel beams, serving as the strain sensing element for acceleration measurement. The electric charges produced from the ZnO-NW-coated paper are converted into a voltage output using a custom-made charge amplifier circuit. The device fabrication only involves cutting of paper and hydrothermal growth of ZnO NWs, and does not require the access to expensive and sophisticated equipment. The performance of the devices with different weight growth percentages of the ZnO NWs was characterized. Over the past three decades, there have been numerous advances made in microfabricated sensors and actuators. As the research and development on microelectromechanical systems (MEMS) progress, it is increasingly common to integrate materials other than silicon into MEMS transducers. Among these developments, piezoelectric materials in either bulk or thin film forms have been integrated into MEMS devices for a variety of applications such as acoustic resonators ,2, quartBesides solid-state materials, paper has also emerged as a substrate material for the development of flexible sensors and electronics as it offers some unique advantages such as low cost, excellent biodegradability and disposability, ease of fabrication, good printability and foldability, high flexibility and light weight. There have been significant advances in paper-based transducers and electronics ,14, and Applications such as smart packaging require vibration monitoring during transportation, and paper-based accelerometers could provide a suitable solution for seamless integration. There are only two designs reported in the literature that is capable of acceleration measurement using functionalized paper substrates ,36. MahaIn this work, we take a different approach to the development of a fully-functional, paper-based piezoelectric accelerometer based on zinc oxide nanowire (ZnO NW)-coated cellulose paper. Through a facile hydrothermal approach, we grow ZnO NWs on a piece of cellulose chromatography paper, which renders the paper piezoelectric. We use the ZnO-NW-coated paper as a strain sensing element and attach it on top of a set of two parallel cantilever beams A. When aE = 1.59 GPa. For device prototyping, the length (L) and width (W) of the parallel beams were set to be 10 mm and 5 mm, respectively. Other beam dimensions could also be used if a different total beam stiffness is desired.As illustrated in The piezoelectric output from the paper-based accelerometer could be attributed to two piezoelectric mechanisms. (i) As the cantilever beams experience acceleration-induced deformations, the root/seed layer of ZnO coated on the paper microfibers is deformed, which produces electric charges. (ii) As the cellulose microfibers of the ZnO-NW-coated paper are deformed, adjacent ZnO NWs grown on them contact and bend against each other, generating electric charges and transporting these charges through the root layer of ZnO and the network of contacted ZnO NWs. Further efforts are needed on multiscale mechanical modelling of the hierarchical structure of the ZnO-NW-coated paper, in order to better understand deformations of the cellulose microfibers and the individual ZnO NWs and thus decipher the piezoelectric strain sensing principle of the ZnO-NW-coated paper.® Grade 1 chromatography paper , which has been previously reported in detail [n = 50). After the seeding solution was cooled down to room temperature, three 30 mm × 30 mm square pieces of Whatman® Grade 1 chromatography paper were immersed into the solution for 3 min and dried at 86 °C for another 3 min. This dipping and drying process was repeated four times and each time the side of the paper piece facing up was alternated so the effect of gravity on the excessive ZnO-NP seeding solution left on either side of the paper substrate was canceled out. At the end of the first step, a uniformly coated ZnO-NP film was formed on the surfaces of the individual cellulose microfibers of the paper substrate.A hydrothermal approach was employed to grow ZnO NWs on Whatmann detail . Briefly2+) and HMTA is to supply the hydroxyl ions that react with Zn2+ ions to form ZnO [In the second step of the hydrothermal growth process, the ZnO-NP-coated paper substrates were immersed in an aqueous solution of zinc nitrate hexahydrate  and hexamethylenetetramine  in a 50 mL flask with stopper. The ZNH is to provide the zinc ions (Znform ZnO . The flaform ZnO . We adjun = 9). Then, a U-shaped ZnO-NW-coated paper was attached to the parallel cantilever beams using double-sided tape. Finally, silver ink  was manually screen-printed onto two ends of the ZnO-NW-coated paper to form two electrodes of 2.5 mm × 2.5 mm, and the ink was dried on a hotplate at 80 °C for an hour. To fabricate a paper-based accelerometer, a laser cutter was used to cut out a device frame using card stock paper , which consists of a rectangular frame connected to a rectangular proof mass at the frame center through a set of two parallel cantilever beams. Three layers of card stock paper were attached to the proof mass using double-sided adhesive tape, leading to a total mass of 61 ± 1.1 mg  as a current on the order of a few nanoamperes. To facilitate the signal measurement from the paper-based accelerometer, we designed a custom-made charge amplifier circuit that performs two tasks: (i) to convert piezoelectric charges generated from the ZnO NWs into a voltage signal; and (ii) to amplify the voltage signal to a level suitable for direct data acquisition (DAQ) using a standard DAQ board . All the experiments in this work were performed using the charge amplifier circuit connected to the DAQ board, unless otherwise indicated. In order to further enhance the portability of the experimental setup, another option is to replace the DAQ board with a portable microprocessor circuit for data collection.GDC is the circuit direct-current (DC) gain: fL and fH are the lower and higher cut-off frequencies of the charge amplifier: fL = fH = fC is the cut-off frequency of the low-pass filter: fC = The overall transfer function of the charge amplifier circuit is:× 3 mm) was performed in a stopper flask , as shown in The hydrothermal growth of ZnO NWs on Whatman grade 1 chromatography paper  and a scanning laser Doppler vibrometer  was used to measure the proof mass vibration of the paper-based accelerometer and monitor its frequency response A. The exWe mounted a paper device (ZnO-NW weight growth percentage: 61%) and a commercial MEMS accelerometer  on the same electrodynamic exciter and let them undergo sinusoidal excitations at 10 Hz and 15 Hz. The MEMS accelerometer is integrated with its signal readout circuit and can directly output an analog voltage with a sensitivity of 117.5 mV/g. As shown in n = 3 devices for each percentage). We calculated the sensitivities of the paper-based accelerometers to be 16.1 mV/g, 11.02 mV/g and 16.3 mV/g for the weight growth percentages of 16%, 41% and 61%, respectively.Finally, we measured the sensitivity of the paper-based accelerometers with three different weight growth percentages of ZnO NWs. For this test, a paper-based accelerometer and a MEMS accelerometer were attached to the top and bottom surfaces of the free end of a metal ruler, and the other end of the ruler was clamped to the surface of a table, as shown in In this work, we demonstrated the feasibility of acceleration measurement using ZnO-NW-coated cellulose paper as the major sensing element. The addition of acceleration sensing capability to common paper substrates is of primary importance to developing monolithic paper-based devices with a variety of sensing capabilities such as strain/touch sensing and energy harvesting. Our design has a few useful characteristics for applications in paper-based electronics. (i) The hydrothermal approach of growing ZnO NWs used in this work is compatible with many types of paper substrates, making our design applicable to a variety of paper-based electronic devices involving different types of paper. (ii) The hydrothermal synthesis of ZnO NWs could be spatially controlled by patterning the seeding layer on a substrate through screen/inkjet printing or other means; this allows the formation of ZnO-NW micro-patterns and thus leads to monolithic, highly-integrated and more versatile designs of paper-based sensors and electronics. (iii) The device fabrication process is low-cost and does not require the access to expensive, sophisticated equipment. Most importantly, the process is compatible with existing techniques for fabricating electronic devices on flexible substrates such as screen and inkjet printing. Roll-to-roll processes can also be adapted for paper cutting and electrode printing.Prior to experimental testing of the paper-based accelerometers, we speculated that the longer the ZnO NWs  growth on paper, the more piezoelectric charges could be generated from the mechanical loading of the ZnO-NW-coated paper during acceleration measurement. However, the data suggested that there is no obvious correlation between the sensitivity of the paper-based accelerometer and the weight growth percentage of ZnO NWs on paper. A possible reason for this experimental observation is that the piezoelectric sensing mechanism of the ZnO-NW-coated paper involves multiple loading modes of the ZnO seeding layer and the individual ZnO NWs. There are two possible sources of the electronic charges produced from the ZnO-NW-coated paper: (i) deformation of the ZnO seeding layer on the paper microfibers when the microfibers are stretched and compressed; and (ii) surface rubbing and rubbing-induced deformation of adjacent ZnO NWs when their rooting paper microfibers are deformed. In addition to the unclear deformation modes of the ZnO NWs, the transport pathways of generated charges could also be significantly altered when adjacent ZnO NWs contact each other during device operation. All these intertwined factors explain the factor that the increase in ZnO-NW length does not necessarily lead to the enhancement of the device sensitivity. As the growth percentages of 16% and 61% lead to similar device sensitivities  In our current design, the ZnO NWs were synthesized on a separate piece of paper, which was then attached to the parallel paper beams as the strain gauge. Direct growth of the ZnO NWs on the parallel beams is also possible through patterning of the ZnO NPs on the parallel beams. This will avoid attaching another piece of ZnO-NW-coated paper onto the paper device structures and thus improve the fabrication yield and device reliability. (ii) For the same growth percentage, the sensitivity calibration data B show reThe paper-based accelerometer is made from low-cost materials including paper and conductive inks, and can be mass-produced through cost-effective approaches such as die cutting of paper and screening printing of conductive inks. We demonstrated that the paper-based accelerometer is capable of monitor vibration reliably but has a lower sensitivity than a MEMS accelerometer. Despite its lower sensitivity, the paper-based accelerometer will find potential applications in areas such as smart packaging and paper-based electronics. For instance, packages of delicate equipment may require real-time vibration monitoring during transportation and paper-based electronic devices  could also employ paper-based accelerometers for user-device interaction.This paper reports the development of a paper-based piezoelectric accelerometer integrating ZnO NWs. We first grew ZnO NWs on cellulose paper through a low-cost hydrothermal approach and then integrated the ZnO-NW-coated paper into a cantilever-based configuration of paper-based accelerometer. As the paper-based accelerometer underwent accelerations/vibrations, the piezoelectric ZnO-NW-coated paper on the cantilever beams experienced stretching or compressive deformations and thus produced electric charges that were converted into voltage outputs through a charge amplifier circuit. The paper-based accelerometer with a proof mass of 61 mg was calibrated to have a sensitivity up to 16.3 mV/g and a natural frequency of 84.75 Hz. This design has potential for use in smart packaging and integration of motion-sensing capability into paper-based flexible electronics.


