Drug development encompasses multiple processes, wherein protein subcellular localization is essential. It promotes target identification, treatment development, and the design of drug delivery systems. In this research, a deep learning framework called LocPro is presented for predicting protein subcellular localization. Specifically, LocPro is unique in (a) combining protein representations from the pre-trained large language model (LLM) ESM2 and the expert-driven tool PROFEAT, (b) implementing a hybrid deep neural network architecture that integrates convolutional neural network (CNN), fully connected (FC) layer, and bidirectional long short-term memory (BiLSTM) blocks, and (c) developing a multi-label framework for predicting protein subcellular localization at multiple granularity levels. Additionally, a dataset was curated and divided using a homology-based strategy for training and validation. Comparative analyses show that LocPro outperforms existing methods in sequence-based multi-label protein subcellular localization prediction. The practical utility of this framework is further demonstrated through case studies on drug target subcellular localization. All in all, LocPro serves as a valuable complement to existing protein localization prediction tools. The web server is freely accessible at https://idrblab.org/LocPro/.

COVID-19 has swept globally and Pakistan is no exception.To investigate the initial introductions and transmissions of the SARS-CoV-2 in Pakistan,we performed the largest genomic epidemiology study of COVID-19 in Pakistan and generated 150 complete SARS-CoV-2 genome sequences from samples collected from March 16 to June 1,2020.We identified a total of 347 mutated positions,31 of which were over-represented in Pakistan.Meanwhile,we found over 1000 intra-host single-nucleotide variants(iSNVs).Several of them occurred concurrently,indicating possible interactions among them or coevolution.Some of the high-frequency iSNVs in Pakistan were not observed in the global population,suggesting strong purifying selections.The genomic epidemiology revealed five distinctive spreading clusters.The largest cluster consisted of 74 viruses which were derived from different geographic locations of Pakistan and formed a deep hierarchical structure,indicating an extensive and persistent nation-wide transmission of the virus that was probably attributed to a signature mutation(G8371T in ORF 1ab)of this cluster.Further-more,28 putative international introductions were identified,several of which are consistent with the epidemiological investigations.In all,this study has inferred the possible pathways of introduc-tions and transmissions of SARS-CoV-2 in Pakistan,which could aid ongoing and future viral surveillance and COVID-19 control.

Objective To explore the risk factors of inguinal metastasis in squamous cell carcinoma of the penis, screening lymph node metastasis high-risk patients. Methods The clinical and pathological data of 81 consecutive patients with squamous cell carcinoma of the penis were analyzed retrospectively. Age at presentation ranged from 27 to 81 years with a median of 49 years. Course of disease within one year of patients with 46 cases (56.8%), 1 year above 35 eases (43.2 %). Seventyfive patients underwent bilateral inguinal lymph node dissection, and 6 patients had unilateral inguinal lymph node dissection. Clinical stage of the primary tumor was assigned according to the 2002 TNM staging system. Variables included patients' age, redundant prepuce and/or phimosis, tumor site,size, number, macroscopic growth pattern, histological grade, inguinal physical examination and the size of inguinal lymph nodes. Results Of the 81 patients, 42 (51.9%) were staged as pN+ and 39 (48. 1%) as pN0. Metastases occurred in 32.0% (16/50) of G1, 78.3% (18/23) of G2 and 100. 0%(8/8) of G3 cases, with significant differences among them (P= 0. 015). According to the inguinal lymph node physical examination results, 63 were staged as clinically node-positive (cN+) and 18 as clinically node-negative (cN0). Metastases occurred in 63. 5% (40/63) of cases of cN+, as compared with 11.1% (2/18) of cases of cN0(P=0. 012). At a median follow up of 40 months (ranged 2-127 months), the 5-year disease free survival rates for positive and negative inguinal lymph nodes metastasis were 71.4% and 92.3%, respectively (P=0. 005) , and the 5-year cancer specific survival rates were 79.0% and 91.4%, respectively (P=0.001). Conclusions Inguinal physical examination and histological grade were the strongest predictors of inguinal metastasis. The patients with inguinal lymph nodes metastasis have lower 5-year disease free survival rates and cancer specific survival rates,and should receive positive treatment measures.