With the popularity of using deep learning-based models in various categorization problems and their proven robustness compared to conventional methods, a growing number of researchers have exploited such methods in environment sound classification tasks in recent years. However, the performances of existing models use auditory features like log-mel spectrogram (LM) and mel frequency cepstral coefficient (MFCC), or raw waveform to train deep neural networks for environment sound classification (ESC) are unsatisfactory. In this paper, we first propose two combined features to give a more comprehensive representation of environment sounds Then, a fourfour-layer convolutional neural network (CNN) is presented to improve the performance of ESC with the proposed aggregated features. Finally, the CNN trained with different features are fused using the Dempster–Shafer evidence theory to compose TSCNN-DS model. The experiment results indicate that our combined features with the four-layer CNN are appropriate for environment sound taxonomic problems and dramatically outperform other conventional methods. The proposed TSCNN-DS model achieves a classification accuracy of 97.2%, which is the highest taxonomic accuracy on UrbanSound8K datasets compared to existing models. Intelligent sound recognition (ISR) is a technology for identifying sound events that exist in the real environment. This method is mainly based on analyzing human auditory awareness characteristics and embedding such percept ability in machines or robots. Environmental sound classification (ESC), also known as sound event recognition, serves as a fundamental and essential step of ISR. The main goal of ESC is to precisely classify the class of a detected sound, such as children playing, car horn and gunshot. With the popular applications of ISR in audio surveillance systems  and healEnvironment sound taxonomy generally consists of two basic components: acoustic features and classifiers. In order to extract acoustic features, sound signals are first separated into frames with a cosine window function (Hamming or Hanning window). Then, features are extracted from each frame and this set of features is used as one instance of training or testing . The claSupport-vector machines (SVM), Gaussian mixture model (GMM) extreme learning machine (ELM) are widely used classifiers in sound related classification tasks in the past decades ,9,10,11 Despite the fact that CNN can solve the limitations of conventional classifiers, the longer temporal context information still cannot be captured by this method. Hence, several works propose to use merged neural networks to address the above-mentioned shortcomings through integrating information from the earlier steps ,18,19,20The main obstacles of current algorithms for ESC tasks are as follows: 1) the most widely used acoustic features applied to ESC tasks were originally designed for ASR and MIR, such as log-mel spectrogram and MFCC. Since the environment sounds are mostly non-stationary signals without meaningful patterns or sub-structures, use a single feature may lead to the failure of capturing important information about environmental audio events. 2) In recent years, with the advancement of deep learning models, the CNN becomes a primary choice in environment sounds recognition and outperform the conventional classifiers like SVM or GMM ,24. EvenIn order to address these two deficiencies, we propose a novel four-layer stacked CNN architecture based on two combined auditory features and DS theory-based information fusion method, called TSCNN. The proposed system consists of three components: feature extraction and combination, CNN training and DS theory-based decision-level fusion. We extract five auditory features: log-mel spectrogram (LM), MFCC, chroma, spectral contrast and tonnetz . Then, LM and CST (LMC) are combined as one feature sets, MFCC and CST (MC) are aggregated as another for training two CNNs, respectively. At last, the outputs derived from the softmax layer of these two CNNs are fused by DS theory to exploit both combined features. The experimental results indicate that the taxonomic accuracy of the proposed architecture can surpass both LCNet (CNN use LMC feature) and MCNet (CNN use MC feature), and is also outperforming the existing models on Urbansound8K  dataset.The remaining structure of this paper is organized as follows. With the growing number of evidence that the CNN-based models outperform conventional methods in various categorization tasks, they have been applied in sound recognition tasks in recent years. Ref.  first evTraditional CNN models have several drawbacks for auditory tasks. For example, pooling layers are generally applied in CNN models for feature dimensional reduction, however, these processes can lead to information loss and hinder the performance of neural networks. Therefore, a considerable number of works attempt to use improved CNNs for ESC tasks. Dilated convolution layers are exploited for ESC ,32 to avFrom these works, we can notice that most ESC models use raw waveform directly or single auditory features to train neural networks. However, after a comprehensive investigation of a considerable number of sound recognition works, Ref.  pointed In this section, we first describe the feature extraction and combination method. Then, the structure of CNN model and DS theory-based information fusion algorithm will be presented.Several works ,9,38,39 As log-mel spectrogram and MFCC are the most widely used auditory features in sound recognition, these two feature sets are extracted at first. Then, chroma , spectra(1)The first layer uses 32 kernels with (2)The second layer uses the same settings as the first layer, where 32 convolution kernels with receptive filed of (3)The third layer uses 64 convolution kernels with a receptive field of (4)The fourth layer 64 convolution kernels with receptive filed of (5)The fifth layer is the fully connected layer with 1024 hidden units and the activation function is Sigmoid.(6)The output is ten units according to the datasets, followed by the softmax activation function.The two networks of TSCNN both contain four convolution layers and one fully connected layer. The framework of the proposed four-layer CNN is shown in At the training stage, we use a 0.5 dropout probability for the second layer, fourth layer and the fully connected layer to prevent overfitting. The CNN is trained through a variant of stochastic gradient descent . The batDempster-Shafer evidence theory (DS theory) was originally established by Ref. , it is a(1)(2)The basis of DS theory is to establish a frame of discernment In this work, the category of sounds in the dataset can be treated as an element in subset The outputs of softmax of LMCNet and MCNet are used as the mass function With the LMCNet, MCNet and the DS theory-based information fusion method, we propose the TSCNN. The overall framework of the this ISR system is shown in From The UrbanSound8K dataset includes 8732 labeled urban sounds  collected from the real-world, totaling 9.7 h. The dataset is separated into 10 audio event classes: air conditioner (ac), car horn (ch), children playing (cp), dog bark (db), drilling (dr), engine idling (ei), gunshot (gs), jackhammer (jh), siren (si) and street music (sm).The same feature extraction method presented by Ref.  is used It can be seen from For each experiment, the ten-fold cross-validation is performed to evaluate the proposed ISR model on UrbanSound8K dataset. The combined features and four-layer CNN architecture are two main contributions of this work. Hence, we first analyze the efficiency of the CNN model trained with combined features. Meanwhile, the influence of the different number of convolution layers (six and eight) on CNN-based ESC system is also investigated. The additional convolution layers in the CNNs for comparison use the same receptive fields of Furthermore, the classification performance of feature level fusion method is also presented. We combined LM, MFCC and CST together to form a new feature set called MLMC, to make a further investigation of the influence of various feature combination strategies in ESC tasks. The feature size of MLMC is The Moreover, in order to further illustrate whether the proposed TSCNN-DS model outperform LMCNet, MCNet and four-layer CNN using MLMC feature sets, we show the standard deviation and time cost in It can be seen in From In general, we can find out that the proposed LMC and MC features present to be efficiency with the proposed ISR system, which clarifies the advantage of the proposed feature combination strategies in ESC tasks. The TSCNN-DS model outperforming other models for both CNN architectures with different convolution layers. Then, the four-layer CNN achieves the best taxonomic accuracy when compared with six-layer and eight-layer CNN models for both methods. Meanwhile, the classification accuracy of both methods with the proposed four-layer CNN are higher than existing models. These results demonstrate the efficiency of the proposed four-layer CNN and DS theory fusion method based TSCNN-DS model.In order to make a comprehensively comparison, we also investigate the two-stream CNN with the layer stack method. This model combined the outputs of the second convolution layer of both CNN and the concatenate feature maps are than used as inputs for the next convolution layers. We test this stacked CNN with 4, 6 and 8 layers as well. The parameter settings of each convolution layers and fully connected layers are equal to the 4-, 6- and 8-layer CNN described above. The classification accuracy of these stacked CNNs on UrbanSound8K dataset are shown in It is clearly that the stacked four-layer CNN models achieve the highest (86.4%) classification accuracy among the three models. Which is 6.6% and 6.3% higher than stacked six- and eight-layer CNN respectively. This result further proves that the proper number of layers and parameters is the key to the deep learning model based ISR system, where the advantage of the proposed four-layer CNN is further proved as well.At last, we compare our TSCNN-DS model with several existing CNN based ISR models as presented by Refs. ,28,32,35In this paper, we proposed the TSCNN-DS model of intelligent sound recognition problems. It consists of two four-layer convolutional neural networks, the LMCNet and MCNet trained by two combined features, LMC and MC feature sets, respectively. Then, the outputs of the softmax layer of both networks are fused through DS evidence theory; the result is the predicted categorization of an environment sound. The performances of two CNNs with the novel combined feature sets and the entire framework are tested on UrbanSound8K dataset and compared with existing models which published in recent years. The LMCNet and MCNet reaches 95.2% and 95.3% on UrbanSound8K dataset, which is 22.5% and 22.6% higher than the Piczak’s model , respectThe DS theory can substantially improve the taxonomic performance of the single CNN model in ESC problems, however, from


Two experiments were conducted to investigate the time course of syllabic and sub-syllabic processing in Cantonese spoken word production by using the picture-word interference task. Cantonese-speaking participants were asked to name individually presented pictures aloud and ignore an auditory word distractor. The targets and distractors were either phonologically related  or unrelated. In Experiment 1, the target syllables were all consonant-vowel (CV)-structured. The phonological distractor was either a CV syllable  or a CVC (consonant-vowel-consonant) syllable . Relative to the unrelated control, Full Syllable Overlap distractors facilitated naming in all stimuli onset asynchronies (SOAs)  whereas Sub-syllable Overlap distractors exhibited facilitation only at 0-ms and +175-ms SOAs. Experiment 2 adopted a similar design to examine the possible influence of syllabic structure similarity on the results of Experiment 1. The target syllables were all CVC-structured. The phonological distractor was either a CVC  or CV  syllable. Comparable priming was observed between the two distractor conditions across the three SOAs. These results indicated that an earlier priming effect was observed with full syllable overlap than sub-syllabic overlap when the degree of segmental overlap was held constant (Experiment 1). The earlier syllable priming observed in Experiment 1 could not be attributed to the effect of syllabic-structure (Experiment 2), thereby suggesting that the syllable unit is important in Cantonese and is retrieved earlier than sub-syllabic components during phonological encoding. One contentious theoretical issue in the language production literature concerns the nature or size of the phonological unit being retrieved following lexical access, and whether this is language-universal or language-specific . A widelHowever, a different picture was observed in non-Indo-European languages such as Chinese and Japanese. Using a similar form-preparation paradigm, researchers did not find a comparable effect of a single phoneme in Chinese or Japanese. Instead, significant priming effects were observed only when the words shared the same atonal syllable  in Mandarin , 11 or mAlthough the behavioral effect of a single segment has rarely been found in Chinese speech production , 15, theTo explain the robust effect of atonal syllables and the null effect of a single segment in Chinese speech production, the proximate unit hypothesis assumes that syllable retrieval precedes sub-syllabic encoding in Chinese. As phonemic specification is sub-ordinated to syllable retrieval, the sub-syllabic effects in Chinese word production are either weak or difficult to observe. This assumption has been included in the Chinese version of the Word-form Encoding and Activation Verification (WEAVER) model .One key assumption of the above account is the order between syllabic and sub-syllabic processing in Chinese word production. However, evidence supporting this key assumption is scarce. In a recent attempt to investigate the time course of syllabic and sub-syllabic processing in overt Mandarin word production, Wang, Wong, & Chen  employedmaa5/ “horse”) and distractor  shared the same atonal syllable, which was consonant-vowel (CV)-structured. Distractors sharing the same CV component with the target but with an additional coda  were also included. Note that there are six possible codas in Cantonese and two in Mandarin. These two types of phonological distractor shared the same number of identical phonemes with their target , and the only difference between the two was whether the overlap constituted a full syllable overlap. According to the proximate unit hypothesis [The proximate unit hypothesis  is an atpothesis , an earlNevertheless, one possible confound in Experiment 1 was that the two phonological conditions also differed in their syllabic structure. By using a masked priming-naming task, Verdonschot et al.  found siThis experiment aims at investigating the time course of syllabic and sub-syllabic processing in Cantonese phonological encoding using a PWI task while the degree of segmental overlap was manipulated across conditions.Thirty Cantonese-speaking undergraduates  from the City University of Hong Kong (CityU) participated. They were all neurologically healthy, without a known history of speech or hearing impairment, and had normal or corrected-to-normal vision. The experiments reported here were approved by the Human Subjects Ethics Sub-Committee of the Research Committee of the City University of Hong Kong. Participants completed the experiment individually in a sound-attenuated room and each received an honorarium of HKD 50 (~USD 7).ho6/ or /maa4/, which was consistent with the corresponding target /ho4 lau 4/ or /maa5/, respectively, in the Full Syllable Overlap condition) and the other one was a consonant-vowel-consonant (CVC) syllable . Distractors were presented auditorily. The two sets of distractors were closely matched in syllable frequency and number of homophones [ts <1. Since Cantonese syllables with a stop coda  are generally shorter in their acoustic duration relative to those without, the mean duration of the CVC distractors (468±116ms) was shorter than that of the CV distractors (547±54 ms), t(58) = 2.87, p < .05. Furthermore, an unrelated control condition was created for the Full Syllable Overlap condition by re-pairing the distractors with the targets within the same condition so that the distractor was unrelated to the target in each pair. A similar unrelated control condition was created for the Sub-syllable Overlap condition by re-pairing the distractors with the targets. Consequently, four distractor conditions were included, namely Full Syllable Overlap Related, Full Syllable Overlap Unrelated, Sub-syllable Overlap Related, and Sub-syllable Overlap Unrelated  x 2 (Distractor Type: Full Syllable Overlap vs. Sub-syllable Overlap) x 2 (Target-distractor Relatedness: Related vs. Unrelated) within-participants design. Each participant named each of the 30 pictures under each SOA and distractor condition, comprising a total of 360 (30 pictures x 3 SOAs x 4 distractor conditions) trials. Six blocks of 60 trials each were formed. Each picture appeared twice in each block. The four distractor conditions were intermixed and equiprobable in each block. Trial order within each block was pseudorandomized with no picture repetition in two consecutive trials. The block presentation order was randomized across participants. The experiment consisted of a learning and a testing phase. In the learning phase, participants were shown on the screen the 30 pictures individually along with their names. Afterward, the picture names were tested immediately to check if participants could name the pictures correctly. In the subsequent testing phase, each trial started with a centered fixation point presented for 1000 ms, followed by a 500-ms blank. The target picture was then presented and stayed on the screen until a naming response was detected or after a lapse of 5000 ms. Depending on the SOA condition, the auditory distractor was presented before (SOA = -175 ms), at (SOA = 0 ms), or after (SOA = +175 ms) the onset of the picture presentation. Participants’ naming latencies were measured from the time the picture was displayed. The next trial began after a 1000-ms blank. Participants were asked to name the target picture aloud as accurately and quickly as possible, and ignore the accompanying distractor. Prior to the start of the experiment, participants learned and named 10 pictures, which were not included in the experimental session, for practice. The entire experiment lasted 45 minutes.Incorrect responses (0.8%), trials in which the voice key malfunctioned or mistriggered (1.6%), and outlier responses, which were 2.5 standard deviations beyond condition means (2.7%), were discarded from the reaction time analyses. F tests on the fixed effects and calculate p values with Satterthwaite approximation to prevent Type 1 error (see [F tests on the fixed effects using Satterthwaite approximation are shown in The remaining naming latency data were first inverse transformed (-1000/RT) and then submitted to linear mixed-effect modeling (LMEM)  implemenror , standard errors (SE), and p values are reported in Similar to Wang et al. , the simExperiment 1 replicated the findings of previous Chinese PWI studies that a significant facilitation effect can be observed when the target and distractor shared the same atonal syllable or syllable body , 17, 20.Furthermore, additional analyses were conducted  from the same pool of participants in Experiment 1 was recruited for Experiment 2, and were paid (HKD 50) for their participation.gun2/ and /caak3/, which were consistent with their corresponding targets /gung1 gai1/ and /caang2/; i.e., Syllable-structure Consistent) and the other was a CV syllable . Distractors were presented auditorily and closely matched in syllable frequency and number of homophones across conditions. Similar to Experiment 1, the mean duration of the CVC distractors (375±121ms) was shorter than that of the CV distractors (516±71 ms), t(58) = 5.46, p < .05. Two corresponding unrelated control conditions were created by re-pairing the related distractors with the targets in the same condition. Consequently, four distractor conditions were included, namely Syllable-structure Consistent Related, Syllable-structure Consistent Unrelated, Syllable-structure Inconsistent Related, and Syllable-structure Inconsistent Unrelated. The target and distractor in each pair were also unrelated orthographically in their written form and were semantically unrelated , trials in which the voice key malfunctioned or mistriggered (2.8%), and outlier responses that were 2.5 standard deviations beyond condition means (2.4%) were discarded from reaction time analyses. The same set of LMEM analyses were conducted on the inverse-transformed naming latencies. As Although the two phonological conditions in Experiment 2 differed in their syllabic structure (one was consistent with the target and the other was not), both conditions exhibited similar patterns of phonological priming, suggesting that the effect of syllabic structure was minimal (if any) under the present PWI paradigm.Two PWI experiments were conducted to investigate the time course of syllabic and sub-syllabic processing in Cantonese spoken word production. Importantly, the degree of segmental overlap between target and distractor was kept constant across phonological conditions. Facilitation effects were observed in Experiment 1 when the target and the distractor shared the same atonal syllable  across all SOA conditions . In contrast, a comparable facilitation effect was observed only in late SOAs (0 and +175 ms) when the target and the distractor shared the same word-initial phonemes but had different atonal syllables . These results indicated the unique role of the atonal syllable, which is retrieved earlier than its sub-syllabic components in Cantonese speech production. Furthermore, two types of phonological distractor with different syllabic structures were included in Experiment 2 where they both shared the same two word-initial phonemes with the CVC-structured targets. An identical pattern of priming was observed across the two phonological conditions, indicating that the time course difference observed in Experiment 1 was not because of the influence of the syllabic structure.According to the proximate unit hypothesis, the first selectable phonological unit in Mandarin Chinese is atonal syllable , 19. Subabsolute timing of the effects might be affected by many factors including participants’ overall naming speed, materials used, and experimental design; however, the more crucial and informative point to the theoretical questions might be the relative timing of the effects. While further research is needed to examine the absolute timing of the sub-syllabic effects, the relative timing of the phonological effects observed in Experiment 1 is consistent with the notion that syllabic processing begins earlier than sub-syllabic processing in Cantonese word production, and that such a pattern cannot be accounted for by the effect of syllabic structure priming (Experiment 2).Note, however, that significant effects of sub-syllabic overlap were observed in Experiment 2 when SOA = -175 ms, but not in Experiment 1 at the same -175-ms SOA. A similar situation has been reported and discussed in the past PWI literature. For instance, Schriefers, Meyer, and Levelt  investigThe current results and the relevant evidence available in the literature , 14, 20 Nevertheless, a very important question remains, which is about what happens to the segments following atonal syllable selection that precludes the effect of onset but allows some form of sub-syllabic priming  in Chinese. We think this issue is still open. What we can see from the literature is that a single segment  has rarely shown a significant priming effect in Chinese. Yet, significant priming effects have been replicated a number of times when multiple segments (not necessarily constituting to a syllable unit) are primed simultaneously , 25, 38.Furthermore, to explain the null effect of a single phoneme in the past Chinese speech production studies, it has been proposed that Chinese speakers either could not or did not orient their attention to the non-proximate segmental units and hence could not benefit from segmental priming . The prePrevious research on language production has shown contrastive patterns with salient effects of a single phoneme frequently observed in Dutch or English but not in Mandarin or Cantonese , 10, 15.S1 File(DOCX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.