Objective To clarify the role of hypothalamic IL-6 in gastric mucosal blood flow, gastric juice pH value and gastric mucosal injury. Method Model of gastric stress ulcer was established by fluid percussion to make craniocerebral trauma. Twenty male SD rats fed for one week in the experiment room were randomly(random number) divided into control group, one hour group, six hours group and 12 hours group after injury. The levels and distribution of IL-6 in hypothalamus were detected by using immunohistochemistry and Western blot. Simultaneously, gastric pH value, gastric mucosal blood flow and gastric mucosal injury index of rats in each group were measured, and the histology of gastric mucosa was observed. Results IL-6 immunoreactive cells were widely distributed in neuronal cells of hypothalamus of the stressed rats especially in the para-ventricular nucleus (PVN).One hour after injury, the pH value rapidly declined, and the lowest point appeared 6 hours later. One hour after injury, the injury of gastric mucosa was found, and the injury became worse and worse as time got longer and longer. The ulcer index (UI) was increased. One hour after injury, there was a brief increase in blood flow to the peak in gastric mucosa, and then the blood flow declined until 6 hours elapsed and got stable. The experiment prompted the gastric stress ulcer appeared. Conclusions In the SD rats with gastric stress ulcer induced by craniocerebral injury incurred by hydraulic percussion, the hypothalamic IL-6 may activate neuronendocrine metabolism mediated through the activation of PVN, inducing gastric mucosal injury.

Objective To investigate standard diagnosis and treatment of cerebrospinal fluid (CSF) leakage to improve the prognosis of the patients. Methods A retrospective study was done on 75 patients with CSF leakage from January 2004 to March 2007 in our hospital. There were 51 patients with rhinorrhea, nine with otorrhea and 15 with wound/incision leakage. Of all, 39 patients had traumatic leakage, 32 postoperative leakage and four spontaneous leakage. In the study, 23 patients were cured by position testing and drug therapy and 16 by cerebrospinal fluid drainage and/or wound debridement but 36 were treated with surgeries including craniotomy repair in 17, extracranial repair in 17 and CSF shunt in five (three received CSF shunt after repair). Results Of all, 64 patients were cured, 10 gained im-provement but one died. Conclusion Standard diagnosis and treatment of CSF leakage helps improve cure rate and reduce complications.

OBJECTIVE: To investigate the protective effects of mild hypothermia (33-35 degrees C) on the outcome of patients with severe traumatic brain injury (TBI) (GCS<8). METHODS: Patients in the mild hypothermia group were cooled to 33-35 degrees C by cooling blanket with muscular relaxant, and patients in the normothermia group were maintained at 37-38 degrees C. RESULTS: The result showed that the mortality was 26.1% (6/23) in the mild hypothermia group and 58.3% (14/24) in the normothermia group respectively (P<0.05). The mild hypothermia also markedly reduced intracranial pressure (P<0.01 and inhibited hyperglycermia (P<0.05). No significant side-effects were found during hypothermic treatment. CONCLUSIONS: Our clinical data have demonstrated that mild hypothermia is a useful method for management of patients with severe traumatic brain injury.

Objective To evaluate the influence of positive end-expiratory pressure (PEEP) on intracranial pressure and cerebral perfusion pressure in dogs with or without intracranial hypertension caused by frontal intracerebral hematoma. Methods Eighteen dogs were randomly divided into three groups. In Group B and Group C, the intracranial hypertension was respectively higher than 25 mmHg but less than 40 mmHg and higher than 40 mmHg induced by autoblood clotting injection into the right frontal lobe, while Group A as control was of normal intracranial pressure. PEEP was applied in increment of 3 cmH2O from 0 to 18 cmH2O, each level lasting 20 min. The intracranial pressure (ICP) was monitored by an optical fiber transducer implanted into left frontal lobe. Mean arterial pressure (MAP), heart rate (HR), and central venous pressure (CVP) were recorded simultaneously. Cerebral perfusion pressure (CPP) was calculated by the equation (CPP=MAP-ICP). Results With increasing PEEP level, ICP increased and CPP fell in Group A; ICP fell, MAP and CPP increased in Group B; ICP fell, MAP and CPP increased in Group C. CVP increased in all groups, and the increment was significantly higher in Group C than the other two groups (P

Objective To investigate the effect of acute high intracranial pressure on the static pressure-volume curve of dogs' total respiratory system in order to evaluate the relationship between brain injury and respiratory insufficiency.Methods Fourteen dogs were divided into two groups.Animals were anesthetized,paralyzed and mechanical ventilated.The intracranial hypertension in experimental group(n=8)was induced by injecting blood-clots into the right frontal lobe.The other six dogs served as control.The intracranial pressure was monitored by an optical fiber transmitter inserted into the left cerebral hemisphere.The pressure-volume curves of the respiratory system were measured before and after induction of high intracranial pressure by a self-made apparatus consisting of two sealed bottles and a U shaped glass tube.The curves were also measured correspondingly in control group.The static compliance was calculated by equation C=?V/?P.The volume of intracerebral hematoma was calculated.The histopathology of lung was studied under microscope.Results The intracerebral hematoma was located in the right frontal lobe with volume from 4.8-11.5ml(average 8.48ml).The intracranial pressure was elevated from 18.13?5.96mmHg to 46.88?16.42mmHg,which induced a shift of pressure-volume curve to the right in experimental group,while no obvious change was found in control group.Compared to pre-injection,the static compliance of total respiratory system decreased significantly(P