Warp-knitted meshes have been widely used for structural reinforcement of rigid, semi-rigid, and flexible composite materials. In order to meet the performance requirements of different engineering applications, four typical warp-knitted meshes  were designed and developed. The mechanical behaviors of these meshes under mono-axial and multi-axial tensile loads were compared. The influence of the initial notch length and orientation on the mechanical performance was also analyzed. The results showed that the biaxial tensile behavior of warp-knitted meshes tended to be more isotropic. The anisotropy level of the diamond warp-knitted mesh was the lowest (λ = 0.099), while the rectangular one was the highest (λ = 0.502). The notch on a significantly anisotropic mesh was propagated along the direction of larger modulus, while for a not remarkably anisotropic mesh, notch propagation was probably consistent with the initial notch orientation. The breaking strength of warp-knitted meshes with the same initial notch orientation decreased with the increase in notch length in both the wale and course directions. For warp-knitted meshes with the same initial notch length, the breaking strength in the wale direction was kept stable at different notch orientations, while that in the course direction decreased remarkably with notch orientation from 0° to 90°. Recently, the proportion of industrial textiles in whole textile applications has been rapidly increasing in China, especially warp-knitted textiles, which have been widely used in the geotechnical construction, transportation, aerospace, and health fields. Warp-knitted mesh fabrics are one of the most promising products that can be used as structural materials such as geogrid , composiThere are various warp-knitted mesh structures with corresponding properties. Different shapes can be realized through the design of knitting patterns during the fabricating process, typically rectangle, square, round, diamond, hexagon, etc. With the increase of applications, some research has been done on the mechanical properties of warp-knitted mesh structures. Mohammad et al.  comparedExtension and propagation of cracks and defects are important characteristics in designing textile-based structural materials . A lot oIn this paper, four typical warp-knitted meshes  were prepared that may have great potential in engineering applications. Their mechanical performance was tested under both mono-axial and bi-axial stresses. A comparison of the mechanical behaviors between different knitting structures, as well as the differences under mono-axial and bi-axial tensile test were presented. The influences of initial crack lengths and orientations on the mechanical performance under biaxial stresses were also investigated.Polypropylene monofilament for warp-knitted meshes was provided by the State Key Laboratory for Modification of Chemical Fibers and Polymer Materials . Its specifications are shown in Four typical warp-knitted meshes with different mesh shapes were designed and prepared, which were rectangular, square, circular, and diamond-shaped. The lapping diagrams and the loop pictures of the warp-knitted mesh are shown in x) direction and course (y) direction, and the mean value was taken as the experimental result. As shown in x and y direction was 50 mm/min. Five valid data points were obtained for both the wale (x) direction and course (y) direction, and the mean value was taken as the experimental result.The mono-axial tensile test was performed on a WDW-20 universal testing machine  with a tensile speed of 50 mm/min and a specimen size of 100 mm × 100 mm. Five valid experimental data points each were obtained in the wale (x) and course direction (y). The initial notch with length L and orientation α relating to the x-axis was located at the center of the specimen. In order to study the effect of initial notch length on the mechanical properties of warp-knitted meshes, three kinds of notched specimens with different notch lengths  and a notch orientation of 0° were prepared. For the influence of crack orientation, three specimens with the same crack length (L = 3 mesh) but different crack orientations  were selected.The shape and size of the bi-axial tensile specimen are shown in Similarities were observed in the deformation process of warp-knitted meshes during a mono-axial tensile test. At the beginning of stretching, the yarns slipped at the crossing points of loop units overcoming small frictions and contact forces . Then thWarp-knitted meshes are mostly subjected to different directional forces. Therefore, it is of practical significance to study the bi-axial mechanical properties. In the case of bi-axial stretching, the warp-knitted mesh will first quickly overcome the friction of the crossing points between the yarns, then the mesh unit is evenly stretched and expanded along both the wale and course directions until the yarn is stretched to breaking point.From the bi-axial tensile curves of warp-knitted meshes, as shown in As shown in TE and LE are the asymptotic modulus in the wale and course direction, respectively. The orthogonal anisotropy degree λ [The results of tensile modulus of four different warp-knitted meshes under mono-axial and bi-axial stresses are shown in degree λ ,25 of thλ, the more anisotropic the mesh will be. It is obvious that the level of orthogonal anisotropy under mono-axial stress is much higher than under bi-axial stresses, because the yarn in load-bearing meshes is more well-distributed and uniform when suffering from multi-directional constraints [λ = 0.099), which means its mechanical behavior in the wale and course directions tended to be relatively close. The anisotropy levels of square warp-knitted mesh (λ = 0.245) and circular warp-knitted mesh (λ = 0.251) were similar, slightly higher than that of diamond. The anisotropy level of the rectangular warp-knitted mesh was the highest (λ = 0.502), so the mechanical properties would exhibit remarkable anisotropy.straints . So the During the knitting process, the phenomena of skipping a stitch, missing a stitch, and the breakage of the knitting yarns when rubbing against metal needles all lead to visible or invisible defects or cracks in the meshes. Furthermore, minor damage may also occur when the meshes are exposed to sharp objects during transportation and utilizations. These kinds of local damage have a significant influence on the performance of composite materials, such as mesh-reinforced concrete . TherefoL = 3, α = 0°) located in the center. By observing the mechanical behavior of different warp-knitted meshes with initial notches, it was found that the direction of notch propagation was related to the anisotropy. For warp-knitted meshes with significant anisotropy, the notches usually propagated along the direction of the larger modulus, such as the rectangular warp-knitted mesh shown in Due to the appearance of notches, the failure mode of warp-knitted mesh under bi-axial stresses seems to be different. During bi-axial stretching of the warp-knitted mesh with initial notch, the stress concentration points were mainly around the notch and near the clamps. The failure process can generally be divided into four stages. Firstly, under the bi-axial loads, the notch in the warp-knitted mesh opened and expanded gradually from the closed state until the edges of the notch were straightened. Then, the deformation was caused by the slippage of the yarns, including the transfer of the top arc to the loop pillar and the extraction of broken yarns from the notch. When the applied loads continued to increase and reached a critical value, the yarns were stretched to breaking point. The notch extended to the next mesh unit. α = 0°) and without a notch are shown in The tensile curves of warp-knitted meshes with the same orientation initial notch (L = 1), the tensile curves of notched warp-knitted mesh were not significantly different from those without initial notches, as well as the difference of breaking strength. This phenomenon is in accordance with the multi-axial warp-knitted fabrics [According to the failure process and tensile curves in  fabrics  and wove fabrics . HoweverL = 3) are shown in The tensile curves of the warp-knitted meshes with different notch orientations  and same notch length (y direction) and the course direction (x direction). In the wale direction, the change of the breaking strength of the warp-knitted mesh was relatively small, indicating that the effect of notch orientation on the breaking strength of the wale direction was insignificant. When the initial notch length was the same, due to the warp-knitted structure, the number of broken yarns in the wale direction with a notch orientation of 0° and 45° was almost the same. At a notch orientation of 90°, the number of warp broken yarns decreased, but the breaking strength of wale direction will also decrease because of the increase in warp yarn breaking length when under bi-axial stresses. So the breaking strength of the wale direction at the notch orientation of 90° was only slightly larger than that at 0° and 45°. In the course direction, the breaking strength of the warp-knitted mesh decreased linearly with the increase of the notch angle, indicating that the weft breaking strength was more sensitive to notch orientation. Under mono-axial stresses, it was found that the breaking strength of warp-knitted mesh was only sensitive to transverse notches, not to oblique and longitudinal notches [The breaking strengths of warp-knitted meshes with different notch orientation are shown in  notches . This is(1)λ = 0.099), while the rectangular one was the most anisotropic (λ = 0.502).Warp-knitted meshes presented different mechanical behavior under mono-axial and bi-axial stresses. The meshes under biaxial stresses tended to be more isotropic, and the anisotropy level was decided by the fabric structure. The anisotropy degree of the diamond warp-knitted mesh was the lowest ((2)λ = 0.502) usually propagated along the direction of the larger modulus (TE = 16.845 MPa). For a not remarkably anisotropic mesh , notch propagation was probably consistent with the initial notch orientation.The mechanical performance of warp-knitted meshes was affected by notches. The failure mode of the meshes with notches under biaxial stresses was related to the anisotropy level. The notch on a significantly anisotropic warp-knitted mesh (rectangular mesh (3)The breaking strength of warp-knitted meshes with the same initial notch orientation decreased with the increase of notch length in both the wale and course directions. The effect varied according to the fabric structure. The diamond warp-knitted mesh had a minimal effect on the reduction of the mechanical performance. For warp-knitted meshes with the same initial notch length, the breaking force in the wale direction was stable at different notch orientations, while that in the course direction decreased remarkably with notch orientation from 0° to 90°.In this research, the mechanical properties of four typical warp-knitted mesh fabrics under bi-axial tension were studied, and the effects of different types of prefabricated initial notches on their mechanical performance were analyzed. Based on the results of the experiments and analysis, the following conclusions were obtained:


To this end, we used MRI, SPECT, and clinical data of de novo drug-naïve PD patients  and age-, sex-matched healthy controls  acquired at baseline. Moreover, we employed clinical data acquired at 1 year follow-up for PD patients with or without L-Dopa treatment in order to predict the progression symptoms severity. Voxel-based group comparisons and covariance analyses were applied to characterize baseline disease-related alterations for DAT-SPECT, DTI, and sMRI. Cortical and subcortical alterations in de novo PD patients were found in all evaluated imaging modalities, in line with previously reported midbrain-striato-cortical network alterations. The combination of these imaging alterations was reliably linked to clinical severity and disease progression at 1 year follow-up in this patient population, providing evidence for the potential use of these modalities as imaging biomarkers for disease severity and prognosis that can be integrated into clinical trials.There is an increasing interest in identifying non-invasive biomarkers of disease severity and prognosis in idiopathic Parkinson’s disease (PD). Dopamine-transporter SPECT (DAT-SPECT), diffusion tensor imaging (DTI), and structural magnetic resonance imaging (sMRI) provide unique information about the brain’s neurotransmitter and microstructural properties. In this study, we evaluate the relative and combined capability of these imaging modalities to predict symptom severity and clinical progression in  Parkinson’s disease (PD) is primarily characterized by progressive accumulation of aggregated α-synuclein in the brainstem, leading to a degeneration of dopaminergic neurons in substantia nigra . This prTo improve the monitoring of disease progression and the evaluation of drug effectiveness, it is essential to identify biomarkers able to detect the neurodegenerative alterations at all circuitry levels. Such biomarkers should demonstrate a strong and reproducible correlation with pathological changes and symptoms severity in multicenter studies .de novo PD patients remains unclear  provides a semi-quantitative assessment of striatal dopaminergic deafferentation. It is a well-established diagnostic biomarker of PD, owing to the strong correlation between the amount of dopamine transporters in the striatum and the number of dopaminergic neurons in substantia nigra . However unclear . Structu unclear . Several unclear . However unclear . Also mi unclear . However unclear . Moreove unclear . In contcontrols . HoweverDespite imaging changes in individual brain regions can be used as diagnostic biomarker, theories on neuro-degenerative disease increasingly focus on the role of brain network alterations as potential predictors of early disease severity and prognosis . In factde novo PD patients. Disease severity was assessed longitudinally through the modified version of the unified Parkinson’s disease rating scale (MDS-UPDRS) evaluated at baseline (same time point at which the imaging data was acquired) and at 1 year follow-up. We used well-established VBM, voxel-based quantification (VBQ)   and strusessment .de novo PD patients (N = 205) and healthy controls (HC) (N = 105) included in this study were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database 1. PPMI is a large multicenter study and each site independently received ethics approval of the protocol. This study was carried out in accordance with Good Clinical Practice (GCP) regulations and International Conference on Harmonization (ICH) guidelines. Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki.Data of De novo PD patients included in the PPMI database had a diagnosis confirmed by DAT-SPECT scans and Hoehn and Yahr stage I or II. The exclusion criteria were diagnosis of dementia, psychiatric disorders or other neurological disease detectable with MRI at baseline. At BL all patients were drug-naïve, while at TP1 some patients started drug treatment with L-Dopa, dopamine agonist, and other unspecified medications. Only categorical (yes/no) information was recorded on the respective treatment categories  without information about the dosage. In the current study, we included patients remaining without drug treatment at TP1  and patients taking only L-Dopa treatment at TP1 . The PD on med group was composed of patients having the MDS-UPDRS3 evaluation performed off medication . From the 205 patients, we identified 56 subjects for the PD no med group, and 44 subjects for the PD on med group.All subjects underwent sMRI, DTI, and DAT-SPECT at baseline, and had MDS-UPDRS 1, 2, 3, and total, acquired at baseline (BL) and after 1 year (TP1). 2).Whole-brain MRI was performed using standardized protocols on different 3T scanners. All acquisition protocols included a standard T1-weighted MPRAGE sequence , and a 2D single-shot echo-planar DTI sequence for diffusion weighted images  .VBM analysis was performed on the T1-weighted images using automated tissue classification and enhanced subcortical tissue probability maps embedded into the unified segmentation framework of SPM12 . Image r2. The pre-processing steps for the estimation of FA and MD maps included correction for distortions due to eddy currents and head motion , using a flexible factorial design, controlling for sex, age, total intracranial volume (TIV) and image acquisition site. These tests were carried out using explicit masks defining GM and WM voxels. The masks were generated as follows: smoothed (FWHM of 6 mm isotropic), Jacobian-modulated tissue probability maps in MNI space were averaged across all subjects for each tissue class (GM and WM). Then binary masks were generated by applying a threshold of 20%, voxels for which neither the GM nor the WM probability exceeded that value were excluded from the analysis. This approach was used to ensure that each voxel was analyzed in only one subspace and that non-brain tissue was excluded.p < 0.05 combined with a voxel-wise p < 0.001. We further estimated the effect size (Cohen’s d) of the observed differences.Similarly, differences in DAT-SPECT were evaluated using voxel-based comparisons, restricting analyses to GM voxels and controlling for age and sex. We applied to all voxel-wise statistical analyses a family-wise error (FWE) corrected cluster threshold of To test for differential interaction between striatal dopamine transporter uptake derived from DAT-SPECT and MRI-based measurements, we performed voxel-wise covariance analyses  between p < 0.05 combined with a voxel-wise p < 0.001 was applied for all analyses. To quantify the differential inter-modality correlations identified in the covariance analyses, we computed Spearman correlation coefficients between the putamen DAT-SPECT signal and the average value of the age and sex adjusted MRI-based measures showing significant between-group differences in the covariance analysis.An FWE-corrected cluster threshold of R2), while the model overfit was evaluated by means of the leave-one-out adjusted R2 coefficient. Additionally, we estimated the Pearson correlation coefficient between each of the above-mentioned imaging measures and the MDS-UPDRS 1, 2, 3, and total separately.To evaluate the combined value of imaging measures as biomarkers of symptoms severity we used multiple linear regression models to predict each MDS-UPDRS subscale. The MDS-UPDRS 1, 2, 3, and total were the dependent variables, while the models regressors were the mean imaging measures extracted from regions showing significant differences between PD patients and HC . For regions identified in covariance analyses we included in the model an interaction term between the MRI measure and DAT-SPECT. All analyses were controlled for age, sex, and symptoms dominant side. The goodness of fit for each model was assessed using the determination coefficient  between TP1 and BL. The ΔMDS-UPDRS 1, 2, 3, and total were the dependent variables, while the model regressors were the FA values in pons nuclei, prefrontal MD, DAT signal in putamen, and the interaction between putamen DAT signal and prefrontal GM volume, brainstem MD, respectively. The longitudinal prediction models were computed using data of both PD no med and on med groups. Patients receiving dopamine agonists at TP1 were not included in this analysis due to the longer wash out time of those treatments and their potential effect on the off medication assessment of symptoms severity.L-Dopa treatment on the prediction models, we performed separate regression analyses for the PD on med and no med groups. Demographic and clinical details of the two subgroups are provided in To account for the effect of p < 0.05. In case of a significant multiple regression model, single regressors were considered as significant at p < 0.01. The Pearson correlation coefficients were corrected for multiple comparison using the false discovery rate (FDR) at q < 0.05.The multiple regression models for each MDS-UPDRS and ΔMDS-UPDRS subscales were considered as significant at Patients and HC were matched for gender and age, as shown in In PD patients significantly higher FA values were found in the brainstem WM corresponding to the pontine tegmentum . Increasp < 0.001), and a significant negative one in HC   .p < 0.001) for patients, and a significant negative correlation for controls   . No signThe linear combinations of DAT-SPECT values in the putamen, and MRI differences found in the group comparison, significantly predicted the BL MDS-UPDRS2 and MDS-UPDRS total but not the other subscales see , 4. The We did not find any significant correlation between the single imaging measures and the BS MDS-UPDRS scores.For the longitudinal prediction models we found that the combination of BL DAT-SPECT and MRI measures was not able to significantly predict the ΔMDS-UPDRS scores for the group of patients with and without medication see , 4.However the linear combination of BL imaging measures significantly predicted ΔMDS-UPDRS2 for the PD no med group, and ΔMDS-UPDRS1 and 2 for the PD on med , 4. The We did not find any significant correlation between the single imaging measures and the ΔMDS-UPDRS scores for both the PD no med and on med groups.de novo PD patients. Consistent with prior literature, we identified DAT-SPECT and MRI abnormalities in patients compared to the HC (Here, we evaluated the relative and combined value of MRI and DAT-SPECT measures as biomarkers of disease severity and clinical progression in o the HC . Most imPrior to perform the image comparison and the prediction analysis of the clinical scores, we statistically compared the MDS-UPDRS across groups. As expected, we found significantly higher clinical scores for the PD patients with respect to the HC. Moreover, we observed significantly higher increase of the MDS-UPDRS 1, 2, and total scores at BL and TP1, as well as ΔMDS-UPDRS1 and ΔMDS-UPDRS2 for the PD group on med with respect to the PD no med group. Those results are in agreement with the fact that patients on medication exhibit more advanced disease stages. The lack of significant difference in MDS-UPDRS3 between the PD on med and PD no med groups might be explained by the fact that the motor assessment is a highly variable measure, involving both patient- and rater-dependent variability . The useEarlier studies have reported altered diffusion MRI measures across different brain areas in PD and associated animal models . ConsistFurthermore, we found increased FA values in PD patients in midbrain regions corresponding to the location of pontine tegmentum. This region is affected by the alpha synuclein pathology at early disease stages , and it de novo PD patients, we found a significantly reduced DAT-SPECT signal in the striatum (In agreement with previous research showing 40–60% loss of striatal dopaminergic innervations from substantia nigra in striatum . Our finstriatum . Accordistriatum , cognitistriatum , sleep dstriatum , sensorystriatum  and autostriatum .Furthermore, in PD patients we found a decrease in putamen DAT being linked to lower GM volume values in the premotor-prefrontal cortex, while in HC a reduction in putamen DAT was associated to a bigger GM volume. While, we did not detect any significant atrophy in those cortical regions using group comparisons, these findings suggested that progressive loss of striatal DAT uptake translates into GM volume loss in premotor-prefrontal regions. This result is in line with studies showing that significant GM volume loss is predominantly observed in more advanced PD patients exhibiting cognitive deficits . The cliAfter identifying these alterations in patients compared to HC, we then evaluated their link to current disease severity and their prognostic value for future symptoms progression measured by the MDS-UPDRS subscales. We showed that the combination of the imaging measures was significantly related to the current clinical severity measured by MDS-UPDRS2 and MDS-UPDRS total. The imaging measures that better predicted the BL MDS-UPDRS2 were the MD values in the operculum and the DAT-SPECT signal in the putamen, while the MDS-UPDRS total was better predicted by the MD values in the operculum, the putamen DAT-SPECT values, and the interaction between putamen DAT-SPECT – GM volume in premotor, prefrontal cortex and insula. The absence of significant correlation between each of those imaging measures and the MDS-UPDRS2 and MDS-UPDRS total is in agreement with results previously reported literature . MoreoveThe MDS-UPDRS2 is a subscale evaluating the subject’s impairment in daily life activities , and it L-Dopa is short enough to achieve a sufficient wash out in 24 h, the half-life of dopamine agonists or other medications could be longer and therefore be not sufficient to estimate a proper off medication symptom severity (L-Dopa.One key objective of the study was to evaluate the association between the imaging biomarkers and disease progression. As dopaminergic treatments have substantial effects on the clinical symptoms measured with MDS-UPDRS, those treatments represent a potential confound that needs to be controlled for. Due to this reason we first performed the predictive analysis of symptoms progression using the entire PD cohort and then we employed separate models for the PD no med and on med groups. For the patients on medications we employed the MDS-UPDRS scores assessed off medication. The off medication clinical assessments performed for the PPMI study were acquired asking the patients not to take PD medication the day before. While, the half-life of severity . For thiWe found that GM volume extracted from the premotor cortex, putamen DAT, the interaction between both, and brainstem FA values were significant predictors for ΔMDS-UPDRS2 in the untreated patients. The ΔMDS-UPDRS2 in the group on medication was significantly predicted by the same measures with the addition of MD assessed in the pons nuclei. Though the separation of PD patients in no med and on med groups was performed to exclude confounds of treatment onto the MDS-UPDRS scales, the separate analyses could be also considered as independent replication samples of the prognostic link of MRI and DAT measures onto clinical symptoms measures. This consistency of the significant association between the identified structural measures and ΔMDS-UPDRS2 across both groups strengthens the confidence in these findings.L-Dopa treatment of the on med group is likely to interfere with the clinical measures of symptoms severity as no off medication assessment was performed for the MDS-UPDRS1. Therefore it is important to replicate this association in an independent cohort in order to evaluate the prognostic ability of those imaging measures for the ΔMDS-UPDRS1.Finally, we found that the MD in the pons nuclei, putamen DAT-SPECT, interaction DAT – MD in the pons nuclei were significant predictors of ΔMDS-UPDRS1, which is associated to non-motor and cognitive deficits. However, the significant prediction of the ΔMDS-UPDRS1 was only observed in the on med group. Beside the possibility of being a false positive finding, this difference could also reflect the more severe phenotype in the on med group or the more complex effects of treatment onto clinical severity captured by MDS-UPDRS1. In fact the The linear combination of DAT-SPECT and MRI measures was not able to significantly predict the symptoms progression at TP1 using the data of both PD no med and on med groups. This results might be indicative of the fact that using heterogeneous groups of patients could confound the reliability of predictive analysis .The lack of significant correlation between each of the imaging measures used in this study and the ΔMDS-UPDRS scores confirms previous literature results . The cruThe findings obtained in the current study can be indicative of the presence of microstructural tissue changes induced by the disease in the early stages. In light of the correlation with the clinical progression, the combination of the imaging measures affected by those tissue changes could be employed as disease progression biomarker.Cross-sectional and longitudinal studies in PD patients will be crucial to confirm our results and establish the value of the identified imaging alterations in more advanced and prodromal PD populations.de novo untreated PD patients. The acquisition of all those imaging modalities might be time-consuming and expensive, limiting their use in clinical protocols. However, recent advances in MRI hardware, such as improved scanner gradient performance, and software, such as parallel imaging and multi-band imaging sequences (Here, we investigate the association between different imaging and clinical measures in a large cohort of equences , can subDespite the good correlation between brain changes and clinical scores, the study provides a reliable prediction only for some symptom subtypes. This might be due to the fact that the disease progression differentially affects the various cortical-subcortical circuits .de novo PD patients. We further show the potential of these alterations as biomarkers of current symptom severity and their prognostic value with respect to evolution of specific PD symptom domains.We find several potential structural and molecular imaging biomarkers altered in https://www.ppmi-info.org/.Publicly available datasets were analyzed in this study. This data can be found here: JD, FS, AB, and BD conceptualized the research project. JD organized the research project. SL executed the research project and statistical analysis, and wrote the first draft of manuscript. SL and JD designed the statistical analysis. JD critically reviewed the statistical analysis. SL, JD, FS, AB, and BD critically reviewed the manuscript.This study was sponsored by F. Hoffmann-La Roche, Basel, Switzerland. The authors received no specific funding for this work. F. Hoffmann-La Roche provided financial contribution in the form of salary for SL, FS, AB, and JD but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The occurrence of medulloblastoma (MB) in the elderly is an absolutely rare event. Concerning this issue we report on two MB patients beyond the 70th year of life. Two patients older than 70 years presented with a mass in the posterior fossa without evidence of a preexisting malignant tumor. After careful radiological work-up the suspected diagnosis was metastasis of an unknown primary tumor. Both patients underwent surgery and histopathological analysis revealed MB in both cases . The two cases presented here represent also one classical MB and one additional desmoplastic MB. To our knowledge we report for the first time that there are different molecular subtypes of MB in the elderly patients that seem to be consistent with those subtypes mainly occurring in young adults. Unfortunately the patients died within one week after surgery due to respiratory insufficiency and an unclear cause. The presented cases show that MB can occur in the elderly. Although this constellation is absolutely rare, MB should be considered in the differential diagnosis, especially when a primary tumor is not known or detected. Medulloblastomas (MB) are small, round, blue cell, neuroectodermal tumors with neuronal differentiation in the cerebellum. These tumors usually occur in childhood. The incidence of MB in young adults is estimated to be less than 1% of all intracranial neoplasms . The meaCase 1 concerned a 71-year-old male presenting with gait difficulties and vertigo. Cranial MRI revealed a low and focal contrast-enhancing nodular tumor in the left cerebellar hemisphere and upper vermis . The lesCase 2 was a 72-year-old male who was referred to the hospital because of change of personality and loss of weight. Cranial MRI showed a large low contrast-enhancing mass in the right cerebellar hemisphere consisting of a lateral solid component and a small medial cystic. The tumor caused occlusive hydrocephalus but no surrounding edema . MR reveUp to now there are four different molecular subtypes of MBs recognized, including activation of WNT-signaling pathway, SHH-signaling pathway, and the Non-WNT-/Non-SHH-subtype, which can be subdivided into group 3 (mostly MYC-amplified) and group 4 (often MYCN-amplified). Most of the desmoplastic MBs are of the SHH-activated subtype, whereas classic MBs are of the WNT- or the Non-WNT-/Non-SHH-subtype.In contrast to children, in young adults the most common molecular subtypes are the SHH-activated/p53-wildtype and group 4 MB , 7. All The two cases presented here represent also one classical MB and one additional desmoplastic MB. To our knowledge we report for the first time that there are different molecular subtypes of MB in the elderly patients that seem to be consistent with those subtypes mainly occurring in young adults.Unfortunately the presented cases had a very unsatisfactory postoperative course, so that we cannot report any response of the patients to the planned radiotherapy in case 1 and combined radiochemotherapy in case 2.Regarding the radiologic findings, we could not detect any differences to MB in younger ages. A moderate contrast-enhancing mass in T1-weighted sequences in the posterior fossa with surrounding brain edema and anatomical contact to the vermis and the fourth ventricle were typical findings. Histologic examination did not show any differences compared to the findings of MB occurring in younger patients.The presented cases show that MB can occur in the elderly. Although this constellation is absolutely rare, MB should be considered in the differential diagnosis, especially when a primary tumor is not known or detected.


In this study, an untargeted metabolomics approach was used to assess the effects of proton irradiation (1 Gy of 150 MeV) on the metabolome and DNA methylation pattern in the murine hippocampus and left ventricle of the heart 22 weeks following exposure using an integrated metabolomics-DNA methylation analysis. The integrated metabolomics-DNA methylation analysis in both tissues revealed significant alterations in aminoacyl-tRNA biosynthesis, but the direction of change was tissue-dependent. Individual and total amino acid synthesis were downregulated in the left ventricle of proton-irradiated mice but were upregulated in the hippocampus of proton-irradiated mice. Amino acid tRNA synthetase methylation was mostly downregulated in the hippocampus of proton-irradiated mice, whereas no consistent methylation pattern was observed for amino acid tRNA synthetases in the left ventricle of proton-irradiated mice. Thus, proton irradiation causes long-term changes in the left ventricle and hippocampus in part through methylation-based epigenetic modifications. Integrated analysis of metabolomics and DNA methylation is a powerful approach to obtain converging evidence of pathways significantly affected. This in turn might identify biomarkers of the radiation response, help identify therapeutic targets, and assess the efficacy of mitigators directed at those targets to minimize, or even prevent detrimental long-term effects of proton irradiation on the heart and the brain. Protons are a major component of galactic cosmic rays (GCR) and solar particle events (SPE) -induced insulin resistance (IR) mouse model  were purchased from Jackson Laboratories, Bar Harbor Maine. The mice were shipped from the Jackson Laboratories to Brookhaven National Laboratory (BNL), Upton, Long Island, New York. After accommodating to the housing facility at BNL for 1 week, the mice were transported to the NASA Space Radiation Laboratory (NSRL) on the BNL campus and irradiated with 1 Gy of 150 MeV protons or sham-irradiated. The mice were loaded into 8 × 3 × 3 cm plastic square enclosures. These enclosures were either placed in a foam fixture in the beam line and exposed to a rectangular beam of ~20 × 20 cm generated by the Booster accelerator at BNL and transferred to the experimental beam line at the NSRL facility or received sham irradiation for the same time as the irradiated mice . Dose calibration was performed to obtain the targeted dose. The week following the irradiation or sham irradiation, the mice were shipped to Oregon Health & Science University (OHSU) and group-housed under standard care for 22 weeks after which they were euthanized by cervical dislocation for tissue analyses. The hippocampus of one hemibrain and half of the left ventricle of nine mice were divided into separate tissues for DNA methylation analyses. The hippocampus of the other hemibrain and the other half of the left ventricle were processed for untargeted metabolomics. The researchers were blinded to the exposure condition until after completion of all DNA methylation and metabolomics data acquisition and analyses. All protocols were reviewed and approved by the Institutional Animal Care and Use Committees (IACUC) of BNL and OHSU and in compliance with all federal regulations. Animal experiments were carried out in accordance with the relevant guidelines and regulations.Six-month-old C57Bl6/J male mice . Metabolites were extracted from 100 μl of hippocampal homogenates and 100 μl of left ventricular homogenates and untargeted metabolomics was completed as described . Metabolites were initially identified by comparisons with an in-house library consisting of 619 IROA standards  and 30 other additional commercially available standards. Additional metabolites were individually identified based on MS isotopic pattern, accurate mass (mass error <5 ppm), MS/MS fragment ions, and matching with spectra in online databases, including Metlin, Human Metabolome Database (HMDB), and Lipidmaps.To assess analytical variability compared to biological variation, we included four technical replicate analyses of a quality control (QC) sample, which was prepared by mixing 5-μl aliquots of all nine biological processed samples from the proton-irradiated and sham-irradiated mice, and visualized the non-centered, Pareto scaled data by Principal Component Analysis of hippocampal tissue , and venDNA methylation was performed as described  on a HiSeq2000 platform was used to identify differentially methylated regions and associated genes throughout the genome. We generated a bioinformatic pipeline to map and annotate DIP-Seq sequencing and statistical algorithms that allow for the identification of differentially methylated regions in DIP-Seq data sets.Mus musculus KEGG pathways in MetaboAnalyst, only metabolites with HMDB number were included. For multi-comparison adjustment, false-discovery rates (FDR) are reported  that are affected by radiation, we used a multi-step statistical analysis approach based in part on previous analyses . The C source code will be provided upon request. DNA methylation data were then merged with metabolomics data in MetaboAnalyst using only methylation regions with treatment group differences with a raw p-value of < 0.01. The R scripts used for MetaboAnalyst are included as a .zip file as For the integrated DNA methylation metabolomics analysis, we first reanalyzed the DNA methylation data of our original publication  in MetaboAnalyst. The visual examination identified one mouse sample (number 11) as an outlier. Therefore, the statistical comparison between sham vs. proton-irradiated mice using the non-parametric Kruskal-Wallis test was done once with and once without number 11. In addition, we used an unpaired student's test to compare sham-irradiated vs. proton-irradiated methylation patterns of amino acid tRNA synthetases. All statistical tests were two-sided. Significance was set at http://GIMP.org). To provide a comparable scale, changes in individual and total amino acids are shown as % changes from sham-irradiated mice (median proton-irradiated mice/median sham-irradiated mice in % −100) in Figure 3.Figures were generated using MetaboAnalyst 4.0 , GraphPad Prism v6 , and GIMP , and glutamate tended to be 23% higher in proton- than sham-irradiated mice (p = 0.08). The sum of all 15 amino acids tended to be 12% higher in proton- than sham-irradiated mice , tryptophan , and methionine , and a tendency for another 4 amino acids, namely alanine , glutamine , histidine , and tyrosine . The sum of all 15 amino acids tended to be 31% lower in proton- vs. sham-irradiated mice .Of the 52 identified KEGG pathways, no pathways were significantly altered following FDR adjustment by proton irradiation in the left ventricle of the heart see . The firp = 0.05), and a tendency for another 3 amino acids, namely arginine, aspartate, and histidine . The only misclassified mouse was number 11. After exclusion of number 11, the mice of the two groups perfectly separated for total amino acid ratio and 3 amino acid ratios  with lower values for proton-irradiated than sham-irradiated mice and a p-value of 0.02. One misclassification and a p-value of 0.04 was achieved for another 4 amino acids .To evaluate whether proton irradiation affected the aminoacyl-tRNA biosynthesis pathway differently in the left ventricle and the hippocampus, we calculated the ratio of the left ventricle and hippocampus for each amino acid. Consistent with the pattern in the left ventricle, the ratio for each amino acid went down following proton irradiation. PLS-DA analysis with those 15 amino acid ratios could separate sham- and proton-irradiated mice . SignifiGSE132588]. Next, we integrated DNA methylation data and metabolomic data using the joint pathway analysis function of MetaboAnalyst, which compared alterations in DNA methylation profiles and metabolic pathways using KEGG annotations as the reference frame.We used our updated bioinformatic pipeline to reanalyze the left ventricle and hippocampal DNA methylation reported in the original publication [, tryptophan , phenylalanine , and isoleucine , and a tendency for arginine . The pattern of down-regulation was consistent as only 1 of 9 amino acid tRNA synthetases had higher methylation values  in proton- than sham-irradiated mice (results not shown).The integrated analysis of hippocampal tissue revealed significant alterations following FDR adjustment in the aminoacyl-tRNA biosynthesis pathway . Of the p = 0.02), whereas isoleucine and threonine were not significantly affected. However, we observed significantly lower values in tRNA synthetase methylation of asparagine . No consistent methylation pattern was observed comparing proton- vs. sham-irradiated mice.The integrated analysis of left ventricular tissue also revealed significant alterations in aminoacyl-tRNA biosynthesis . Next, wThe data of the current study support the value of metabolomics and especially integrated analyses of metabolomics and DNA methylation to identify long-term changes in distinct tissues following whole body radiation. Below we first discuss the metabolomics analysis by itself, followed by the integrated metabolomics DNA methylation analysis.Using untargeted metabolomics analysis by itself, the current study was not able to identify pathways that were significantly altered by proton irradiation in the hippocampus and the left ventricle of the heart using FDR adjustment. However, the pathway analysis revealed aminoacyl-tRNA biosynthesis as the most promising pathway to further pursue for targeted analysis. Previous work in metabolic profiling of urine samples from C57BL/6J mice 4 h following proton irradiation (0.5 and 2 Gy of 1 GeV) revealed profound alterations in energy metabolism, amino acid metabolism, and purine and pyrimidine metabolism (Laiakis et al., Aminoacyl-tRNA biosynthesis, key for protein synthesis including the accuracy of translation (Ibba and Söll, In summary, proton irradiation causes long-term changes in the left ventricle and hippocampus. The aminoacyl tRNA biosynthesis pathway might be especially valuable as a biomarker of the proton radiation response. Future studies should address to what extent this pathway could be targeted to attenuate detrimental long-term effects of proton irradiation on the heart and the brain. Thus, integrated analysis of metabolomics and DNA methylation is a powerful approach to obtain converging evidence of pathways significantly affected by proton irradiation. Our findings also suggest the importance of assessing tissue-specific compensatory changes. Such tissue-dependent compensatory directional changes will likely depend on the time interval after radiation exposure. A limitation of our study is that we included only behaviorally naïve mice, as behavioral testing would be expected to affect DNA methylation and metabolic pathways and we wanted to assess the effects of proton irradiation by itself. As permutation and cross-validation tests require relative large data sets and the statistical power of ranking tests is limited, we did not adjust for multiple comparisons in the targeted analysis of the 15 identified amino acids of the amino-tRNA biosynthesis pathways as well as the methylation status of their tRNA synthetases. Therefore, future studies are warranted to compare radiation responses at distinct intervals following radiation exposure and involving larger group sizes and comparisons between behaviorally naïve and behaviorally tested mice following proton irradiation.This study was carried out in accordance with the recommendations of the OHSU and BNL IACUC committee. The protocol was approved by the OHSU and BNL IACUC committees.SI, JS, and JR conceived and planned this study. ET, RH, GB, JC, CP, and SI analyzed the data. All authors discussed the results and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To meet this demand, the development of new targeting vectors as well as the use of uncommon radionuclides becomes increasingly important. Uncommon nuclides in this regard enable the utilization of various selectively accumulating bioactive molecules such as peptides, antibodies, their fragments, other proteins and artificial structures for PET imaging in personalized medicine. Among these radionuclides, 89Zr (t1/2 = 3.27 days and mean Eβ+ = 0.389 MeV) has attracted increasing attention within the last years due to its favorably long half-life, which enables imaging at late time-points, being especially favorable in case of slowly-accumulating targeting vectors. This review outlines the recent developments in the field of 89Zr-labeled bioactive molecules, their potential and application in PET imaging and beyond, as well as remaining challenges.Molecular imaging—and especially Positron Emission Tomography (PET)—is of increasing importance for the diagnosis of various diseases and thus is experiencing increasing dissemination. Consequently, there is a growing demand for appropriate PET tracers which allow for a specific accumulation in the target structure as well as its visualization and exhibit decay characteristics matching their  The development of new radiotracers for application in personalized medicine with PET has experienced enormous progress over the last decade, which is reflected in the large and still growing number of valuable compounds used for imaging of different diseases. A tendency that can be observed in this PET tracer development is the utilization of labeled targeting vectors that accumulate with high specificity at the target site, allowing for a highly sensitive target visualization. Many of these vectors are relatively large structures exhibiting high molecular weights as well as slow pharmacokinetics, necessitating the use of radionuclides with long half-lives in order to fully exploit the potential of the used targeting vectors for diagnostic imaging.89Zr has increased over the last several years as it exhibits a long half-life, making it ideally suited for imaging studies with slowly-accumulating bioactive molecules, allowing for imaging of biological processes at late time-points after tracer application. 89Zr—about which excellent other reviews are available FDG FDG ,17. 124IFFDG ,17. (0.13%) ). Thus, C t1/2 =  min whic89Zr is mainly used for in vivo PET imaging, its use is not restricted to PET alone, as it can also be used for in vivo Cerenkov luminescence imaging (CLI) FDG), it also showed high uptake in kidneys, liver and bone as well as inflammatory abscesses, hindering an efficient transferrin receptor detection in solid tumors [Apart from antibody fragments, also other proteins such as albumin and transferrin can be radiolabeled with ) effect . In anotpression . While td tumors .89Zr has also been used in radiolabeling and in vivo imaging of large synthetic structures such as microspheres, nanoparticles, nanotubes and liposomes. Besides peptides and medium scale proteins, 89Zr-labeled microspheres  of tumors) that were evaluated regarding their in vivo biodistribution in terms of therapy planning and dosimetry purposes with PET before therapy with the 90Y-labeled particles takes place [64Cu-, 86Y- and 89Zr-labeled microspheres were prepared and studied), the 89Zr-labeled derivatives were the most valuable PET imaging surrogates for the 90Y-labeled spheres and could be useful for therapy planning and dosimetry calculations due to their valuable in vivo PET imaging properties and the comparable half-lives of 89Zr and 90Y of 78.4 and 64.1 h, respectively. The 86Y-labeled spheres (t86Y)1/2( = 14.7 h) were also shown to be useful for this application whereas the 64Cu-labelled derivatives showed an insufficient in vitro stability.Examples include es place . It was 89Zr-DFO-albumin were shown to be applicable for the detection of sentinel lymph nodes and were demonstrated to accumulate within several minutes in a rabbit lymphogenic metastasis model [89Zr-DFO-albumin particles where subsequently used in a continuing clinical study enabling a successful identification of tumorous sentinel lymph nodes even in direct vicinity to the primary tumor and yielding even more reliable results than the commonly applied 99mTc-albumin nanocolloids [89Zr-labeled nanoparticles, short chain dextran nanoparticles (DNPs) that were intended for imaging of macrophages and inflammation, was recently described. Here, it could be shown that 89Zr-DFO-cross-linked dextran nanoparticles accumulated specifically in tissue resident macrophages within 24h of administration, which could also be useful for the detection of tumor associated macrophages (TAMs) in tumor diagnosis and therapy [Nanocolloids of is model . These ncolloids . Another therapy . 89Zr-labeled synthetic structures include single wall carbon nanotubes (SWCNT) which were shown to be useful as scaffold structures for surface-modification with targeting vectors and radionuclides due to their large surface and low immunogenicity. For example, carbon nanotubes derivatized with the tumor neovasculature-targeting antibody E4G10 and DFO were described. These nanotubes were subsequently labeled with 89Zr and evaluated using in vivo PET tumor imaging studies in tumor-bearing mice. The 89Zr-labeled constructs showed a rapid blood clearance and specific tumor accumulation but also a very high liver and kidney accumulation limiting the application of these constructs for imaging or therapy of tumors [Further examples of f tumors . 89Zr-labeled liposomes were described recently. These liposomes, comprising the somatostatin receptor-affine peptide octreotide for tumor targeting, were labeled with 89Zr  as well as gadolinium ions  to offer a platform for combined PET/MRI [in vitro stability of the liposomes was shown to be suboptimal: the incubation in mouse serum or in a solution of bovine serum albumin at 37 °C for 24 h to 96 h resulted in a release of approximately 50% of the radioactivity being a consequence of the direct labeling with 89Zr without using a chelator in the lipid monolayer of the liposome.In addition to nanotubes,  PET/MRI . Althoug89Zr is still the labeling of antibodies for preclinical as well as clinical PET imaging studies [89Zr. The main application of  studies ,84,85. Tin vivo target visualization. However, the immunoreactivity was determined in only about half of all studies. When determined, the immunoreactivity in the vast majority of cases was in a reasonable range between 70 and 96% [An important point in antibody derivatization and radiolabeling is the immunoreactivity of the obtained conjugates as only a preserved immunoreactivity can result in a high bioactivity of the radioimmunoconjugates allowing for a successful  and 96% ,58,62,79 and 96% ,54. 89Zr-labeled antibodies and their application in preclinical or clinical imaging studies is given in 89Zr-labeling and subsequent in vivo imaging was shown to provide valuable information about antibody biodistribution properties via PET, allowing the visualization of target tissues  as well as receptor-expression also enabling to assess the efficiency of tumor therapeutics and pre-therapeutic dosimetry [A summary of osimetry ,91,92.in vivo tumor visualization using 89Zr-labeled antibodies in clinical studies could be shown to depend on the specific activity of the radiolabeled antibody. It was demonstrated in a human imaging study with patients suffering from metastatic breast cancer that the ideal time-point for imaging as well as the optimal specific activity of 89Zr-trastuzumab depend on the pretreatment the patient had received. In patients who had already received trastuzumab for treatment purposes, the best imaging results were obtained using a mixture of 89Zr-trastuzumab and 10 mg of the unlabeled antibody , whereas a mixture of 89Zr-trastuzumab and 50 mg of the unlabeled antibody had to be applied in trastuzumab-naive patients  and the best tumor-to-background-contrasts could be achieved 4–5 days after 89Zr-trastuzumab application [The efficient lication . 89Zr- and 111In-labeled antibodies in order to evaluate the potential of the 89Zr-labeled compounds as surrogates for the 111In-labeled ones in order to make use of the advantages of PET imaging versus SPECT. Although the 89Zr-labeled antibodies showed a significant liberation of the radionuclide from the complex reflected in higher bone and liver radioactivity accumulation, they were found to give almost identical in vivo biodistribution results regarding tumor accumulation and uptake into other tissues compared to the respective 111In-labeled analogs in preclinical studies [Furthermore, some studies are available that directly compare  studies ,52,59,9489Zr-labeled substances is not limited to diagnostic imaging alone. 89Zr-labeled radiopharmaceuticals were also shown to be useful as surrogates for the respective therapeutic 90Y- or 177Lu-labeled antibodies in order to perform dosimetry calculations and therapy planning in preclinical as well as clinical studies [The use of  studies ,53,72,9589Zr-labeled drugs is in combined multimodal imaging using PET/OI . This has been shown to be a successful approach by the example of a 89Zr- and 800CW-NIR dye-labeled TRC105 antibody that was used for a pre-surgical tumor detection and intraoperative optical visualization of tumor material [Another possible application of material .89Zr shows very promising results in the in vivo PET imaging of slowly accumulating radiopharmaceuticals. However, some challenges remain such as the high energy photons emitted by this nuclide which can result in background noise of the images as well as the limited stability of the current chelator complexes. Without any doubt, work will be carried out to develop chelators and conjugation strategies that allow for a stable 89Zr-introduction into biomolecules, yielding compounds with optimized properties for the imaging of biological processes in clinical imaging applications. In addition, improvements in image reconstruction will overcome the obstacles of image background noise. These developments will thus enable to exploit the full potential of 89Zr.89Zr-labeled bioactive molecules show the general applicability of this radiometal nuclide for long-term in vivo PET imaging. Furthermore, GMP-compliant 89Zr is already commercially available which allows using this most favorable nuclide in clinical routine. With regards to individual patient-tailored diagnostics and therapies, the development of new target-specific compounds—and among these presumably many antibodies or other large biomolecules—is still under way. Thus, 89Zr possesses a high potential for PET imaging applications in the future.The numerous successful examples of imaging studies with


In the past decades, there have been several studies concerning the efficacy of sequencing of chemotherapy on disease control and survival in locoregionally advanced (LA) nasopharyngeal carcinoma (NPC). The addition of concurrent cisplatin to radiotherapy has demonstrated survival improvements that are attributable to both distant metastasis and locoregional control. Specific to the latter, the advent of intensity-modulated radiotherapy has resulted in superior tumor control given the better dosimetry compared to conventional techniques . HoweverStill, controversy remains regarding the superiority of the NACT or ACT approaches –4. A posJournal of the National Comprehensive Cancer Network entitled “Neoadjuvant or Adjuvant Chemotherapy Plus CCRT Versus CCRT Alone in the Treatment of Nasopharyngeal Carcinoma: A Study Based on EBV DNA” explored the value of adding NACT or ACT to CCRT in locoregionally advanced NPC patients, who have been stratified into disparate risk groups of distant metastasis  vs. 70.2% [CCRT]). These findings are consistent with a randomized controlled phase 3 trial conducted by Sun et al. which showed that the addition of the triplet combination of taxotere, 5-fluorouracil and cisplatin (TPF) to CCRT improved survival. Interestingly, the investigators found that NACT followed by CCRT offered better distant metastasis-free survival than CCRT alone in the N1-subgroup, but not in the N2–3-subgroups, although admittedly, this was an unplanned subgroup analysis .n = 53), and therefore over-interpretation of this finding should be avoided. Moreover, 37 (69.8%) of the 53 patients received only 1–2 cycles of ACT and had dose reductions, and hence the improvement in survival was unexpected considering the suboptimal treatment intensity. The role of ACT remains to be defined, and we await the ongoing trials of adjuvant capecitabine  and immunotherapy [Another interesting observation was that CCRT + ACT yielded the most impressive distant metastasis-free survival than CCRT alone in the high-risk group (5-year: 82.4% vs. 70.2%). This result was in line with findings of the network meta-analysis demonstrated by Ribassin-Majed et al. . Howeverotherapy , which motherapy  vs. convCurrently, most clinical trials concerning NACT followed by CCRT were primarily conducted in patients at high-risk of treatment failure. The results of this study provided another direction for trials investigating the addition of NACT to CCRT in the low-risk group. Meanwhile, for patients in the intermediate and high-risk group, prescribing combinations of new drugs with reduced toxicities or immune checkpoint inhibitors to improve compliance with ACT or modify the cycles of NACT (more vs. less) might result in improvements in survival. Additionally, these trials will help to validate this method of risk stratifying patients that integrates EBV DNA and TNM-stage classification. Future trials can also be designed to compare the efficacy of NACT plus CCRT versus CCRT followed by ACT, particularly in the high-risk group. Meanwhile, the data presented in the study could help guide clinical practice.In summary, we provided some insights on the optimal treatment intensity of different risk-groups for locoregionally advanced NPC patients. This is aligned with the direction of future management to personalize the treatment intensity for these patients by employing and monitoring robust biomarkers such as EBV DNA at baseline, post-NACT  and prio